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Quinta-feira, 29.05.14




Northwest Biotherapeutics: Management Discusses Interim Data On Phase I/II Trial Of DCVax-Direct

May. 28, 2014 5:13


  • Interim results are for 19 patients who      received two weeks of treatment; the protocol calls for 8 months of      treatment.
  • Early results indicate that 11 patients      have shown tumor necrosis and an immunological effect on the tumor.
  • Six patients have shown tumor shrinkage or      stable disease, with one patient showing tumor shrinkage of 28%, just      short of 30% which qualifies as a partial response.
  • The key is whether these early responses      translate into complete or partial responses as patients progress through      the next 7 1/2 months of treatment.


Northwest Biotherapeutics (NWBO) held a conference call on May 27th to discuss interim results of its Phase I/II, first-in-human trial of DCVax-Direct. This is a new type of dendritic cell vaccine in which the dendritic cells are injected directly into the tumor mass and pick up cancer antigens that are present in that specific tumor. This differs from its lead product, DCVax-L, in which tumor antigens are loaded into dendritic cells ex vivo and then reinjected into the body. This is an interesting new concept because of the means of administration, and because this is a more advanced dendritic cell that in animal studies has been shown to be several times more powerful in loading tumor antigens. This is dendritic cell cancer vaccine 2.0.

In this note, I summarize what I found to be key takeaway points in the conference call. I start with CEO Linda Powers' opening remarks. After that, she addressed questions that had been submitted before the meeting by participants. I found this to be a more informative way of conducting the call than the conventional method of letting analysts ask questions. This usually results in long-winded grandstanding by analysts.

Opening Remarks by Linda Powers

Ms. Powers stated that this Phase I/II trial involves both new technology platform and a new disease target. The Company's first product, DCVax-L, is targeted at glioblastoma multiforme initially, but has also been in preliminary trials in ovarian cancer and prostate cancer. In the case of glioblastoma multiforme, it is being studied as part of standard of care which is given shortly after surgical resection. Patients have not previously received chemotherapy or radiation.

Ms. Powers emphasized that the results are very early, and more time is needed to evaluate the ultimate effect of DCVax-Direct, but that the Company and investigators from MD Anderson are very encouraged. MD Anderson, which is conducting this trial, is one of the top two or three cancer centers in the US and very highly regarded.

In the treatment of most solid tumors, the first treatment is surgical resection of the tumor to remove as much of the primary tumor mass as possible. This is then followed by chemotherapy and radiation to further reduce the size of the tumor and its metastases. This trial is being conducted in patients with inoperable tumors, due either to the location of the tumor or because the tumor has metastasized to the extent that surgery would not be of benefit.

The patient group in which DCVax-Direct is being tested has very advanced disease. These patients have exhausted treatment options, often having gone through several prior courses of therapy. Most have the option of palliative therapy or an experimental drug like DCVax-Direct. Because the tumors have not been surgically resected, they are large tumors with metastases that are growing rapidly. These are very-difficult-to-treat patients in whom any kind of response is of great interest; this represents an urgent and unmet medical need. If DCVax-Direct is ultimately approved, its primary use will be in less severely ill, surgically resected patients who would be expected to respond better.

Ms. Powers said that over 58% of the first 19 patients in the trial who have received at least three injections over a 2-week period are showing responses to the drug. As a reminder, the trial protocol calls for six treatments given at day 0, day 7, day 14, and week 8, week 16, and week 32. These patients showing responses are only two weeks into an 8-month course of therapy

She compared this to the checkpoint inhibitor, nivolumab, of Bristol-Myers Squibb (BMY). Nivolumab was used as a single agent in 94 heavily pre-treated melanoma patients. Of these patients, 28% had a complete or partial response. In 76 non-small cell lung cancer patients, 18% had complete or partial responses. Many of these responses were durable, lasting up to a year.

She emphasized that we can't directly compare results of DCVax-L with nivolumab. We don't know if the initial responses, which are based on the detection of significant tumor necrosis and immune cell infiltration into the tumor, with some cases of tumor shrinkage, will translate into durable complete or partial responses. So far, the best response seen in any patient is a 28% shrinkage of the tumor, which falls just short of the 30% shrinkage which qualifies as a partial response. On the other hand, the responses seen with DCVax-Direct are based on just two weeks of therapy. In immune therapy, responses usually improve over time, but this remains to be determined.

If DCVax-Direct can show 20% to 30% objective responses, it has to be viewed as an extremely significant drug. Wall Street analysts are super excited about the potential of nivolumab and Merck's (MRK) similar drug lambrolizumab, with sales estimates of as much as $5 billion for these two drugs by 2020. This means that investors will be closely watching updates on the status of patients in the DCVax-Direct trial as the year progresses. Investors will want to see some objectives responses develop that are durable.

The DCVax-Direct trial is composed of a Phase I trial that will enroll 36 patients. In this conference call, Ms. Powers reported on the first 19 patients treated in the Phase I segment. After completion, the trial will roll seamlessly into a Phase II trial of 24 patients. This is an unusually large for a first-in-human trial. Ordinarily, such trials involve 12 to 18 patients.

The main focus of the Phase I portion of the trial is on safety, but indications of efficacy can also be seen. In terms of safety, the drug is extremely well-tolerated. The main side effect being seen is a fever at the time of injection that lasts for a day or two. This is a result of the biological effect of the drug, which causes an immune response. This can be treated with Tylenol. There has been one case of mild nausea reported, but investigators believe that this was caused by another drug being taken by the patient. There is pain upon injection of the needle that is comparable to that of a biopsy that can be treated with a local anesthetic. Relative to chemotherapy, the side effect profile is benign; this is an extremely important aspect of the drug.

Physicians involved in the trial report that DCVax-Direct is easy to administer using an imaging technology, such as ultrasound or CT, to direct the needle to the tumor in which it is to be injected. They believe that DCVax-Direct can be easily incorporated into their treatment regimens.

Early Results

The early results, as reported by NWBO on the 11 of 19 patients treated that showed an early response, were as follows:

  • 8 of 11 patients have shown signs of tumor      necrosis (cell death), immune cell infiltration into the tumor and stable      disease. Biopsies showed substantial or extensive tumor necrosis, as well      as substantial accumulation of immune cells in and around the tumors.
  • 6 of these 8 patients showed tumor      shrinkage or no disease progression, based on imaging studies.
  • The other 2 of 8 patients showed enlargement      of their tumor, but the tumors based on biopsies had substantial necrosis      and substantial infiltration of immune cells.
  • In addition to these 8 patients, there were      3 other patients that showed stable disease, but with no evidence of tumor      necrosis or infiltration of immune cells.

In judging these results, she pointed out that we have to take into account that the results are early, as none of the patients have completed therapy that calls for six injections over 32 weeks or 8 months. The data indicates a meaningful initial effect on 11 of those 19 patients who have received at least three injections over a two-week period. She stated that what will be extremely important is whether these effects are temporary or whether they will hold or improve over time. Generally, immune therapies produce results more slowly, with an improving response over time, so she said she would hope there would be improvement with time, but this remains to be seen.

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por cyto às 08:41

Quarta-feira, 28.05.14


Is human cytomegalovirus a target in cancer therapy?

John Inge Johnsen,1 Ninib Baryawno,1 and Cecilia Söderberg-Nauclér2

1 Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institute, 171 76 Stockholm, Sweden

2 Karolinska Institute, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital in Solna, 171 76 Stockholm, Sweden

Correspondence to:John Inge Johnsen, Email:


Human cytomegalovirus (HCMV) is a herpesvirus that is prevalent in the human population. HCMV has recently been implicated in different cancer forms where it may provide mechanisms for oncogenic transformation, oncomodulation and tumour cell immune evasion. Moreover, antiviral treatment against HCMV has been shown to inhibit tumour growth in preclinical models. Here we describe the possible involvement of HCMV in cancer and discuss the potential molecular impact expression of HCMV proteins have on tumour cells and the surrounding tumour microenvironment.

Keywords: cancer, human cytomegalovirus


The interplay between cancer cells and the surrounding microenvironment is essential for the growth and spread of a tumour. The development of malignant tumours requires a microenvironment that supports the uncontrolled proliferation and spread of cancer cells but also conditions that avoid destruction from the various arms of the immune system must be present. The immune system represents an important tool for the destruction of the majority of cancer cells and precancerous conditions in the human body. However, malignant growing tumours have in most, if not all, cases developed immune evasion strategies to avoid destruction by immune cells. One essential immune evasion strategy that can be induced or applied by tumour cells is the formation of an inflammatory microenvironment. Tumour cells can induce inflammation directly through oncogenes that induce transcriptional programs responsible for the production of pro-inflammatory eicosanoids, cytokines and chemokines that attract different cells of the immune system to the microenvironment. Also chronic inflammation caused by viral or microbial infections, autoimmune diseases, dietary products or inflammatory conditions caused by unknown reasons can create an inflammatory microenvironment that support tumour growth [1]. Immune cells that are recruited to the tumour are generally disabled to eliminate tumour cells. Indeed, tumour-related inflammation is regarded as one enabling characteristic crucial for the tumour cell to sustain a proliferative state, evade apoptosis, increase angiogenesis, invasion, metastasis and suppression of immune responses [2].

Although it has been both experimentally difficult and heavily debated, it is today well accepted that approximately 20% of the global cancer burden can be linked to infectious agents including viruses, bacteria and parasites [3]. Recent studies indicate that the list of infectious agents linked to certain cancer forms will increase in the future.

Human cytomegalovirus (HCMV) is a beta-herpesvirus that is common in the human population. Although HCMV is not currently causally implicated in human cancer, a number of recent evidence suggests that HCMV may be specifically associated with some human malignancies. HCMV nucleic acids and proteins have been detected in 90-100% of glioblastomas and medulloblastomas, prostate, breast and colon cancers and in mucoepidermoid carcinomas of salivary glands [4-12]. Consistently, HCMV proteins are not detected in healthy tissues surrounding HCMV positive tumors. HCMV protein expression is restricted to the tumour; mainly in tumour cells, but virus proteins are sometimes found in endothelial cells and inflammatory cells within the tumour. However, infectious virus is not recovered from primary tumours. There is also a discrepancy between the number of protein positive cells and DNA positive cells within the tumour.

We have consistently observed that HCMV proteins are widespread and easily detected in a majority of tumour samples, whereas viral DNA is detected only in few cells within the tumour ([12] and unpublished observations). Recently, Ranganathan et. al. sequenced viral DNA from 20 different HCMV gene regions in samples obtained from glioblastoma patients and also found that only a minority of the cells in the tumour harbour the virus genome [13]. The authors suggested that HCMV may enhance the growth or survival of a tumour through mechanisms that are distinctly different compared to classic tumour viruses that express transforming viral oncoproteins in the tumour cells. Thus, it is not likely that HCMV is an opportunistic virus capable of reactivating in the tumour and then only infects cells within in the tumour. Instead, HCMV proteins, rather than a productive infection may aid the development of HCMV positive tumours through yet undiscovered mechanisms.







As of today, HCMV is not considered to have direct oncogenic properties; its potential role in cancer seems to be oncomodulatory, which imply that expression of HCMV gene products in cancer cells may promote tumour growth by enabling different hallmarks of cancer [2, 14, 15]. However, numerous recent data also indicate that several HCMV encoded proteins have biological properties that are directly related to cellular transformation and tumour development.

The US28 chemokine receptor encoded by HCMV has several characteristics resembling a viral oncoprotein [16-19]. Expression of US28 in NIH3T3 cells render these cells tumourigenic when injected into nude mice and transgenic mice with targeted expression of US28 to intestinal epithelial cells results in the development of intestinal neoplasia, which can be enhanced by inflammation [16]. US28 targeted expression in intestinal cells inhibits glycogen synthase-3β (GSK-3β) function resulting in increased β-catenin activity and induced expression of Wnt target genes, including cyclin D, survivin and c-myc, that are involved in the control of cell proliferation [16]. These findings provide a direct molecular link between the expression of US28 and oncogenesis. In addition, US28 has also been shown to activate the transcription factor nuclear factor κB (NF-κb) that is a critical regulator of immunity, stress responses, apoptosis and differentiation [19, 20].

In glioblastoma cells, we found that the HCMV IE72 protein directly interacts with the hTERT promoter at SP1 binding sites to induce telomerase activity and telomere lengthening [4]. We also found that HCMV-IE72 and hTERT were co-expressed in primary glioblastoma samples [4]. Enhanced telomerase activity is necessary for tumour cells to divide indefinitely and is commonly induced by oncogenic viruses [21]. Recently, Melnick et al. suggested that HCMV fulfils the criteria of Koch's Postulates as revised for viruses and cancer, and that HCMV therefore should be designated as an “oncovirus” [9]. They demonstrated cell specific localization of HCMV in 97% of mucoepidermoid carcinomas of salivary glands. HCMV IE and pp65 were expressed in tumour cells, but not in non-tumour cells and positively correlated with severity. HCMV protein expression correlated with activation of known oncogenic pathways such as epidermal growth factor receptor (EGFR), cyclooxygenase-2 (COX-2), Erk and amphiregulin. They also used a mouse salivary gland organ culture model and showed that murine CMV infection induces dysplasia through an upregulation of Erk phosphorylation. Phosphorylation of the ErbB receptor family members and downstream signalling may therefore be relevant targets for drug discovery also of HCMV positive tumours [9, 22].

The interaction of HCMV with its cellular receptor ligands, like integrins, during infection results in the activation of the PI3K/Akt signalling pathway and expression of IE72 protein in glioblastoma cells induces constitutive activation of Akt [23, 24]. HCMV has been shown to also activate the PI3K/Akt signalling cascade via binding of HCMV proteins to platelet-derived growth factor receptor alpha (PDGFR) and by selective phosphorylation of the cellular focal adhesion kinase (FAK) in glioblastoma and prostate cancer cells [25-27]. Furthermore, HCMV UL38 was shown to interact with tuberous sclerosis complex resulting in dysregulation of the mammalian target of rapamycin complex 1 [28].

HCMV encodes several proteins that interfere with the cellular apoptotic machinery. Direct anti-apoptotic activity of HCMV proteins has been located to transcripts encoded by the HCMV UL36-UL38 genes [29]. CMV blocks apoptosis mediated by death receptors and encodes a mitochondria-localized inhibitor of apoptosis that suppresses apoptosis induced by diverse stimuli. The HCMV UL37 gene product inhibits Fas-mediated apoptosis downstream of caspase-8 activation and Bid cleavage in the mitochondria through inhibition of the pro-apoptotic Bcl-2 family members Bax and Bak [30, 31]. The HCMV UL36 gene product inhibits Fas-mediated apoptosis by binding to and inhibiting the function of caspase-8. [32]. HCMV infection has also been shown to inhibit apoptosis and induce drug resistance by induction of the p53 tumour suppressor homologue gene product ΔN-p73α, resulting in abnormal neural cell survival [33]. The HCMV IE86 protein binds to p53 and inhibits its transactivating function and suppresses p53-mediated apoptosis after DNA damage [26, 34-37]. The HCMV UL97 protein is a viral homologue of cellular cyclin-dependent kinases (CDK) that phosphorylates and inactivates the retinoblastoma (Rb) tumour suppressor protein resulting in cell cycle progression and inhibition of apoptosis in mammalian cells [38].

The functional inhibition of the p53 and Rb families of tumour suppressor proteins by HCMV encoded proteins implicates that HCMV is able to promote cell cycle progression, increase DNA synthesis and block apoptosis resulting in increased chromosomal instability [39-43]. In neuroblastoma cells HCMV induces expression of Bcl-2 resulting in inhibition of apoptosis and chemoresistance, a process that can be reversed by treatment of neuroblastoma cells with the antiviral drug ganciclovir [44]. Interestingly, case reports of neuroblastoma patients have shown increased HCMV antibody titers and detection of HCMV in urine of small children with neuroblastoma[45]. HCMV DNA also has been detected in neuroblastoma tissue sample [45-47]. Unpublished results from our laboratory demonstrate HCMV DNA, RNA and proteins in the majority of neuroblastoma tissue samples and in neuroblastoma cell lines. Treatment of neuroblastoma cells with the anti-viral drug ganciclovir in vitro or in vivo inhibits tumour growth (Wolmer-Solberg 2011, submitted).

Hence, HCMV encodes for a number of different proteins that have profound effects on cellular processes leading to increased proliferation, inhibition of apoptosis, stimulation of cellular migration, the release stimulatory factors, induction chemotherapeutic resistance and increased telomerase activity.





Symptoms of a primary HCMV infection are usually mild or asymptomatic in immunocompetent individuals but can cause severe disease in fetuses and immunocompromised patients such as transplant recipients and AIDS patients. The virus is spread through all bodily fluids and establishes a life-long latent/persistent infection. Reactivation from latency appears to be triggered by inflammation, which the virus can initiate by inducing cytokine and chemokine production and by enhancing the synthesis of pro-inflammatory eicosanoids. Indeed, the biological responses elicited by HCMV reactivation mimic those seen in leukocyte dysfunction, wound healing and chronic inflammation [14]. HCMV reactivation has also been shown to stimulate the expression of VEGF that can induce angiogenesis [17, 18] and inhibit the expression of the potent anti-angiogenic protein thrombospondin-1 [48].

During evolution HCMV has coevolved with the human host and the virus has developed several immune evasion strategies to allow persistent infection and viral spread without harming its host. HCMV contains a 250 kb ds DNA genome that has 252 open reading frames and encodes approximately 200 proteins, of which only about 50 are essential for viral replication [49]. Hence, the majority of HCMV encoded proteins have other functions in the viral lifecycle and many of these proteins are involved in immune evasion. For instance, the US11, US2 and US3 gene products prevent host cell MHC class I antigen expression that is required for CD8+ cytotoxic tumour killing. HCMV also induces a specific block in presentation of peptides of the HCMV encoded IE1 protein; one of the earliest immunodominant HCMV epitopes [50-52]. US3 and US8 inhibit presentation of MHC class II molecules on the cell surface and thereby inhibit CD4 + T cell responses [53, 54]. The HCMV pp65 protein encoded by the UL83 gene redirect HLA class II molecules to lysosomes where the alpha chain of the HLADR molecule is degraded [55]. HCMV inhibits NK mediated lysis by several different strategies; the virus encodes for an MHC class I homologue that prevents NK cells to become activated through the missing self-hypothesis. The viral protein UL16 retains the NKG2D ligands ULBP1, 2 and MIC-B in the ER that are essential to activate an NK cell response (reviewed in [56]). UL16 also protects the cells from lysis mediated by cytotoxic peptides [57]. Thus, cancer cells expressing UL16 would be protected against the action of both NK cells and T cells. Interestingly, the HCMV encoded UL83 protein pp65 and IE1/IE2 are frequently detected in both gliomas and medulloblastomas [11, 12].

We recently showed that HCMV nucleic acids and proteins are present in the majority of medulloblastoma primary tumours and cell lines. We also found that US28 (the HCMV encoded chemokine receptor homologue with potential oncogenic functions) was expressed in medulloblastoma and induced expression of COX-2 in these tumours [12]. Microarray analysis of US28 transfected cells and HCMV infected cells showed that the expression of COX-2 is highly up-regulated in these cells as compared to mock-transfected or HCMV negative cells [17, 39]. Moreover, transgenic mice with targeted expression of US28 to intestinal epithelial cells exhibit a hyperplastic intestinal epithelium resulting in tumour development, indicating that US28 is involved in tumour initiation and progression [16].

COX-2 is over- expressed in a number of different adult cancers of epithelial origin as well as in gliomas where high expression often is correlated with poor prognosis (reviewed in [58-60]). In paediatric solid tumours high expression of COX-2 has been found in neuroblastoma [61, 62], medulloblastoma [63, 64] and sarcomas [65]. COX-2 is one of the major enzymes responsible for the conversion of arachidonic acid to the pro-inflammatory eicosanoid, prostaglandin E2 (PGE2). Increased levels of prostaglandin E2 (PGE2) are perceived in malignancies of different origin, including brain tumors [66-68]. PGE2 exerts its physiological effects by interacting with a subfamily of four distinct G-protein–coupled receptors designated EP1, EP2, EP3, and EP4. PGE2 promotes tumour growth in an autocrine and/or paracrine manner by stimulating EP receptor signalling with subsequent enhancement of cellular proliferation, promotion of angiogenesis, inhibition of apoptosis and stimulation of invasion [58]. In addition, PGE2 is an important mediator for the interaction between tumour cells and cells in the tumor microenvironment where PGE2 contributes to the generation of a tumor promoting inflammatory microenvironment that suppress the activities from cells in the immune system [58].

Different nonsteroidal anti-inflammatory drugs (NSAIDs) which inhibit the enzymatic function of cyclooxygenases and the production of prostaglandins and other inflammatory mediators has been shown to be promising agents for the prevention and treatment of various cancers [69]. Elevated levels of PGE2 are required for efficient replication of HCMV by facilitating the production of the HCMV immediate-early 2 protein [70]. Daily aspirin reduce both the risk of development of cancer and cancer deaths [71]; the benefit increased with duration of treatment [72]. Interestingly, NSAIDs abrogate virus-mediated production of PGE2 and reduce the virus burden in HCMV infected cells [70, 73]; thus acting as an anti-viral agent against HCMV. Moreover, the COX-2 specific NSAID celecoxib reduces the levels of PGE2 and the expression of HCMV proteins in medulloblastoma, as well as tumour growth in vitro and in vivo [12].

US28 that induces the expression of COX-2 in HCMV infected cells can bind different chemokines, including CCL2, CCL5, and CX3CL1 [74], and suppress the host immune responses [75]. Moreover, US28 activates NF- κB resulting in activation of the IL-6–JAK1–STAT3 signalling axis and increased interleukin-6 (IL-6), VEGF and endothelial nitric oxide synthase (e-NOS) production [14, 19]. Analysis of clinical glioblastoma samples in situ showed co-localization of US28 with phosphorylated STAT3, COX-2, VEGF and e-NOS, suggesting that US28 in addition to promoting an inflammatory microenvironment also contribute to tumour invasiveness and angiogenesis [14, 19]. Taken together US28 could provide a target for therapy in HCMV-positive tumours.

HCMV establishes latency in myeloid lineage cells, and reactivation is dependent on inflammation and differentiation of monocytes into macrophages of dendritic cells. HCMV can also persistently infect monocyte/macrophage lineage cells and induce a strong inflammatory response in these cells [76]. In human breast and colon cancer HCMV protein expression has been detected in infiltrating inflammatory cells in the tumour microenvironment and in gliomas, macrophages and microglia cells as well as tumor cells exhibit positive HCMV protein staining [77, 78]. HCMV infection of moncyte/macrophages is associated with an induction of IL-1, IL-6, IL-10, TNF-α and TGF-β that are potent cytokines with both immune stimulating and immunosuppressive effects on the host anti-tumour response [1, 79]. In particular, CMVIL-10 and TGF-β would provide an immunosuppressive microenvironment in HCMV positive tumours [80, 81]. These evidences raise the prospect that a persistent HCMV infection could induce the same kind of “smoldering” inflammation at the same time as it creates an immunosuppressive environment, which is frequently observed in the tumour microenvironment [1, 78].



HCMV is a neurotropic virus that can persistently infect neural precursor cells. As a consequence HCMV is the major infectious cause of birth defects in infants, including sensori-neural hearing loss or neuronal migration disturbances during brain development, and in the most severe cases, microcephaly or anencephaly. We have demonstrated that HCMV can block the ability of neural progenitor cells to differentiate into neurons or astrocytes [82, 83]. HCMV DNA and gene products have repeatedly been detected by several laboratories in preneoplastic and neoplastic tumour cells in human glioblastoma tissue samples and the fractions of tumour cells infected with HCMV correlate significantly with tumour staging and patient survival [5, 84]. We recently reported that the majority of primary human medulloblastoma and cell lines propagated for years in laboratories contain HCMV DNA, RNA and express HCMV IE and late proteins [12]. Our unpublished data also demonstrate that HCMV is present in the majority of childhood primary neuroblastoma and cell lines, an observation which is consistent with other reports [15, 45].

Medulloblastoma and neuroblastoma are embryonal tumours of the central and peripheral nervous systems, respectively. Compared to adult tumours, paediatric tumours generally have a dramatically shortened latency period and harbour fewer genetic aberrations causing oncogene activation or loss of apoptotic regulators. The reason for these differences is that these malignancies probably arise from stem or progenitor cells which already possess proliferative capacity as a part of the normal developmental process [85]. Medulloblastoma and neuroblastoma are linked to dysfunctional pathways that are operative during normal development [85]. The clinical presentation and treatment response also suggests that a tumour initiating cell population exist in these tumours [86-91].

Although the cellular origin of gliomas still is contended, recent evidence suggests that multipotent neural stem or progenitors of the subventricular zone (SVZ) are cells with the potential to form gliomas [92]. Subpopulations of CD133+ and/or CD15+ cells in both medulloblastomas and glioblastomas have been recognized as potential cancer stem cells [89, 93]. In neuroblastoma, on the other hand, no true marker for potential cancer stem cells have been found, although CD133 and CD44 are implied as potential markers [88]. We have detected HCMV DNA, RNA and proteins in medulloblastoma, glioblastoma and neuroblastoma cell lines used world-wide for decades in laboratories, which may indicate that the virus in condemned in a stem cell that is maintained in culture and gives rise to tumours [12]. We observed that the expression of HCMV proteins in both medulloblastoma and neuroblastoma cell lines varied considerably between different sampling occasions over a one year period, and that protein expression increased when the cells were engrafted in nude mice. We therefore hypothesize that HCMV DNA and proteins are maintained in a stem-cell like phenotype. Indeed we observed HCMV protein expression in the majority of CD133+ medulloblastoma cells whereas in neuroblastoma this number varied between 4-34% depending on cell line and sampling time ([12], and unpublished observations). Likewise, in glioblastoma tissue samples 40-60% of the CD133+ cell population expressed HCMV IE1 [14] and our own unpublished observations). These data indicate that HCMV is present in tumour cells that express stem cell markers, and that the virus is maintained in cell lines over long periods of time. The fact that HCMV is able to inhibit the differentiation of neural progenitor cells raises the possibility that HCMV encoded proteins are involved in the maintenance of a cancer stem cell population within neural tumours.


The findings that several cancer forms are HCMV positive, including those with a neural origin that usually have a dismal prognosis, opens up the possibility to treat these cancers with anti-viral drugs against HCMV. In nude mice engrafted with human medulloblastoma cells, the antiviral drug valganciclovir, significantly inhibited tumour growth. Interestingly the treatment effect was extensively enhanced when valganciclovir was combined with the COX-2 specific inhibitor celecoxib [12], which is known to also inhibit HCMV infection. Importantly, the inhibition of tumour growth clearly corresponded with reduction in the expression of late HCMV proteins in these tumours. However, neither valganciclovir by itself or in combination with celecoxib was able to completely eliminate the HCMV presence. In sharp contrast, valganciclovir had no effect neither on the clonogenic capacity or tumour growth of two HCMV-negative cell lines derived from prostate and pancreas adenocarcinomas [12]. This strongly suggests that the inhibitory effect of valganciclovir on medulloblastoma growth is HCMV specific and not mediated by potential non-specific drug effects inhibiting cellular proliferation.

Medulloblastoma, neuroblastoma and glioblastoma tumors express high levels of COX-2 and NSAIDs, inhibitors of COX-2 and PGE2 production, have profound effects on the growth of these tumours [64, 94-96]. These inhibitors also efficiently prevent HCMV replication and reduce the growth of US28-expressing tumour cells [17, 18, 70, 73]. Hence, the beneficial effects seen with aspirin and other NSAIDs in cancer prevention studies could partly be due to inhibition of HCMV replication in pre-malignant lesions. Compared to conventional chemotherapeutic drugs currently used for the treatment of these tumours, both antiviral drugs for HCMV and NSAIDs are well tolerated. Hence, these drugs should undergo clinical testing in combination with conventional therapies in patients carrying HCMV-infected tumours.

In a randomized double-blinded phase II study we are currently evaluating antiviral drugs against HCMV as an adjuvant therapy for glioblastoma. Results from this study are expected to be ready soon. Also a phase I/II immunotherapy clinical trial of autologous HCMV pp65 RNA loaded dendritic cells has been initiated in which 13 patients with newly diagnosed glioblastoma multiforme were enrolled. Initial results from this study are promising. Patients exhibited a median progression-free survival of 15.4 months and overall survival of 20.6 months, numbers which are highly significant compared to historical controls [97].

The promising preclinical and clinical results obtained using antiviral drugs against HCMV to treat tumours carrying HCMV should be extended to include larger controlled clinical trials. Also, developing drugs that specifically inhibit the functions of HCMV encoded US28 may be of future benefit in cancer treatment since the US28 protein may possess important functions in tumour initiation through the activation of intracellular signalling pathways, angiogenesis and effects on the tumour microenvironment.


The presence and functions of HCMV in cancer is still debated and scepticism vestiges regarding the relationship between HCMV and cancer. This mainly originates from conflicting results regarding the detection of HCMV in tumour samples and since HCMV by itself not has been shown to transform normal cells into cancer cells [47]. The last statement has recently been challenged since the HCMV encoded chemokine receptor homologue US28 renders NIH3T3 cells tumorigenic when injected into nude mice and transgenic mice with targeted expression to intestinal epithelial cells develop intestinal neoplasia [16, 18, 19]. Compared to the high degree of HCMV replication and protein expression seen in primary HCMV infections and in HCMV reactivation in immunocompromised individuals, the expression of viral proteins in cancer cells is very low. The term “microinfection” has been used to describe the low levels of HCMV infection found in cancer [84]. Clearly, the infection is different in cells that replicate the virus and produce infectious virus compared to tumour cells in vivo; in spite of the fact that several HCMV proteins are expressed, infectious virus are not isolated from tumour cells of primary tumors, primary tumour cell cultures or established tumour cell lines. Therefore, as detection of HCMV in cancer cells using standard protocols developed for the detection of active HCMV infection associated with a high HCMV replication rate and high-level expression of HCMV proteins is usually insufficient in these cases, it is believed that low levels of HCMV exists in tumours [13, 15]. However, using flow cytometry examining fresh tumour cells or indirect immunofluorescence examining frozen tumor biopsy specimens, we demonstrated the feasibility of detecting HCMV proteins in primary tumour cells from medulloblastoma, glioblastoma and neuroblastoma patients (Wolmer-solberg, submitted, [12, 98]). Research laboratories that have shown a high prevalence of HCMV nucleic acids and proteins in tumour samples have used highly sensitive immunohistochemical and molecular methods in order to detect the presence of HCMV.

As of today HCMV has been detected in glioma, medulloblastoma, neuroblastoma, breast, prostate and colon cancer and mucoepidermoid tumors of the salivary gland. Although the exact molecular functions of HCMV in these tumours still need to be further investigated, the findings that antiviral HCMV treatment inhibit the growth of certain tumours ([12], Wolmer-Solberg, unpublished) is exciting and future studies will elucidate whether these antiviral therapies should be included as an adjuvant treatment for patients having HCMV-positive tumours.




We apologize to our colleagues whose work we were unable to cite due to space limitations and to the specific focus of this review. The authors have no conflicting financial interests (although CS-N holds an independent grant support from Roche supporting the clinical trial evaluating the efficacy and safety of valganciclovir treatment in glioblastoma patients). This work was supported by grants from Torsten and Ragnar Söderbergs Stiftelse, Ragnar Söderbergs Foundation, The Swedish Children's Cancer Foundation, The Swedish Cancer Society, The Swedish Research Council, the Märta and Gunnar V Philipson Foundation, The Mary Bevé Foundation, The Hans and Märit Rausing Charitable Fund, The Dämman Foundation, Swedish Society for Medical Research (SLS), Goljes Memory Foundation, Magnus Bergvalls Foundation, Swedish Society for Medical Research (SSMF) and Tore Nilsons Foundation.

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por cyto às 16:42

Quarta-feira, 28.05.14




1. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–444. [PubMed]

2. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. [PubMed]

3. Zur Hausen H. The search for infectious causes of human cancers: where and why. Virology. 2009;392(1):1–10. [PubMed]

4. Straat K, Liu C, Rahbar A, Zhu Q, Liu L, Wolmer-Solberg N, Lou F, Liu Z, Shen J, Jia J, et al. Activation of telomerase by human cytomegalovirus. J Natl Cancer Inst. 2009;101(7):488–497. [PubMed]

5. Scheurer ME, Bondy ML, Aldape KD, Albrecht T, El-Zein R. Detection of human cytomegalovirus in different histological types of gliomas. Acta Neuropathol. 2008;116(1):79–86. [PMC free article] [PubMed]

6. Samanta M, Harkins L, Klemm K, Britt WJ, Cobbs CS. High prevalence of human cytomegalovirus in prostatic intraepithelial neoplasia and prostatic carcinoma. J Urol. 2003;170(3):998–1002. [PubMed]

7. Prins RM, Cloughesy TF, Liau LM. Cytomegalovirus immunity after vaccination with autologous glioblastoma lysate. N Engl J Med. 2008;359(5):539–541. [PMC free article] [PubMed]

8. Mitchell DA, Xie W, Schmittling R, Learn C, Friedman A, McLendon RE, Sampson JH. Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol. 2008;10(1):10–18. [PMC free article] [PubMed]

9. Melnick M, Sedghizadeh PP, Allen CM, Jaskoll T. Human cytomegalovirus and mucoepidermoid carcinoma of salivary glands: Cell-specific localization of active viral and oncogenic signaling proteins is confirmatory of a causal relationship. Experimental and molecular pathology. 2011;92(1):118–125. [PubMed]

10. Harkins L, Volk AL, Samanta M, Mikolaenko I, Britt WJ, Bland KI, Cobbs CS. Specific localisation of human cytomegalovirus nucleic acids and proteins in human colorectal cancer. Lancet. 2002;360(9345):1557–1563. [PubMed]

11. Cobbs CS, Harkins L, Samanta M, Gillespie GY, Bharara S, King PH, Nabors LB, Cobbs CG, Britt WJ. Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res. 2002;62(12):3347–3350. [PubMed]

12. Baryawno N, Rahbar A, Wolmer-Solberg N, Taher C, Odeberg J, Darabi A, Khan Z, Sveinbjornsson B, Fuskevag OM, Segerstrom L, et al. Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target. J Clin Invest. 2011;121(10):4043–4055. [PMC free article] [PubMed]

13. Ranganathan P, Clark PA, Kuo JS, Salamat MS, Kalejta RF. Significant Association of Multiple Human Cytomegalovirus Genomic Loci with Glioblastoma Multiforme Samples. J Virol. 2011 [PMC free article] [PubMed]

14. Soroceanu L, Cobbs CS. Is HCMV a tumor promoter? Virus Res. 2011;157(2):193–203. [PMC free article] [PubMed]

15. Michaelis M, Doerr HW, Cinatl J., Jr. Oncomodulation by human cytomegalovirus: evidence becomes stronger. Med Microbiol Immunol. 2009;198(2):79–81. [PubMed]

16. Bongers G, Maussang D, Muniz LR, Noriega VM, Fraile-Ramos A, Barker N, Marchesi F, Thirunarayanan N, Vischer HF, Qin L, et al. The cytomegalovirus-encoded chemokine receptor US28 promotes intestinal neoplasia in transgenic mice. J Clin Invest. 2010;120(11):3969–3978. [PMC free article] [PubMed]

17. Maussang D, Langemeijer E, Fitzsimons CP, Stigter-van Walsum M, Dijkman R, Borg MK, Slinger E, Schreiber A, Michel D, Tensen CP, et al. The human cytomegalovirus-encoded chemokine receptor US28 promotes angiogenesis and tumor formation via cyclooxygenase-2. Cancer Res. 2009;69(7):2861–2869. [PubMed]

18. Maussang D, Verzijl D, van Walsum M, Leurs R, Holl J, Pleskoff O, Michel D, van Dongen GA, Smit MJ. Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis. Proc Natl Acad Sci U S A. 2006;103(35):13068–13073. [PMC free article] [PubMed]

19. Slinger E, Maussang D, Schreiber A, Siderius M, Rahbar A, Fraile-Ramos A, Lira SA, Soderberg-Naucler C, Smit MJ. HCMV-encoded chemokine receptor US28 mediates proliferative signaling through the IL-6-STAT3 axis. Sci Signal. 2010;3(133):ra58. [PubMed]

20. Oeckinghaus A, Hayden MS, Ghosh S. Crosstalk in NF-kappaB signaling pathways. Nat Immunol. 2011;12(8):695–708. [PubMed]

21. Bellon M, Nicot C. Regulation of telomerase and telomeres: human tumor viruses take control. J Natl Cancer Inst. 2008;100(2):98–108. [PubMed]

22. Melnick M, Abichaker G, Htet K, Sedghizadeh P, Jaskoll T. Small molecule inhibitors of the host cell COX/AREG/EGFR/ERK pathway attenuate cytomegalovirus-induced pathogenesis. Experimental and molecular pathology. 2011;91(1):400–410. [PMC free article] [PubMed]

23. Cinatl J, Jr., Vogel JU, Kotchetkov R, Wilhelm Doerr H. Oncomodulatory signals by regulatory proteins encoded by human cytomegalovirus: a novel role for viral infection in tumor progression. FEMS Microbiol Rev. 2004;28(1):59–77. [PubMed]

24. Luo MH, Fortunato EA. Long-term infection and shedding of human cytomegalovirus in T98G glioblastoma cells. J Virol. 2007;81(19):10424–10436. [PMC free article] [PubMed]

25. Blaheta RA, Beecken WD, Engl T, Jonas D, Oppermann E, Hundemer M, Doerr HW, Scholz M, Cinatl J. Human cytomegalovirus infection of tumor cells downregulates NCAM (CD56): a novel mechanism for virus-induced tumor invasiveness. Neoplasia. 2004;6(4):323–331. [PMC free article] [PubMed]

26. Cobbs CS, Soroceanu L, Denham S, Zhang W, Britt WJ, Pieper R, Kraus MH. Human cytomegalovirus induces cellular tyrosine kinase signaling and promotes glioma cell invasiveness. J Neurooncol. 2007;85(3):271–280. [PubMed]

27. Soroceanu L, Akhavan A, Cobbs CS. Platelet-derived growth factor-alpha receptor activation is required for human cytomegalovirus infection. Nature. 2008;455(7211):391–395. [PubMed]

28. Moorman NJ, Cristea IM, Terhune SS, Rout MP, Chait BT, Shenk T. Human cytomegalovirus protein UL38 inhibits host cell stress responses by antagonizing the tuberous sclerosis protein complex. Cell Host Microbe. 2008;3(4):253–262. [PMC free article] [PubMed]

29. McCormick AL, Roback L, Mocarski ES. HtrA2/Omi terminates cytomegalovirus infection and is controlled by the viral mitochondrial inhibitor of apoptosis (vMIA) PLoS Pathog. 2008;4(5):e1000063. [PMC free article] [PubMed]

30. Goldmacher VS, Bartle LM, Skaletskaya A, Dionne CA, Kedersha NL, Vater CA, Han JW, Lutz RJ, Watanabe S, Cahir McFarland ED, et al. A cytomegalovirus-encoded mitochondria-localized inhibitor of apoptosis structurally unrelated to Bcl-2. Proc Natl Acad Sci U S A. 1999;96(22):12536–12541. [PMC free article] [PubMed]

31. Norris PS, Jepsen K, Haas M. High-titer MSCV-based retrovirus generated in the pCL acute virus packaging system confers sustained gene expression in vivo. J Virol Methods. 1998;75(2):161–167. [PubMed]

32. Skaletskaya A, Bartle LM, Chittenden T, McCormick AL, Mocarski ES, Goldmacher VS. A cytomegalovirus-encoded inhibitor of apoptosis that suppresses caspase-8 activation. Proc Natl Acad Sci U S A. 2001;98(14):7829–7834. [PMC free article] [PubMed]

33. Allart S, Martin H, Detraves C, Terrasson J, Caput D, Davrinche C. Human cytomegalovirus induces drug resistance and alteration of programmed cell death by accumulation of deltaN-p73alpha. J Biol Chem. 2002;277(32):29063–29068. [PubMed]

34. Tsai HL, Kou GH, Chen SC, Wu CW, Lin YS. Human cytomegalovirus immediate-early protein IE2 tethers a transcriptional repression domain to p53. J Biol Chem. 1996;271(7):3534–3540. [PubMed]

35. Tanaka K, Zou JP, Takeda K, Ferrans VJ, Sandford GR, Johnson TM, Finkel T, Epstein SE. Effects of human cytomegalovirus immediate-early proteins on p53-mediated apoptosis in coronary artery smooth muscle cells. Circulation. 1999;99(13):1656–1659. [PubMed]

36. Speir E, Modali R, Huang ES, Leon MB, Shawl F, Finkel T, Epstein SE. Potential role of human cytomegalovirus and p53 interaction in coronary restenosis [see comments] Science. 1994;265(5170):391–394. [PubMed]

37. Lukac DM, Alwine JC. Effects of human cytomegalovirus major immediate-early proteins in controlling the cell cycle and inhibiting apoptosis: studies with ts13 cells. J Virol. 1999;73(4):2825–2831. [PMC free article] [PubMed]

38. Hume AJ, Finkel JS, Kamil JP, Coen DM, Culbertson MR, Kalejta RF. Phosphorylation of retinoblastoma protein by viral protein with cyclin-dependent kinase function. Science. 2008;320(5877):797–799. [PubMed]

39. Zhu H, Shen Y, Shenk T. Human cytomegalovirus IE1 and IE2 proteins block apoptosis. J Virol. 1995;69(12):7960–7970. [PMC free article] [PubMed]

40. Yu Y, Alwine JC. Human cytomegalovirus major immediate-early proteins and simian virus 40 large T antigen can inhibit apoptosis through activation of the phosphatidylinositide 3'-OH kinase pathway and the cellular kinase Akt. J Virol. 2002;76(8):3731–3738. [PMC free article] [PubMed]

41. Poma EE, Kowalik TF, Zhu L, Sinclair JH, Huang ES. The human cytomegalovirus IE1-72 protein interacts with the cellular p107 protein and relieves p107-mediated transcriptional repression of an E2F-responsive promoter. J Virol. 1996;70(11):7867–7877. [PMC free article] [PubMed]

42. Fortunato EA, Dell'Aquila ML, Spector DH. Specific chromosome 1 breaks induced by human cytomegalovirus. Proc Natl Acad Sci U S A. 2000;97(2):853–858. [PMC free article] [PubMed]

43. Castillo JP, Kowalik TF. Human cytomegalovirus immediate early proteins and cell growth control. Gene. 2002;290(1-2):19–34. [PubMed]

44. Cinatl J, Jr., Cinatl J, Vogel JU, Kotchetkov R, Driever PH, Kabickova H, Kornhuber B, Schwabe D, Doerr HW. Persistent human cytomegalovirus infection induces drug resistance and alteration of programmed cell death in human neuroblastoma cells. Cancer Res. 1998;58(2):367–372. [PubMed]

45. Nigro G, Schiavetti A, Booth JC, Clerico A, Dominici C, Krzysztofiak A, Castello M. Cytomegalovirus-associated stage 4S neuroblastoma relapsed stage 4. Med Pediatr Oncol. 1995;24(3):200–203. [PubMed]

46. Wertheim P, Voute PA. Neuroblastoma, Wilms' tumor, and cytomegalovirus. J Natl Cancer Inst. 1976;57(3):701–703. [PubMed]

47. Michaelis M, Doerr HW, Cinatl J., Jr. Oncomodulation by human cytomegalovirus: evidence becomes stronger. Med Microbiol Immunol. 2009;198(2):79–81. [PubMed]

48. Cinatl J, Jr., Kotchetkov R, Scholz M, Cinatl J, Vogel JU, Driever PH, Doerr HW. Human cytomegalovirus infection decreases expression of thrombospondin-1 independent of the tumor suppressor protein p53. Am J Pathol. 1999;155(1):285–292. [PMC free article] [PubMed]

49. Murphy E, Yu D, Grimwood J, Schmutz J, Dickson M, Jarvis MA, Hahn G, Nelson JA, Myers RM, Shenk TE. Coding potential of laboratory and clinical strains of human cytomegalovirus. Proc Natl Acad Sci U S A. 2003;100(25):14976–14981. [PMC free article] [PubMed]

50. Greijer AE, Verschuuren EA, Dekkers CA, Adriaanse HM, van der Bij W, The TH, Middeldorp JM. Expression dynamics of human cytomegalovirus immune evasion genes US3, US6, and US11 in the blood of lung transplant recipients. J Infect Dis. 2001;184(3):247–255. [PubMed]

51. Besold K, Wills M, Plachter B. Immune evasion proteins gpUS2 and gpUS11 of human cytomegalovirus incompletely protect infected cells from CD8 T cell recognition. Virology. 2009;391(1):5–19. [PubMed]

52. Benz C, Reusch U, Muranyi W, Brune W, Atalay R, Hengel H. Efficient downregulation of major histocompatibility complex class I molecules in human epithelial cells infected with cytomegalovirus. Journal of General Virology. 2001;82(Pt 9):2061–2070. [PubMed]

53. Tomazin R, Boname J, Hegde NR, Lewinsohn DM, Altschuler Y, Jones TR, Cresswell P, Nelson JA, Riddell SR, Johnson DC. Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition by CD4+ T cells. Nat Med. 1999;5(9):1039–1043. [PubMed]

54. Hegde NR, Tomazin RA, Wisner TW, Dunn C, Boname JM, Lewinsohn DM, Johnson DC. Inhibition of HLA-DR assembly, transport, and loading by human cytomegalovirus glycoprotein US3: a novel mechanism for evading major histocompatibility complex class II antigen presentation. J Virol. 2002;76(21):10929–10941. [PMC free article] [PubMed]

55. Odeberg J, Plachter B, Branden L, Soderberg-Naucler C. Human cytomegalovirus protein pp65 mediates accumulation of HLA-DR in lysosomes and destruction of the HLA-DR alpha-chain. Blood. 2003;101(12):4870–4877. [PubMed]

56. Soderberg-Naucler C. Human cytomegalovirus persists in its host and attacks and avoids elimination by the immune system. Crit Rev Immunol. 2006;26(3):231–264. [PubMed]

57. Odeberg J, Browne H, Metkar S, Froelich CJ, Branden L, Cosman D, Soderberg-Naucler C. The human cytomegalovirus protein UL16 mediates increased resistance to natural killer cell cytotoxicity through resistance to cytolytic proteins. J Virol. 2003;77(8):4539–4545. [PMC free article] [PubMed]

58. Wang D, Dubois RN. Eicosanoids and cancer. Nat Rev Cancer. 2010;10(3):181–193. [PMC free article] [PubMed]

59. Shono T, Tofilon PJ, Bruner JM, Owolabi O, Lang FF. Cyclooxygenase-2 expression in human gliomas: prognostic significance and molecular correlations. Cancer Res. 2001;61(11):4375–4381. [PubMed]

60. Joki T, Heese O, Nikas DC, Bello L, Zhang J, Kraeft SK, Seyfried NT, Abe T, Chen LB, Carroll RS, et al. Expression of cyclooxygenase 2 (COX-2) in human glioma and in vitro inhibition by a specific COX-2 inhibitor, NS-398. Cancer Res. 2000;60(17):4926–4931. [PubMed]

61. Johnsen JI, Lindskog M, Ponthan F, Pettersen I, Elfman L, Orrego A, Sveinbjornsson B, Kogner P. NSAIDs in neuroblastoma therapy. Cancer Lett. 2005;228(1-2):195–201. [PubMed]

62. Johnsen JI, Lindskog M, Ponthan F, Pettersen I, Elfman L, Orrego A, Sveinbjornsson B, Kogner P. Cyclooxygenase-2 is expressed in neuroblastoma, and nonsteroidal anti-inflammatory drugs induce apoptosis and inhibit tumor growth in vivo. Cancer Res. 2004;64(20):7210–7215. [PubMed]

63. Patti R, Gumired K, Reddanna P, Sutton LN, Phillips PC, Reddy CD. Overexpression of cyclooxygenase-2 (COX-2) in human primitive neuroectodermal tumors: effect of celecoxib and rofecoxib. Cancer Lett. 2002;180(1):13–21. [PubMed]

64. Baryawno N, Sveinbjornsson B, Eksborg S, Orrego A, Segerstrom L, Oqvist CO, Holm S, Gustavsson B, Kagedal B, Kogner P, et al. Tumor-growth-promoting cyclooxygenase-2 prostaglandin E2 pathway provides medulloblastoma therapeutic targets. Neuro Oncol. 2008;10(5):661–674. [PMC free article] [PubMed]

65. Dickens DS, Kozielski R, Khan J, Forus A, Cripe TP. Cyclooxygenase-2 expression in pediatric sarcomas. Pediatr Dev Pathol. 2002;5(4):356–364. [PubMed]

66. Kokoglu E, Tuter Y, Yazici Z, Sandikci KS, Sonmez H, Ulakoglu EZ, Ozyurt E. Profiles of the fatty acids in the plasma membrane of human brain tumors. Cancer Biochem Biophys. 1998;16(4):301–312. [PubMed]

67. Loh JK, Hwang SL, Lieu AS, Huang TY, Howng SL. The alteration of prostaglandin E2 levels in patients with brain tumors before and after tumor removal. J Neurooncol. 2002;57(2):147–150. [PubMed]

68. Nathoo N, Barnett GH, Golubic M. The eicosanoid cascade: possible role in gliomas and meningiomas. J Clin Pathol. 2004;57(1):6–13. [PMC free article] [PubMed]

69. Burn J, Gerdes AM, Macrae F, Mecklin JP, Moeslein G, Olschwang S, Eccles D, Evans DG, Maher ER, Bertario L, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet. 2011 Oct 27; [Epub ahead of print]. [PMC free article] [PubMed]

70. Zhu H, Cong JP, Yu D, Bresnahan WA, Shenk TE. Inhibition of cyclooxygenase 2 blocks human cytomegalovirus replication. Proc Natl Acad Sci U S A. 2002;99(6):3932–3937. [PMC free article] [PubMed]

71. Din FV, Theodoratou E, Farrington SM, Tenesa A, Barnetson RA, Cetnarskyj R, Stark L, Porteous ME, Campbell H, Dunlop MG. Effect of aspirin and NSAIDs on risk and survival from colorectal cancer. Gut. 2010;59(12):1670–1679. [PubMed]

72. Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011;377(9759):31–41. [PubMed]

73. Speir E, Yu ZX, Ferrans VJ, Huang ES, Epstein SE. Aspirin attenuates cytomegalovirus infectivity and gene expression mediated by cyclooxygenase-2 in coronary artery smooth muscle cells. Circ Res. 1998;83(2):210–216. [PubMed]

74. Bodaghi B, Jones TR, Zipeto D, Vita C, Sun L, Laurent L, Arenzana-Seisdedos F, Virelizier JL, Michelson S. Chemokine sequestration by viral chemoreceptors as a novel viral escape strategy: withdrawal of chemokines from the environment of cytomegalovirus-infected cells. Journal of Experimental Medicine. 1998;188(5):855–866. [PMC free article] [PubMed]

75. Randolph-Habecker JR, Rahill B, Torok-Storb B, Vieira J, Kolattukudy PE, Rovin BH, Sedmak DD. The expression of the cytomegalovirus chemokine receptor homolog US28 sequesters biologically active CC chemokines and alters IL-8 production. Cytokine. 2002;19(1):37–46. [PubMed]

76. Sinclair J, Sissons P. Latent and Persistent Infections Of Monocytes and Macrophages. Intervirology. 1996;39(5-6):293–301. [PubMed]

77. Harkins LE, Matlaf LA, Soroceanu L, Klemm K, Britt WJ, Wang W, Bland KI, Cobbs CS. Detection of human cytomegalovirus in normal and neoplastic breast epithelium. Herpesviridae. 2010;1(1):8. [PMC free article] [PubMed]

78. Soroceanu L, Matlaf L, Bezrookove V, Harkins L, Martinez R, Greene M, Soteropoulos P, Cobbs CS. Human Cytomegalovirus US28 Found in Glioblastoma Promotes an Invasive and Angiogenic Phenotype. Cancer Res. 2011;71(21):6643–6653. [PMC free article] [PubMed]

79. Chan G, Bivins-Smith ER, Smith MS, Smith PM, Yurochko AD. Transcriptome analysis reveals human cytomegalovirus reprograms monocyte differentiation toward an M1 macrophage. J Immunol. 2008;181(1):698–711. [PMC free article] [PubMed]

80. Kotenko SV, Saccani S, Izotova LS, Mirochnitchenko OV, Pestka S. Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10) Proc Natl Acad Sci U S A. 2000;97(4):1695–1700. [PMC free article] [PubMed]

81. Michelson S, Alcami J, Kim SJ, Danielpour D, Bachelerie F, Picard L, Bessia C, Paya C, Virelizier JL. Human cytomegalovirus infection induces transcription and secretion of transforming growth factor beta 1. J Virol. 1994;68(9):5730–5737. [PMC free article] [PubMed]

82. Odeberg J, Wolmer N, Falci S, Westgren M, Seiger A, Soderberg-Naucler C. Human cytomegalovirus inhibits neuronal differentiation and induces apoptosis in human neural precursor cells. J Virol. 2006;80(18):8929–8939. [PMC free article] [PubMed]

83. Odeberg J, Wolmer N, Falci S, Westgren M, Sundtrom E, Seiger A, Soderberg-Naucler C. Late human cytomegalovirus (HCMV) proteins inhibit differentiation of human neural precursor cells into astrocytes. J Neurosci Res. 2007;85(3):583–593. [PubMed]

84. Soderberg-Naucler C. HCMV microinfections in inflammatory diseases and cancer. J Clin Virol. 2008;41(3):218–223. [PubMed]

85. Scotting PJ, Walker DA, Perilongo G. Childhood solid tumours: a developmental disorder. Nat Rev Cancer. 2005;5(6):481–488. [PubMed]

86. Baryawno N, Sveinbjornsson B, Kogner P, Johnsen JI. Medulloblastoma: a disease with disorganized developmental signaling cascades. Cell Cycle. 2010;9(13):2548–2554. [PubMed]

87. Hambardzumyan D, Becher OJ, Rosenblum MK, Pandolfi PP, Manova-Todorova K, Holland EC. PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev. 2008;22(4):436–448. [PMC free article] [PubMed]

88. Hansford LM, McKee AE, Zhang L, George RE, Gerstle JT, Thorner PS, Smith KM, Look AT, Yeger H, Miller FD, et al. Neuroblastoma cells isolated from bone marrow metastases contain a naturally enriched tumor-initiating cell. Cancer Res. 2007;67(23):11234–11243. [PubMed]

89. Read TA, Fogarty MP, Markant SL, McLendon RE, Wei Z, Ellison DW, Febbo PG, Wechsler-Reya RJ. Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma. Cancer Cell. 2009;15(2):135–147. [PMC free article] [PubMed]

90. Schuller U, Heine VM, Mao J, Kho AT, Dillon AK, Han YG, Huillard E, Sun T, Ligon AH, Qian Y, et al. Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell. 2008;14(2):123–134. [PMC free article] [PubMed]

91. Yang ZJ, Ellis T, Markant SL, Read TA, Kessler JD, Bourboulas M, Schuller U, Machold R, Fishell G, Rowitch DH, et al. Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell. 2008;14(2):135–145. [PMC free article] [PubMed]

92. Gilbertson RJ, Rich JN. Making a tumour's bed: glioblastoma stem cells and the vascular niche. Nat Rev Cancer. 2007;7(10):733–736. [PubMed]

93. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB. Identification of human brain tumour initiating cells. Nature. 2004;432(7015):396–401. [PubMed]

94. Ma HI, Chiou SH, Hueng DY, Tai LK, Huang PI, Kao CL, Chen YW, Sytwu HK. Celecoxib and radioresistant glioblastoma-derived CD133+ cells: improvement in radiotherapeutic effects. Laboratory investigation. J Neurosurg. 2011;114(3):651–662. [PubMed]

95. Sareddy GR, Geeviman K, Ramulu C, Babu PP. The nonsteroidal anti-inflammatory drug celecoxib suppresses the growth and induces apoptosis of human glioblastoma cells via the NF-kappaB pathway. J Neurooncol. 2012;106(1):99–109. [PubMed]

96. Sharma V, Dixit D, Ghosh S, Sen E. COX-2 regulates the proliferation of glioma stem like cells. Neurochem Int. 2011;59(5):567–571. [PubMed]

97. Cobbs CS. Evolving evidence implicates cytomegalovirus as a promoter of malignant glioma pathogenesis. Herpesviridae. 2011;2(1):10. [PMC free article] [PubMed]

98. Dziurzynski K, Wei J, Qiao W, Hatiboglu MA, Kong LY, Wu A, Wang Y, Cahill D, Levine N, Prabhu S, et al. Glioma-associated cytomegalovirus mediates subversion of the monocyte lineage to a tumor propagating phenotype. Clin Cancer Res. 2011;17(14):4642–4649. [PMC free article] [PubMed]











Oncoimmunology. 2012 August 1; 1(5): 739–740. doi:  10.4161/onci.19441  PMCID: PMC3429578

Cytomegalovirus infection in brain tumors A potential new target for therapy?

Cecilia Söderberg-Nauclér 1 ,* and John Inge Johnsen 2

1Department of Medicine, Solna; Center for Molecular Medicine and Childhood; Stockholm, Sweden

2Childhood Cancer Research Unit; Department of Women’s and Children’s Health; Karolinska Institutet; Stockholm, Sweden

*Correspondence to: Cecilia Söderberg-Nauclér, Email:


Emerging evidence demonstrate a high prevalence of cytomegalovirus (CMV) proteins and nucleic acids in different tumors. CMV is confined to tumor cells and non-cancer cells in close proximity to tumors are consistently virus negative. CMV confers both oncogenic and oncomodulatory mechanisms, and may therefore provide a novel target in cancer treatment.

Keywords: cytomegalovirus, immunotherapy, cancer, COX-2, brain tumor, anti-viral treatment

Emerging evidence demonstrate a frequent presence of human cytomegalovirus (CMV) proteins and nucleic acids in brain tumors in both adults (glioblastoma) and children (medulloblastoma).1,2 Other more common cancer forms such as breast cancer, colon and prostate cancer as well as salivary gland mucoepidermoid carcinomas are also frequently virus positive, with a prevalence approaching 90–100%.3-5 CMV proteins are expressed only in tumor cells, while non-tumor cells surrounding the tumor are CMV negative. CMV proteins confer both oncogenic and oncomodulatory mechanisms; they control cell cycle progression by interacting with p53, Rb and cyclins, activates oncogenic signaling pathways (PI3K/Akt, Erk, Wnt and NFκB), inhibit cellular differentiation, induce chromosomal damage, affect epigenetic mechanisms, induce DNA damage and inhibit DNA repair mechanisms, induce oncogene expression and telomerase activity, induce inflammation and at the same time avoid recognition by the immune system.4,6 Furthermore, CMV encoded proteins inhibit apoptosis through interactions with key proteins in the extrinsic and intrinsic apoptotic signaling cascade, and can induce drug resistance to chemotherapeutic agents, which may impair the efficiency of cancer therapy4 (Fig. 1).


Figure 1. CMV encodes proteins that have important functions on tumor cell growth and the tumor microenvironment.

Although CMV proteins may both trigger oncogenesis and confer oncomodulatory functions, it is under debate if the virus truly plays a role in tumorigenesis and tumor progression. Glioblastoma patients have a very dismal prognosis with a mean survival of 12–14 mon. We recently found that a low grade CMV infection in glioblastomas was associated with longer time to tumor progression and improved survival.7 These observations imply that CMV may be involved in tumor progression rather than representing an epiphenomenon in these tumors. However, regardless of its role in the development of a tumor, the presence of CMV in tumor cells but not in normal cells surrounding the tumor, makes it a potential new and novel therapeutic target. We recently demonstrated that 92% of primary medulloblastoma tumors are positive for CMV proteins; viral DNA and RNA were detected in primary tumors and in medulloblastoma cell lines.2 The expression of CMV proteins varied over time in medulloblastoma cell lines, and was highly induced by xenografting in nude mice. Established human medulloblastoma xenografts were positive for CMV immediately early (IE) and late proteins; two viral proteins that are expressed during different phases of CMV replication, but infectious virus were not obtained from primary tumors or xenografts.2 These observations imply that CMV behaves differently in tumor cells compared with an acute infection that often results in virus-induced lysis of infected cells. Instead viral proteins exhibiting oncogenic and oncomodularatory functions may act to aggravate tumor growth and disease progression.

Earlier studies have demonstrated that CMV induces the expression of cyclooxygenase-2 (COX-2). COX-2 inhibitors are efficient anti-CMV drugs, as virus replication appear to depend on the synthesis of prostaglandin E 2 (PGE2).6 Several cancer types including those that are frequently CMV positive often demonstrate high levels of COX-2; in some of these tumors high levels of COX-2 expression correlates with poor patient outcome.6 COX-2 inhibitors are under evaluation as additional treatment options for several cancer forms, and a recent study demonstrates up to 70% reduced incidence of colon cancer in individuals receiving long-term aspirin treatment.8 It is possible that CMV contributes to induced COX-2 levels in certain tumors and that COX-2 inhibitors interfere with viral effects in CMV positive tumors. Interestingly, we found that only CMV positive medulloblastoma cells in culture expressed COX-2, and CMV proteins and COX-2 were also co-expressed in medulloblastoma tumors in patients.2 Nude mice carrying human medulloblastoma xenografts treated with either celecoxib or the anti-CMV drug valganciclovir demonstrated approximately 40% inhibition of tumor growth in vivo whereas combined celecoxib and valganciclovir treatment resulted in 72% reduced tumor growth without the use of chemotherapy.2 Importantly, no significant effects were observed on the growth of CMV negative tumor cells or xenografts treated with ganciclovir/valganciclovir.2 The expression of CMV late proteins was reduced by about 80% in CMV positive xenografts. In a recent study of a salivary gland tumor model, small molecule inhibitors of the COX/Amphiregulin/EGFR/Erk pathways also attenuated CMV induced pathogenesis.9 These observations imply that interfering with CMV in CMV positive tumors may provide a new therapeutic option for patients carrying such tumors. Further studies need to evaluate which chemotherapy that is most suitable to combine with celecoxib and valganciclovir in patients. Importantly, we propose that this therapeutic strategy is further evaluated as an additional treatment option also for other CMV positive tumors than medulloblastoma.

Recently, we have evaluated the effect of valganciclovir in glioblastoma patients.(unpublished data) The drug was well tolerated in patients receiving combined chemotherapy and radiotherapy and indicates an unexpectedly high survival in patients undergoing radical surgery and receiving long-term treatment with valganciclovir in combination with chemotherapy and radiation. However, the study was small including only 42 patients, and therefore well-powered studies have to further evaluate the efficacy of valganciclovir in glioblastoma patients. Several small immunotherapy trials are also ongoing to evaluate whether enhanced CMV specific immunity improve the survival of glioblastoma patients. The described studies should encourage for further investigations on this topic; the role of CMV needs to be further evaluated in tumor biology and medical and immunotherapeutic strategies targeting CMV should be further evaluated for potentially improved outcome of patients carrying CMV positive tumors.


1. Cobbs CS, Harkins L, Samanta M, Gillespie GY, Bharara S, King PH, et al. Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res. 2002;62:3347–50. [PubMed]

2. Baryawno N, Rahbar A, Wolmer-Solberg N, Taher C, Odeberg J, Darabi A, et al. Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target. J Clin Invest. 2011;121:4043–55. doi: 10.1172/JCI57147. [PMC free article] [PubMed] [Cross Ref]

3. Harkins LE, Matlaf LA, Soroceanu L, Klemm K, Britt WJ, Wang W, et al. Detection of human cytomegalovirus in normal and neoplastic breast epithelium. Herpesviridae. 2010;1:8. doi: 10.1186/2042-4280-1-8. [PMC free article] [PubMed] [Cross Ref]

4. Soroceanu L, Cobbs CS. Is HCMV a tumor promoter? Virus Res. 2011;157:193–203. doi: 10.1016/j.virusres.2010.10.026. [PMC free article] [PubMed] [Cross Ref]

5. Melnick M, Sedghizadeh PP, Allen CM, Jaskoll T. Human cytomegalovirus and mucoepidermoid carcinoma of salivary glands: Cell-specific localization of active viral and oncogenic signaling proteins is confirmatory of a causal relationship. Exp Mol Pathol. 2012;92:118–25. doi: 10.1016/j.yexmp.2011.10.011. [PubMed] [Cross Ref]

6. Johnsen JI, Baryawno N, Söderberg-Nauclér C. Is human cytomegalovirus a target in cancer therapy? Oncotarget. 2011;2:1329–38. [PMC free article] [PubMed]

7. Rahbar A, Orrego A, Stragliotto G, Peredo I, Dzabic M, Wolmer-Solberg N, et al. Human cytomegalovirus infection levels in glioblastoma multiforme are of high prognostic value for time to tumour progression and survival. Herpesviridae. 2011;3:3. doi: 10.1186/2042-4280-3-3. [Cross Ref]

8. Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011;377:31–41. doi: 10.1016/S0140-6736(10)62110-1. [PubMed] [Cross Ref]

9. Melnick M, Abichaker G, Htet K, Sedghizadeh P, Jaskoll T. Small molecule inhibitors of the host cell COX/AREG/EGFR/ERK pathway attenuate cytomegalovirus-induced pathogenesis. Exp Mol Pathol. 2011;91:400–10. doi: 10.1016/j.yexmp.2011.04.014. [PMC free article] [PubMed] [Cross Ref]

10. Effects of Valganciclovir as an add-on therapy in patients with cytomegalovirus-positive glioblastoma: A randomised, double-blind, proof-of-concept study. [PubMed]


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por cyto às 16:41

Quarta-feira, 28.05.14

Novel Vaccine Dramatically Boosts Survival in Glioblastoma

Novel Vaccine Dramatically Boosts Survival in Glioblastoma

Roxanne Nelson/December 05, 2013 

Brain Cancer News & Perspectives

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A novel therapy has extended survival in glioblastoma patients far beyond the current median. After undergoing surgical resection and standard treatment, half the patients treated with the experimental vaccine in a small phase 1 study survived more than 5 years.

The usual median survival in such patients is around 15 months, but in this study, 7 of the 16 participants are still alive, with survival ranging from 60.7 to 82.7 months after diagnosis.

The findings were published earlier this year (Cancer Immunol Immunother. 2013; 62:125 -135) and were presented last month at the 4th Quadrennial Meeting of the World Federation of Neuro-Oncology in San Francisco.

It is striking that this many patients are still alive, said study author Keith Black, MD, chair of the Department of Neurosurgery and director of the Neurosurgical Institute at Cedars-Sinai Medical Center in Los Angeles. "Some patients are approaching 7 years, and 4 are alive without any sign of recurrence and living normal lives," he told Medscape Medical News. "Another patient has some signs of recurrence but is stable."

"I am not aware of any other trial that has had such dramatic results for glioblastoma multiforme," Dr. Black said. However, a question remains: "Is this just a statistical fluke, or is the mechanism of action of this vaccine really providing such a robust increase in survival?"


I am not aware of any other trial that has had such dramatic results. Dr. Keith Black  

The experimental therapy, known as ICT-107, is an autologous vaccine that consists of a patient's dendritic cells pulsed with 6 peptides from tumor-associated antigens: AIM-2, TRP-2, HER2/neu, IL-13Ra2, gp100, and MAGE1. The vaccine is being developed by ImmunoCellular Therapeutics.

"One of the speculations is that the antigens are also targeting cancer stem cells, which may actually be part of the mechanism for the robustness of these results," Dr. Black explained. "We have also initiated 2 other vaccine trials at Cedars-Sinai targeting these cancer stem cells."

Survival Beyond 5 Years

The primary objective of the study was to determine the benefit of the ICT-107 vaccine in patients newly diagnosed with glioblastoma multiforme and to identify patients who survived longer than 5 years or who were disease free more than 5 years after receiving the vaccine.

The 16 study patients had undergone surgical resection and standard follow-up therapy with concurrent temozolomide and radiation. Only 4 patients did not undergo complete resection.

Patients were human leukocyte antigen serotype A1 or A2, and had at least 1 of the vaccine antigens present in their tumor. The vaccine was administered intradermally 3 times at 2-week intervals.



Median progression-free survival in the cohort was 16.9 months, and the 5-year rate of progression-free survival was 37.5%. Median overall survival was 38.4 months, and the 5-year rate of overall survival was 50%.

Eight of the 16 patients survived more than 5 years, and 7 are still alive (at 60.7, 65.1, 67.5, 67.4, 69.4, 77.9, and 82.7 months).

In 6 patients, progression-free survival has been more than 5 years. Four of the 6 continue to be disease-free at 65.1, 67.4, 77.9, and 82.7 months. One patient died of leukemia at 61 months, but the leukemia was not related to the therapy, Dr. Black explained. Another patient, who developed tumor progression at 62 months and underwent surgery and active treatment with temozolomide, is currently stable and doing well, he reported.

All of the long-term survivors had tumors with at least 5 antigens, and 75% percent had tumors with all 6 antigens. In addition, 100% expressed at least 4 cancer stem cell antigens (AIM2, TRP-2, HER2/neu, IL-13Ra2).

The secondary outcome of interferon-gamma response was significantly higher in those who survived at least 5 years than in those who did not (P = .0499).

Phase 2 Trial Underway

On the basis of this single-institution phase 1 trial, a phase 2 trial was initiated. "It is being conducted at 25 medical centers, and is randomized, placebo-controlled, and blinded," Dr. Black reported.

About 125 patients are now enrolled, and preliminary results will be released after 64 events, he explained.

"If the results are as good as the phase 1 trial, where we saw a very robust response, and if there is a greater than 9-month median survival increase, there will be a lot of interest in talking with the FDA about accelerated approval," Dr. Black said. "But if it is an intermediate increase, such as 3 to 4 months, we will be looking at a larger phase 3 trial."

Dr. Black reports owning stock in ImmunoCellular Therapeutics. Several members of the research team report ties to the company.

4th Quadrennial Meeting of the World Federation of Neuro-Oncology.

Presented November 23, 2013.



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por cyto às 16:36

Quarta-feira, 28.05.14


Vaccine Prolongs Survival in Patients with Glioblastoma

Fran Lowry, August 22, 2012


August 22, 2012 — An autologous dendritic cell vaccine has been shown to be safe and feasible and to have significant bioactivity in newly diagnosed glioblastoma patients, according to the results of a phase 1 trial, published online July 31 in Cancer Immunology, Immunotherapy.

In this open-label single-institution trial, led by Surasak  Phuphanich, MD, director of the neuro-oncology program at Cedars-Sinai Medical Center in Los Angeles, California, treatment with the vaccine prolonged progression-free survival for a median of 16.9 months, and prolonged overall survival, with 8 of 16 patients alive, at a median of 38.4 months.

Typically, the overall survival of patients with newly diagnosed glioblastoma receiving standard radiation plus chemotherapy alone is 14.6 months, and progression-free survival is 6.9 months, the investigators note.

Patients were enrolled in this study from May 2007 to January 2010. Median age was 52 years (range, 26 to 79 years), and median Karnofsky score was 90 (range, 70 to 100).

The dendritic cell vaccine (ICT-107) targets 6 tumor antigens involved in the development of glioblastoma cells: HER2/neu, TRP-2, gp100, MAGE-1, IL13Ra2, and AIM-2.

It was administered intradermally 3 times at 2-week intervals after the patients had undergone radiation and chemotherapy. In all, 62 vaccinations were administered. They were well tolerated, with only grade 1 or 2 adverse events, including fatigue, pruritus, rash, flushing, and redness of the skin.

In all patients, the tumors expressed at least 3 of the targeted antigens, and in 14 patients (74%), the tumors expressed all 6 antigens.

The investigators found that the expression of the AIM-2 and MAGE-1 antigens was significantly correlated with progression-free and overall survival, and that the expression of the HER2 and gp100 antigens showed a trend toward longer progression-free and overall survival.

They also found a decrease in CD133 expression in 5 of the vaccinated patients who underwent a second resection after their glioblastoma returned.

"Previous studies showed an increase in CD133 expression in patients who underwent treatment with radiation and chemotherapy," Dr. Phuphanich said in a statement. "Our findings suggest that targeting antigens that are highly expressed by cancer stem cells may be a viable strategy for treating patients who have glioblastoma."

Keith L. Black, MD, chair of the Department of Neurosurgery at Cedars-Sinai, and one of the trial investigators, told Medscape Medical News that the results suggest that the vaccine is effective.




"The thing about this phase 1 study is that essentially 6 of 16 glioblastoma patients are alive and disease-free past 4 years, and 3 of the 16 are alive and disease-free past 5 years. That strongly suggests that the signal that we are looking at is real," he said.

All of the caveats about a phase 1 trial hold true, Dr. Black added. "One is always concerned that the trial is done at a single institution, it's not randomized, not placebo controlled.... [However], when you look at all the other phase 1 trials that have been done for glioblastoma, you don't see this long-term survival. It's not as if it is a slightly positive effect. To get this many long-term survivors indicates that it's a fairly significant signal that we are seeing," he said.

A phase 2 trial, already underway, is randomizing patients on a 2:1 basis to receive vaccine or placebo. This trial will confirm that the phase 1 signal is indeed real, Dr. Black said.

"The phase 2 trial has completed enrolment, and some 300 patients have been enrolled. Hopefully, we will see the results of those data in about 18 months," he said.

A good phase 2 trial results might persuade the US Food and Drug Administration (FDA) to rush the vaccine to market, especially because glioblastoma is essentially an orphan cancer.

"One cannot predict what the FDA will do, but we don't have a lot of patients with glioblastoma, as we do with breast or lung cancer, to get a lot of major pharmaceutical companies excited. I think the FDA has an interest in trying to move products like this along a faster track so that they can get this to patients who desperately need the therapy, but a lot depends on how robust the signal is in the phase 2 trial," Dr. Black explained.


Michael Lim, MD, director of the brain tumor immunotherapy program at the Johns Hopkins University School of Medicine in Baltimore, Maryland, who is involved in the phase 2 trial, told Medscape Medical News that the data from the phase 1 trial are exciting.

"Ultimately, I think we will need a phase 3 trial, but these are pretty exciting data and there is a lot of potential for this approach. Looking at the 6 most common antigens and then creating an army of immune cells to attack all of them is clever," Dr. Lim said.

Jump Start the Immune System


"By trying to approach 6 different antigens at once, you may be able to get a much higher percentage of cancer cells and perhaps jump start the immune system. This study shows that we're smarter today than we were 20 years ago, when we didn't know what some of the specific antigens of tumors were and what markers to attack," he said.

Henry Friedman, MD, professor of medicine at the Duke University Medical Center in Durham, North Carolina, endorsed the potential for vaccines in the treatment of brain cancer in general.

"The role of vaccines in the treatment of malignant glioma is being pursued actively by a number of centers using a number of different approaches," he told Medscape Medical News. "No one has yet determined the best approach, if indeed there is one best approach, but the early results with a spectrum of vaccines, including the one used in this trial, support the rationale for this treatment modality."




The study was funded by the Musella Foundation for Brain Tumor Research & Information and ImmunoCellular Therapeutics. Dr. Phuphanich, Dr. Lim, and Dr. Friedman have disclosed no relevant financial relationships. Dr. Black reports being a consultant for and owning stock in ImmunoCellular Therapeutics.

Cancer Immunol Immunother. Published online July 31, 2012. Abstract


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por cyto às 16:33

Quarta-feira, 28.05.14





ASCO 2013

CHICAGO – The combination of Bevacizumab and Irinotecan far outshone Temozolomide in delaying disease progression among patients with MGMT-unmethylated glioblastoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

In the phase II GLARIUS trial, 79.6% of patients treated with Bevacizumab (Avastin) and Irinotecan (Camptosar) were free of progression at 6 months, compared with 41.3% of patients randomized to receive temozolmide (Temodar) (P less than .0001), reported Dr. Ulrich Herrlinger from the department of neurology at University Clinic of Bonn, Germany.

Progression-free survival at 6 months (PFS-6) was the study's primary endpoint.


A preliminary analysis also hinted at a potential overall survival advantage for the bevacizumab-irinotecan (BEV/IRI) combination. After nearly 50% of patients in each arm had died, median overall survival was 16.6 months for the BEV/IRI group, compared with 14.8 months for the temozolomide group (hazard ratio, 0.60; P = .031).

"Obviously we did not harm our patients by omitting temozolomide and choosing something different, BEV/IRI, for treating these patients," Dr. Herrlinger said.

The combination is a promising alternative to temozolomide therapy in patients with with MGMT (O6-methylguanine-DNA methyltransferase) - unmethylated glioblastoma, he said. About 55%-65% of newly diagnosed glioblastomas are not methylated by MGMT, a DNA repair enzyme, and these have a worse prognosis than those in which MGMT promotes methylation, according to Dr. Herrlinger.

Investigators at 22 centers in Germany tested patients with glioblastoma for MGMT status, and randomized a total of 182 patients with newly diagnosed, histologically confirmed MGMT-unmethylated glioblastoma. Of these, 170 received at least one course of drug therapy and were evaluable for response; these patients were included in the analysis.

All patients received 60 Gy localized radiation in 30 fragments of 2 Gy each. They were randomized 2:1 to BEV-IRI (116 patients) or temozolomide (54 patients).

The experimental arm received Bevacizumab 10 mg/kg every 2 weeks during radiotherapy followed by maintenance Bevacizumab at the same dose and irinotecan 125 mg/m2 every 2 weeks without or with enzyme-inducing antiepileptic drugs at a dose of 340 mg/m2.

The standard therapy arm was given temozolomide 75 mg/m2 daily during radiotherapy, followed by 6 courses of temozolomide 150-200 mg/m2 for 5 days every 4 weeks.

In addition to the advantage in progression-free survival at 6 months, median progression-free survival also was longer with BEV/IRI: 9.74 months vs. 6 months in patients treated with temozolomide (HR 0.30, P less than .0001).





In addition patients on the combination used fewer mean daily steroids than patients on temozolomide.

The safety analysis showed that grade 3 or 4 vascular disorders – including deep vein thrombosis, pulmonary embolism, and hypertension – occurred in 10.9% of patients on BEV/IRI, compared with 3.6% of those on temozolomide. The combination was also associated with more grade 3 or 4 diarrhea and nausea, wound infections, and proteinuria. However, hematotoxicity was higher among patients on temozolomide, occurring in 14.8%, compared with 1.7% of patients on BEV/IRI.

"I think it’s important to recognize that there is a [bevacizumab] toxicity signal," said Dr Albert Lai, a neuro-oncologist at the University of California, Los Angeles, who was the invited discussant.

Dr. Lai commented that the overall survival signal seen by the GLARIUS investigators may have been affected by an optional crossover to BEV/IRI after disease progression on temozolomide. Of the 54 patients in the temozolomide arm, 29 crossed over to BEV/IRI.

The GLARIUS trial was sponsored by Hoffman-La Roche. Dr. Herrlinger disclosed being a consultant and speaker and receiving research support from the company. Dr. Lai disclosed serving as a consultant and receiving research funding from Genentech/Roche.


  • ·Figures

Targeting Src Family Kinases Inhibits Bevacizumab-Induced Glioma Cell Invasion (DASATINIB)

Published: February 14, 2013 DOI: 10.1371/journal.pone.0056505


Anti-VEGF antibody therapy with Bevacizumab provides significant clinical benefit in patients with recurrent glioblastoma multiforme (GBM). Unfortunately, progression on bevacizumab therapy is often associated with a diffuse disease recurrence pattern, which limits subsequent therapeutic options. Therefore, there is an urgent need to understand bevacizumab's influence on glioma biology and block it's actions towards cell invasion.

To explore the mechanism(s) of GBM cell invasion we have examined a panel of serially transplanted human GBM lines grown either in short-term culture, as xenografts in mouse flank, or injected orthotopically in mouse brain. Using an orthotopic xenograft model that exhibits increased invasiveness upon Bevacizumab treatment, we also tested the effect of Dasatinib, a broad spectrum SFK inhibitor, on bevacizumab-induced invasion.




We show that:

1) activation of Src family kinases (SFKs) is common in GBM,

2) the relative invasiveness of 17 serially transplanted GBM xenografts correlates strongly with p120 catenin phosphorylation at Y228, a Src kinase site, and,

3) SFK activation assessed immunohistochemically in orthotopic xenografts, as well as the phosphorylation of downstream substrates occurs specifically at the invasive tumor edge. Further, we show that SFK signaling is markedly elevated at the invasive tumor front upon bevacizumab administration, and that Dasatinib treatment effectively blocked the increased invasion induced by bevacizumab.

Our data are consistent with the hypothesis that the increased invasiveness associated with anti-VEGF therapy is due to increased SFK signaling, and support testing the combination of dasatinib with bevacizumab in the clinic.




Expert Review of Anticancer Therapy

Antiangiogenic Therapies in Glioblastoma Multiforme

Mairéad G McNamara, Warren P Mason Expert Rev Anticancer Ther. 2012;12(5):643-654. 



Dasatinib (Sprycel) is an ATP-competitive small molecule SRC, BCR–ABL, c-KIT, receptor tyrosine kinase EPH receptor A2 (EPHA2) and PDGFR-β inhibitor. SRC is frequently phosphorylated in GBM cell lines and is also activated in primary GBM patient samples. Dasatinib inhibits viability and cell migration in vitro and tumor growth in vivo.[39] Combination treatment of glioma cells with dasatinib and temozolomide resulted in a significant increase in cell cycle disruption and autophagic cell death.

Dasatinib, when given in combination with temozolomide, more effectively increased the therapeutic efficacy of temozolomide than when dasatanib was combined with carboplatin or irinotecan. These findings support the clinical use of dasatinib in the treatment of GBM and provide a rationale for combining it with temozolomide.[40]

An additional study suggested the potential of combining IGF-1 receptor inhibition with other tyrosine kinase inhibitors to potentiate therapeutic efficacy. Indeed, combination treatment with the IGF-1 receptor inhibitor NVP-AEW541 and dasatinib induced significantly more apoptosis than either agent alone in glioma cells.[41]

A retrospective study of dasatinib for recurrent GBM after bevacizumab failure concluded that dasatinib 70–100 mg twice daily in combination with bevacizumab did not appear to have activity in patients with recurrent, heavily pretreated GBM.[42]


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por cyto às 16:27

Quarta-feira, 28.05.14

p53 Keeps Immune Responses Specific

Sci. Signal., 27 May 2014
Vol. 7, Issue 327, p. ec144
[DOI: 10.1126/scisignal.2005515]


p53 Keeps Immune Responses Specific

John F. Foley Science Signaling, AAAS, Washington, DC 20005, USA

To become fully activated, T cells receive antigen-specific signals through their T cell receptors (TCRs) and coreceptors by interacting with antigen-presenting cells (APCs). Cytokines, such as interleukin-2 (IL-2), generate a third signal that then stimulates T cell proliferation. Understanding the mechanism by which only antigen-exposed T cells, but not bystander cells, proliferate in response to IL-2 could help in designing therapies to prevent inappropriate immune responses. Watanabe et al. found that, whereas T cells from both wild-type mice and mice deficient in the tumor suppressor protein p53 proliferated similarly in response to costimulation with antigen-loaded APCs and IL-2, only the p53-deficient T cells proliferated in response to IL-2 alone. Flow cytometric and biochemical analyses showed that there were no differences in the amounts of IL-2 receptor subunits or in the extent of IL-2 signaling between wild-type and p53-deficient T cells. Compared with wild-type T cells, p53-deficient T cells showed increased DNA synthesis and enhanced cell division when costimulated with antigen-loaded APCs and IL-2. Stimulation of wild-type T cells through the TCR alone led to a transient increase, but then a substantial decrease in p53 abundance, whereas stimulation of T cells with IL-2 alone did not reduce p53 abundance. In addition, stimulation of wild-type T cells through the TCR, but not the IL-2 receptor, increased the mRNA and protein abundance of Mdm2, an E3 ubiquitin ligase that targets p53 for degradation. Exposure of wild-type T cells to the Mdm2 inhibitor Nutlin3a prevented the loss of p53 and blocked proliferation in response to antigen-loaded APCs and IL-2. When wild-type mouse CD4+ T cells that had been exposed to antigen in vivo were isolated and stimulated with antigen in vitro, their proliferation was blocked by Nutlin3a. Together, these data suggest that p53 acts in T cells to block inappropriate proliferation in response to IL-2 until the cells receive antigen-specific signals.

M. Watanabe, K. D. Moon, M. S. Vacchio, K. S. Hathcock, R. J. Hodes, Downmodulation of tumor suppressor p53 by T cell receptor signaling is critical for antigen-specific CD4+ T cell responses. Immunity 40, 1–11 (2014). [PubMed]

M. A. Fray, S. C. Bunnell, p53 keeps bystanders at the gates. Immunity 40, 633–635 (2014). [PubMed]

Citation: J. F. Foley, p53 Keeps Immune Responses Specific. Sci. Signal. 7, ec144 (2014).

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por cyto às 16:16

Terça-feira, 27.05.14

Improved survival in glioblastoma patients who take bevacizumab


Practice Essentials

Essential update:

Improved survival in glioblastoma patients who take bevacizumab


A population-based analysis of 5607 adult patients with glioblastoma in the SEER (Surveillance Epidemiology and End Results) database found that Bevacizumab therapy may improve survival. In the study, glioblastoma patients who died in 2010 (after the FDA approved bevacizumab for this condition) survived significantly longer than those who died of the disease in 2008. Median survival was 8 months for patients who died in 2006, 7 months in 2008, and 9 months in 2010. This difference in survival was highly significant between 2008 (pre-bevacizumab) and 2010 (post-bevacizumab). This survival difference was unlikely due to improvements in supportive care during this time interval, because there was no significant difference between those who died in 2006 and patients who died 2 years later, in 2008.[1, 2]

Signs and symptoms

The clinical history of a patient with glioblastoma multiforme (GBM) is usually short (< 3 months in >50% of patients).

Common presenting symptoms include the following:

  • Slowly progressive      neurologic deficit, usually motor weakness
  • Headache
  • Generalized symptoms of      increased intracranial pressure, including headaches, nausea and vomiting,      and cognitive impairment
  • Seizures

Neurologic symptoms and signs can be either general or focal and reflect the location of the tumor, as follows:

  • General symptoms:      Headaches, nausea and vomiting, personality changes, and slowing of      cognitive function International
  • Focal signs: Hemiparesis,      sensory loss, visual loss, aphasia, and others

The etiology of GBM is unknown in most cases.

Suggested causes include the following: Genetic factors, Cell phone use (controversial), Head injury, N-nitrous compounds, occupational hazards, electromagnetic field exposure (inconclusive)[3] Race 



No specific laboratory studies are helpful in diagnosing GBM. Tumor genetics are useful for predicting response to adjuvant therapy.

Imaging studies of the brain are essential for making the diagnosis, including the following:

  • Computed tomography
  • Magnetic resonance imaging,      with and without contrast (study of choice)
  • Positron emission tomography
  • Magnetic resonance spectroscopy
  • Cerebral angiography is not necessary

Other diagnostic measures that may be considered include the following:

  • Electroencephalography: May      show suggestive findings, but findings specific for GBM will not be      observed
  • Lumbar puncture (generally contraindicated but occasionally necessary      for ruling out lymphoma)
  • Cerebrospinal fluid studies      do not significantly facilitate specific diagnosis of GBM

In most cases, complete staging is neither practical nor possible. These tumors do not have clearly defined margins; they tend to invade locally and spread along white matter pathways, creating the appearance of multiple GBMs or multicentric gliomas on imaging studies.


No current treatment is curative. Standard treatment consists of the following:

  • Maximal surgical resection,      radiotherapy, and concomitant and adjuvant chemotherapy with temozolomide[4, 5]
  • Patients older than 70      years: Less aggressive therapy is sometimes considered, using radiation or      temozolomide alone[6, 7, 8]

 Key points regarding radiotherapy for GBM include the following:[9, 10, 11]

  • The addition of      radiotherapy to surgery increases survival.[12, 13]
  • The responsiveness of GBM      to radiotherapy varies.
  • Interstitial brachytherapy      is of limited use and is rarely used.
  • Radiosensitizers, such as      newer chemotherapeutic agents,[14] targeted molecular agents,[15] [16] and antiangiogenic agents[16] may increase the therapeutic effect of radiotherapy.[17]
  • Radiotherapy for recurrent      GBM is controversial.

The optimal chemotherapeutic regimen for glioblastoma is not yet defined, but adjuvant chemotherapy appears to yield a significant survival benefit in more than 25% of patients.[18, 3, 19, 20, 21, 22]

Agents used include the following:

  • Temozolomide
  • Nitrosoureas (eg, carmustine [BCNU])
  • Inhibitors of MGMT (eg,      O6-benzylguanine)
  • Cisplatin
  • Bevacizumab (alone or with      irinotecan) for recurrent glioma
  • Tyrosine kinase inhibitors      (eg, Gefitinib, Erlotinib)
  • Investigational therapies      (eg, gene therapy, peptide and dendritic cell vaccines, synthetic      chlorotoxins, radiolabeled drugs and antibodies[23, 24, 25, 26, 27, 28]

Because GBM cannot be cured surgically, the surgical goals are as follows:

  • To establish a pathologic diagnosis
  • To relieve any mass effect
  • If possible, to achieve a      gross total resection to facilitate adjuvant therapy[29]
  • The extent of surgery      (biopsy vs resection) has been shown in a number of studies to affect      length of survival. Surgical options include the following:
  • Gross total resection      (better survival)
  • Subtotal resection

In some cases, stereotactic biopsy followed by radiation therapy (eg, for patients with a tumor located in an eloquent area of the brain, patients whose tumors have minimal mass effect, and patients in poor medical condition who cannot undergo general anesthesia) 



Glioblastoma multiforme (GBM) is by far the most common and most malignant of the glial tumors. Attention was drawn to this form of brain cancer when Senator Ted Kennedy was diagnosed with glioblastoma and ultimately died from it.

Of the estimated 17,000 primary brain tumors diagnosed in the United States each year, approximately 60% are gliomas. Gliomas comprise a heterogeneous group of neoplasms that differ in location within the central nervous system, in age and sex distribution, in growth potential, in extent of invasiveness, in morphological features, in tendency for progression, and in response to treatments. 


Composed of a heterogenous mixture of poorly differentiated neoplastic astrocytes, glioblastomas primarily affect adults, and they are located preferentially in the cerebral hemispheres. Much less commonly, glioblastoma multiforme can affect the brainstem (especially in children) and the spinal cord. These tumors may develop from lower-grade astrocytomas (World Health Organization [WHO] grade II) or anaplastic astrocytomas (WHO grade III), but, more frequently, they manifest de novo, without any evidence of a less malignant precursor lesion. The treatment of glioblastomas is palliative and includes surgery, radiotherapy, and chemotherapy.[30, 31, 32]


Glioblastomas can be classified as primary or secondary. Primary glioblastoma multiforme accounts for the vast majority of cases (60%) in adults older than 50 years. These tumors manifest de novo (ie, without clinical or histopathologic evidence of a preexisting, less-malignant precursor lesion), presenting after a short clinical history, usually less than 3 months. 


Secondary glioblastoma multiformes (40%) typically develop in younger patients (< 45 y) through malignant progression from a low-grade astrocytoma (WHO grade II) or anaplastic astrocytoma (WHO grade III). The time required for this progression varies considerably, ranging from less than 1 year to more than 10 years, with a mean interval of 4-5 years.

Increasing evidence indicates that primary and secondary glioblastomas constitute distinct disease entities that evolve through different genetic pathways, affect patients at different ages, and differ in response to some of the present therapies. Of all the astrocytic neoplasms, glioblastomas contain the greatest number of genetic changes, which, in most cases, result from the accumulation of multiple mutations.

Over the past decade, the concept of different genetic pathways leading to the common phenotypic endpoint (ie, GBM) has gained general acceptance. Genetically, primary and secondary glioblastomas show little overlap and constitute different disease entities. Studies are beginning to assess the prognoses associated with different mutations. Some of the more common genetic abnormalities are described as follows:

  • Loss of      heterozygosity (LOH): LOH on chromosome arm 10q is the most frequent gene      alteration for both primary and secondary glioblastomas; it occurs in      60-90% of cases. This mutation appears to be specific for glioblastoma      multiforme and is found rarely in other tumor grades. This mutation is      associated with poor survival. LOH at 10q plus 1 or 2 of the additional      gene mutations appear to be frequent alterations and are most likely major      players in the development of glioblastomas.
  • p53:      Mutations in p53, a tumor suppressor gene, were among the first genetic      alterations identified in astrocytic brain tumors. The p53 gene appears to      be deleted or altered in approximately 25-40% of all glioblastoma      multiformes, more commonly in secondary glioblastoma multiformes. The p53      immunoreactivity also appears to be associated with tumors that arise in      younger patients.
  • Epidermal      growth factor receptor (EGFR) gene: The EGFR gene is involved in the      control of cell proliferation. Multiple genetic mutations are apparent,      including both overexpression of the receptor as well as rearrangements      that result in truncated isoforms. However, all the clinically relevant      mutations appear to contain the same phenotype leading to increased      activity. These tumors typically show a simultaneous loss of chromosome 10      but rarely a concurrent p53 mutation. Overexpression or activation mutations      in this gene are more common in primary glioblastoma, with mutations      appearing in 40-50% of these tumors. One such common variant, EGFRvIII,      has shown promise as a target for kinase inhibitors, immunotoxins, and      peptide vaccines.[33, 4, 34] 
  • MDM2:      Amplification or overexpression of MDM2 constitutes an alternative      mechanism to escape from p53-regulated control of cell growth by binding      to p53 and blunting its activity. Overexpression of MDM2 is the second      most common gene mutation in glioblastoma multiformes and is observed in 10-15%      of patients. Some studies show that this mutation has been associated with      a poor prognosis.[35]
  • Platelet-derived      growth factor–alpha (PDGF-alpha) gene: The PDGF gene acts as a major      mitogen for glial cells by binding to the PDGF receptor (PDGFR).      Amplification or overexpression of PDGFR is typical (60%) in the pathway      leading to secondary glioblastomas.
  • PTEN:      PTEN (also known as MMAC and TEP1) encodes a tyrosine phosphatase located      at band 10q23.3. The function of PTEN as a cellular phosphatase, turning      off signaling pathways, is consistent with possible tumor-suppression      action. When phosphatase activity is lost because of genetic mutation,      signaling pathways can become activated constitutively, resulting in      aberrant proliferation. PTEN mutations have been found in as many as 30%      of glioblastomas, more commonly in primary glioblastoma multiformes.[5, 36]

Less frequent but more malignant mutations include the following:

  • MMAC1-E1      - A gene involved in the progression of gliomas to their most malignant      form
  • MAGE-E1 -      A glioma-specific member of the MAGE family that is expressed at up to      15-fold higher levels in glioblastoma multiformes than in normal      astrocytes
  • NRP/B - A      nuclear-restricted protein/brain, which is expressed in neurons but not in      astrocytes (NRP/B mutants are found in glioblastoma cells.)

Additional genetic alterations in primary glioblastomas include p16 deletions (30-40%), p16INK4A, and retinoblastoma (RB) gene protein alterations. Progression of secondary glioblastomas often includes LOH at chromosome arm 19q (50%), RB protein alterations (25%), PTEN mutations (5%), deleted-in-colorectal-carcinoma gene (DCC) gene loss of expression (50%), and LOH at 10q.



Glioblastoma multiformes occur most often in the subcortical white matter of the cerebral hemispheres. In a series of 987 glioblastomas from University Hospital Zurich, the most frequently affected sites were the temporal (31%), parietal (24%), frontal (23%), and occipital (16%) lobes.47 Combined frontotemporal location is particularly typical. Tumor infiltration often extends into the adjacent cortex or the basal ganglia. When a tumor in the frontal cortex spreads across the corpus callosum into the contralateral hemisphere, it creates the appearance of a bilateral symmetric lesion, hence the term butterfly glioma. Sites for glioblastomas that are much less common are the brainstem (which often is found in affected children), the cerebellum, and the spinal cord.Proceed to Clinical Presentation 


Contributor Information and Disclosures


Jeffrey N Bruce, MD  Edgar M Housepian Professor of Neurological Surgery Research, Vice-Chairman and Professor of Neurological Surgery, Director of Brain Tumor Tissue Bank, Director of Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Columbia University College of Physicians and Surgeons

Jeffrey N Bruce, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Neurological Surgeons, American Society of Clinical Oncology, Congress of Neurological Surgeons, New York Academy of Sciences, North American Skull Base Society, Pituitary Society, Society for Neuro-Oncology, and Society of Neurological Surgeons

Disclosure: NIH Grant/research funds Other


Benjamin Kennedy  Columbia University College of Physicians and Surgeons

Disclosure: Nothing to disclose.

Specialty Editor Board

Robert C Shepard, MD, FACP  Associate Professor of Medicine in Hematology and Oncology at University of North Carolina at Chapel Hill; Vice President of Scientific Affairs, Therapeutic Expertise, Oncology, at PRA International

Robert C Shepard, MD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physician Executives, American College of Physicians, American Federation for Clinical Research, American Federation for Medical Research, American Medical Association, American Medical Informatics Association, American Society of Hematology, Association of Clinical Research Professionals, Eastern Cooperative Oncology Group, European Society for Medical Oncology, Massachusetts Medical Society, and Society for Biological Therapy

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Rajalaxmi McKenna, MD, FACP  Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD  Clinical Professor of Medicine, Section of Hematology/Oncology, University of Arizona College of Medicine, Arizona Cancer Center

Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research

Disclosure: Nothing to disclose.

Additional Contributors

We would like to acknowledge previous contributions to this chapter from Katharine Cronk, MD,PhD; Richard C Anderson, MD; Chris E Mandigo, MD; Andrew T Parsa MD, PhD; Patrick B Senatus, MD, PhD; and Allen Waziri, MD.


Autoria e outros dados (tags, etc)

por cyto às 20:49

Terça-feira, 27.05.14




  1. Nelson R. Bevacizumab May Boost Survival in Glioblastoma. Medscape      Medical News. Available at      Accessed September 5, 2013.
  2. Johnson DR, Leeper HE, Uhm JH. Glioblastoma survival in the United      States improved after Food and Drug Administration approval of      bevacizumab: A population-based analysis. Cancer. Jul 18 2013;[Medline].
  3. Farrell CJ, Plotkin SR. Genetic causes of brain tumors:      neurofibromatosis, tuberous sclerosis, von Hippel-Lindau, and other      syndromes. Neurol Clin. Nov 2007;25(4):925-46, viii. [Medline].
  4. Hardell L, Carlberg M, Söderqvist F, Mild KH, Morgan LL. Long-term use      of cellular phones and brain tumours: increased risk associated with use      for > or =10 years. Occup Environ Med. Sep 2007;64(9):626-32. [Medline].
  5. Lahkola A, Auvinen A, Raitanen J, Schoemaker MJ, Christensen HC,      Feychting M, et al. Mobile phone use and risk of glioma in 5 North      European countries. Int J Cancer. Apr 15 2007;120(8):1769-75. [Medline].
  6. Inskip PD, Tarone RE, Hatch EE, Wilcosky TC, Shapiro WR, Selker RG, et      al. Cellular-telephone use and brain tumors. N Engl J Med. Jan 11      2001;344(2):79-86. [Medline].
  7. Weintraub MI. Glioblastoma multiforme and the cellular telephone      scare. J Neurosurg. Jan 1994;80(1):169-70. [Medline].
  8. Kan P, Simonsen SE, Lyon JL, Kestle JR. Cellular phone use and brain      tumor: a meta-analysis. J Neurooncol. Jan 2008;86(1):71-8. [Medline].
  9. International Electromagnetic Field (EMF) Collaborative. Cellphones      and Brain Tumors: 15 Reasons for Concern. Science, Spin and the Truth      Behind Interphone. Available at      Accessed October 19, 2009.
  10. Mukundan S, Holder C, Olson JJ. Neuroradiological assessment of newly      diagnosed glioblastoma. J Neurooncol. Sep 2008;89(3):259-69. [Medline].
  11. Piroth MD, Holy R, Pinkawa M, et al. Prognostic impact of      postoperative, pre-irradiation (18)F-fluoroethyl-l-tyrosine uptake in      glioblastoma patients treated with radiochemotherapy. Radiother Oncol.      May 2011;99(2):218-24. [Medline].
  12. Russell DS, Rubinstein LJ. Pathology of tumors of the nervous      system. 6th ed. London, England: Edward Arnold; 1998:426-52.
  13. Daumas-Duport C, Scheithauer B, O'Fallon J, Kelly P. Grading of      astrocytomas. A simple and reproducible method. Cancer. Nov 15      1988;62(10):2152-65. [Medline].
  14. Kim TS, Halliday AL, Hedley-Whyte ET, Convery K. Correlates of      survival and the Daumas-Duport grading system for astrocytomas. J      Neurosurg. Jan 1991;74(1):27-37. [Medline].
  15. Pedersen PH, Rucklidge GJ, Mork SJ, et al. Leptomeningeal tissue: a      barrier against brain tumor cell invasion. J Natl Cancer Inst. Nov      2 1994;86(21):1593-9. [Medline].
  16. Nagashima G, Suzuki R, Hokaku H, et al. Graphic analysis of      microscopic tumor cell infiltration, proliferative potential, and vascular      endothelial growth factor expression in an autopsy brain with      glioblastoma. Surg Neurol. Mar 1999;51(3):292-9. [Medline].
  17. Pompili A, Calvosa F, Caroli F, et al. The transdural extension of      gliomas. J Neurooncol. Jan 1993;15(1):67-74. [Medline].
  18. Brat DJ, Prayson RA, Ryken TC, Olson JJ. Diagnosis of malignant      glioma: role of neuropathology. J Neurooncol. Sep      2008;89(3):287-311. [Medline].
  19. Lampl Y, Eshel Y, Gilad R, Sarova-Pinchas I. Glioblastoma multiforme      with bone metastase and cauda equina syndrome. J Neurooncol. Apr      1990;8(2):167-72. [Medline].
  20. Hulbanni S, Goodman PA. Glioblastoma multiforme with extraneural      metastases in the absence of previous surgery. Cancer. Mar      1976;37(3):1577-83. [Medline].
  21. Hoffman HJ, Duffner PK. Extraneural metastases of central nervous      system tumors. Cancer. Oct 1 1985;56(7 Suppl):1778-82. [Medline].
  22. Barnard RO, Geddes JF. The incidence of multifocal cerebral gliomas. A      histologic study of large hemisphere sections. Cancer. Oct 1      1987;60(7):1519-31. [Medline].
  23. Batzdorf U, Malamud N. The Problem of Multicentric Gliomas. J      Neurosurg. Feb 1963;20:122-36. [Medline].
  24. Pasquier B, Pasquier D, N'Golet A, Panh MH, Couderc P. Extraneural      metastases of astrocytomas and glioblastomas: clinicopathological study of      two cases and review of literature. Cancer. Jan 1      1980;45(1):112-25. [Medline].
  25. Preusser M, de Ribaupierre S, Wohrer A, et al. Current concepts and      management of glioblastoma. Ann Neurol. Jul 2011;70(1):9-21. [Medline].
  26. Sathornsumetee S, Reardon DA, Desjardins A, Quinn JA, Vredenburgh JJ,      Rich JN. Molecularly targeted therapy for malignant glioma. Cancer.      Jul 1 2007;110(1):13-24. [Medline].
  27. Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, et al.      Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes      Dev. Nov 1 2007;21(21):2683-710. [Medline]. [Full Text].
  28. Keime-Guibert F, Chinot O, Taillandier L, Cartalat-Carel S, Frenay M,      Kantor G, et al. Radiotherapy for glioblastoma in the elderly. N Engl J      Med. Apr 12 2007;356(15):1527-35. [Medline]. [Full Text].
  29. Roa W, Brasher PM, Bauman G, Anthes M, Bruera E, Chan A, et al.      Abbreviated course of radiation therapy in older patients with      glioblastoma multiforme: a prospective randomized clinical trial. J      Clin Oncol. May 1 2004;22(9):1583-8. [Medline]. [Full Text].
  30. Glantz M, Chamberlain M, Liu Q, Litofsky NS, Recht LD. Temozolomide as      an alternative to irradiation for elderly patients with newly diagnosed      malignant gliomas. Cancer. May 1 2003;97(9):2262-6. [Medline].
  31. Scott J, Tsai YY, Chinnaiyan P, Yu HH. Effectiveness of radiotherapy      for elderly patients with glioblastoma. Int J Radiat Oncol Biol Phys.      Sep 1 2011;81(1):206-10. [Medline].
  32. Malmstrom A, et al. Temozolomide versus standard 6-week radiotherapy      versus hypofractionated radiotherapy in patients older than 60 years with      glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncology.      9/12;13:916-26.
  33. Liang BC, Thornton AF Jr, Sandler HM, Greenberg HS. Malignant      astrocytomas: focal tumor recurrence after focal external beam radiation      therapy. J Neurosurg. Oct 1991;75(4):559-63. [Medline].
  34. Hochberg FH, Pruitt A. Assumptions in the radiotherapy of      glioblastoma. Neurology. Sep 1980;30(9):907-11. [Medline].
  35. Shapiro WR, Green SB, Burger PC, et al. Randomized trial of three      chemotherapy regimens and two radiotherapy regimens and two radiotherapy      regimens in postoperative treatment of malignant glioma. Brain Tumor      Cooperative Group Trial 8001. J Neurosurg. Jul 1989;71(1):1-9. [Medline].
  36. Stupp R, Hegi ME, Gilbert MR, Chakravarti A. Chemoradiotherapy in      malignant glioma: standard of care and future directions. J Clin Oncol.      Sep 10 2007;25(26):4127-36. [Medline].
  37. Chi AS, Wen PY. Inhibiting kinases in malignant gliomas. Expert      Opin Ther Targets. Apr 2007;11(4):473-96. [Medline].
  38. Duda DG, Jain RK, Willett CG. Antiangiogenics: the potential role of      integrating this novel treatment modality with chemoradiation for solid      cancers. J Clin Oncol. Sep 10 2007;25(26):4033-42. [Medline]. [Full Text].
  39. Fisher JL, Schwartzbaum JA, Wrensch M, Wiemels JL. Epidemiology of      brain tumors. Neurol Clin. Nov 2007;25(4):867-90, vii. [Medline].
  40. Caccamo DV, Rubenstein LJ. Tumors: Applications of immunohistochemical      methods. In: Neuropathology: The diagnostic approach. St Louis, Mo:      Mosby-Year Book; 1997:193-218.
  41. [Best Evidence] Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn      MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and      adjuvant temozolomide versus radiotherapy alone on survival in      glioblastoma in a randomised phase III study: 5-year analysis of the      EORTC-NCIC trial. Lancet Oncol. May 2009;10(5):459-66. [Medline].
  42. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ.      Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N      Engl J Med. Mar 10 2005;352(10):987-96. [Medline]. [Full Text].
  43. Chamberlain MC, Kormanik PA. Practical guidelines for the treatment of      malignant gliomas. West J Med. Feb 1998;168(2):114-20. [Medline]. [Full Text].
  44. Wernicke AG, Edgar MA, Lavi E, et al. Prostate-specific membrane      antigen as a potential novel vascular target for treatment of glioblastoma      multiforme. Arch Pathol Lab Med. Nov 2011;135(11):1486-9. [Medline].
  45. Barker FG, Prados MD, Chang SM, et al. Radiation response and survival      time in patients with glioblastoma multiforme. J Neurosurg. Mar      1996;84(3):442-8. [Medline].
  46. Leibel SA, Scott CB, Loeffler JS. Contemporary approaches to the      treatment of malignant gliomas with radiation therapy. Semin Oncol.      Apr 1994;21(2):198-219. [Medline].
  47. Buatti J, Ryken TC, Smith MC, Sneed P, Suh JH, Mehta M, et al.      Radiation therapy of pathologically confirmed newly diagnosed glioblastoma      in adults. J Neurooncol. Sep 2008;89(3):313-37. [Medline].
  48. Walker MD, Alexander E Jr, Hunt WE, MacCarty CS, Mahaley MS Jr, Mealey      J Jr, et al. Evaluation of BCNU and/or radiotherapy in the treatment of      anaplastic gliomas. A cooperative clinical trial. J Neurosurg. Sep      1978;49(3):333-43. [Medline].
  49. Halperin EC, Bruger PC. Conventional external beam radiotherapy for      central nervous system malignancies. In: Frank BD, ed. Symposium on      Neuro-Oncology. Vol 3. 4th ed. New      York, NY: Neurologic Clinics; 1985:867-82.
  50. Waters JD, Rose B, Gonda DD, Scanderbeg DJ, Russell M, Alksne JF, et      al. Immediate post-operative brachytherapy prior to irradiation and      temozolomide for newly diagnosed glioblastoma. J Neurooncol. May 15      2013;[Medline].
  51. Rodrigus P. Motexafin gadolinium: a possible new radiosensitiser. Expert      Opin Investig Drugs. Jul 2003;12(7):1205-10. [Medline].
  52. Butowski NA, Sneed PK, Chang SM. Diagnosis and treatment of recurrent      high-grade astrocytoma. J Clin Oncol. Mar 10 2006;24(8):1273-80. [Medline].
  53. Combs SE, Thilmann C, Edler L, Debus J, Schulz-Ertner D. Efficacy of      fractionated stereotactic reirradiation in recurrent gliomas: long-term      results in 172 patients treated in a single institution. J Clin Oncol.      Dec 1 2005;23(34):8863-9. [Medline].
  54. Tsao MN, Mehta MP, Whelan TJ, Morris DE, Hayman JA, Flickinger JC, et      al. The American Society for Therapeutic Radiology and Oncology (ASTRO)      evidence-based review of the role of radiosurgery for malignant glioma. Int      J Radiat Oncol Biol Phys. Sep 1 2005;63(1):47-55. [Medline].
  55. Kornblith PL. The role of cytotoxic chemotherapy in the treatment of      malignant brain tumors. Surg Neurol. Dec 1995;44(6):551-2. [Medline].
  56. Kornblith PL, Walker M. Chemotherapy for malignant gliomas [published      erratum appears in J Neurosurg 1988 Oct;69(4):645]. J Neurosurg.      Jan 1988;68(1):1-17. [Medline].
  57. Lesser GJ, Grossman S. The chemotherapy of high-grade astrocytomas. Semin      Oncol. Apr 1994;21(2):220-35. [Medline].
  58. Levin VA. Chemotherapy of primary brain tumors. In: Frank BD, ed. Symposium      on Neuro-Oncology. Vol 3. 4th ed. New      York, NY: Neurologic Clinics; 1985:855-66.
  59. Levin VA, Silver P, Hannigan J, et al. Superiority of      post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and      vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final      report. Int J Radiat Oncol Biol Phys. Feb 1990;18(2):321-4. [Medline].
  60. Fadul CE, Wen PY, Kim L, Olson JJ. Cytotoxic chemotherapeutic      management of newly diagnosed glioblastoma multiforme. J Neurooncol.      Sep 2008;89(3):339-57. [Medline].
  61. Fine HA, Dear KB, Loeffler JS, Black PM, Canellos GP. Meta-analysis of      radiation therapy with and without adjuvant chemotherapy for malignant      gliomas in adults. Cancer. Apr 15 1993;71(8):2585-97. [Medline].
  62. Stewart LA. Chemotherapy in adult high-grade glioma: a systematic      review and meta-analysis of individual patient data from 12 randomised      trials. Lancet. Mar 23 2002;359(9311):1011-8. [Medline].
  63. Westphal M, Ram Z, Riddle V, Hilt D, Bortey E. Gliadel wafer in      initial surgery for malignant glioma: long-term follow-up of a multicenter      controlled trial. Acta Neurochir (Wien). Mar 2006;148(3):269-75;      discussion 275. [Medline].
  64. Gutenberg A, Bock HC, Brück W, Doerner L, Mehdorn HM, Roggendorf W, et      al. MGMT promoter methylation status and prognosis of patients with      primary or recurrent glioblastoma treated with carmustine wafers. Br J      Neurosurg. May 11 2013;[Medline].
  65. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M.      MGMT gene silencing and benefit from temozolomide in glioblastoma. N      Engl J Med. Mar 10 2005;352(10):997-1003. [Medline]. [Full Text].
  66. Hegi ME, Liu L, Herman JG, Stupp R, Wick W, Weller M, et al.      Correlation of O6-methylguanine methyltransferase (MGMT) promoter      methylation with clinical outcomes in glioblastoma and clinical strategies      to modulate MGMT activity. J Clin Oncol. Sep 1 2008;26(25):4189-99.      [Medline].
  67. Broniscer A, Gururangan S, MacDonald TJ, Goldman S, Packer RJ, Stewart      CF, et al. Phase I trial of single-dose temozolomide and continuous      administration of o6-benzylguanine in children with brain tumors: a      pediatric brain tumor consortium report. Clin Cancer Res. Nov 15      2007;13(22 Pt 1):6712-8. [Medline]. [Full Text].
  68. Kaiser MG, Parsa AT, Fine RL, Hall JS, Chakrabarti I, Bruce JN. Tissue      distribution and antitumor activity of topotecan delivered by      intracerebral clysis in a rat glioma model. Neurosurgery. Dec      2000;47(6):1391-8; discussion 1398-9. [Medline].
  69. Bruce JN, Falavigna A, Johnson JP, et al. Intracerebral clysis in a      rat glioma model. Neurosurgery. Mar 2000;46(3):683-91. [Medline].
  70. Lopez KA, Waziri AE, Canoll PD, Bruce JN. Convection-enhanced delivery      in the treatment of malignant glioma. Neurol Res. Jul      2006;28(5):542-8. [Medline].
  71. Brem H, Piantadosi S, Burger PC, et al. Placebo-controlled trial of      safety and efficacy of intraoperative controlled delivery by biodegradable      polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor      Treatment Group. Lancet. Apr 22 1995;345(8956):1008-12. [Medline].
  72. Bota DA, Desjardins A, Quinn JA, Affronti ML, Friedman HS.      Interstitial chemotherapy with biodegradable BCNU (Gliadel) wafers in the      treatment of malignant gliomas. Ther Clin Risk Manag. Oct      2007;3(5):707-15. [Medline]. [Full Text].
  73. FDA. Avastin Approval History. U.S. Food and Drug Administration.      Available at      Accessed 5/7/09.
  74. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA,      Quinn JA, et al. Phase II trial of bevacizumab and irinotecan in recurrent      malignant glioma. Clin Cancer Res. Feb 15 2007;13(4):1253-9. [Medline]. [Full Text].
  75. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA,      Quinn JA, et al. Bevacizumab plus irinotecan in recurrent glioblastoma      multiforme. J Clin Oncol. Oct 20 2007;25(30):4722-9. [Medline].
  76. Cloughesy TF, Prados MD, Wen PY. A phase II, randomized,      non-comparative clinical trial of the effect of bevacizumab (BV) alone or      in combinationwith irinotecan (CPT) on 6-month progressionfree survival      (PFS6) in recurrent, treatment-refractory glioblastoma (GBM). J Clin      Oncol. 2008;26:Suppl:91s.
  77. Rich JN, Rasheed BK, Yan H. EGFR mutations and sensitivity to      gefitinib. N Engl J Med. Sep 16 2004;351(12):1260-1; author reply      1260-1. [Medline].
  78. Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL. Phase II      trial of gefitinib in recurrent glioblastoma. J Clin Oncol. Jan 1      2004;22(1):133-42. [Medline]. [Full Text].
  79. Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ.      Molecular determinants of the response of glioblastomas to EGFR kinase      inhibitors. N Engl J Med. Nov 10 2005;353(19):2012-24. [Medline]. [Full Text].
  80. Fulci G, Chiocca EA. The status of gene therapy for brain tumors. Expert      Opin Biol Ther. Feb 2007;7(2):197-208. [Medline]. [Full Text].
  81. Reardon DA, Akabani G, Coleman RE, Friedman AH, Friedman HS, Herndon      JE 2nd, et al. Salvage radioimmunotherapy with murine iodine-131-labeled      antitenascin monoclonal antibody 81C6 for patients with recurrent primary      and metastatic malignant brain tumors: phase II study results. J Clin      Oncol. Jan 1 2006;24(1):115-22. [Medline].
  82. Mamelak AN, Rosenfeld S, Bucholz R, Raubitschek A, Nabors LB, Fiveash      JB, et al. Phase I single-dose study of intracavitary-administered      iodine-131-TM-601 in adults with recurrent high-grade glioma. J Clin      Oncol. Aug 1 2006;24(22):3644-50. [Medline].
  83. Ferguson S, Lesniak MS. Convection enhanced drug delivery of novel      therapeutic agents to malignant brain tumors. Curr Drug Deliv. Apr      2007;4(2):169-80. [Medline].
  84. Quang TS, Brady LW. Radioimmunotherapy as a novel treatment regimen:      (125)I-labeled monoclonal antibody 425 in the treatment of high-grade      brain gliomas. Int J Radiat Oncol Biol Phys. Mar 1      2004;58(3):972-5. [Medline].
  85. Rich JN, Bigner DD. Development of novel targeted therapies in the      treatment of malignant glioma. Nat Rev Drug Discov. May      2004;3(5):430-46. [Medline]. [Full Text].
  86. Ammirati M, Vick N, Liao YL, et al. Effect of the extent of surgical      resection on survival and quality of life in patients with supratentorial      glioblastomas and anaplastic astrocytomas. Neurosurgery. Aug      1987;21(2):201-6. [Medline].
  87. Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, et      al. A multivariate analysis of 416 patients with glioblastoma multiforme:      prognosis, extent of resection, and survival. J Neurosurg. Aug      2001;95(2):190-8. [Medline].
  88. Keles GE, Anderson B, Berger MS. The effect of extent of resection on      time to tumor progression and survival in patients with glioblastoma      multiforme of the cerebral hemisphere. Surg Neurol. Oct      1999;52(4):371-9. [Medline].
  89. Sanai N, Berger MS. Glioma extent of resection and its impact on      patient outcome. Neurosurgery. Apr 2008;62(4):753-64; discussion      264-6. [Medline].
  90. Fadul C, Wood J, Thaler H, et al. Morbidity and mortality of      craniotomy for excision of supratentorial gliomas. Neurology. Sep      1988;38(9):1374-9. [Medline].
  91. Ryken TC, Frankel B, Julien T, Olson JJ. Surgical management of newly      diagnosed glioblastoma in adults: role of cytoreductive surgery. J      Neurooncol. Sep 2008;89(3):271-86. [Medline].
  92. Ciric I, Rovin R, Cozzens JW. Role of surgery in the treatment of      malignant cerebral gliomas. In: Malignant Cerebral Glioma. Park      Ridge, Ill: American Association of Neurological Surgeons; 1990:141-53.
  93. El Hindy N, Bachmann HS, Lambertz et al. Association of the CC      genotype of the regulatory BCL2 promoter polymorphism (-938C>A) with      better 2-year survival in patients with glioblastoma multiforme. J      Neurosurg. Jun 2011;114(6):1631-9. [Medline].
  94. Coffey RJ, Lunsford LD, Taylor FH. Survival after stereotactic biopsy      of malignant gliomas. Neurosurgery. Mar 1988;22(3):465-73. [Medline].
  95. Jakola AS, Unsgard G, Solheim O. Quality of life in patients with      intracranial gliomas: the impact of modern image-guided surgery. J      Neurosurg. Jun 2011;114(6):1622-30. [Medline].
  96. Glantz MJ, Cole BF, Forsyth PA, et al. Practice parameter:      anticonvulsant prophylaxis in patients with newly diagnosed brain tumors.      Report of the Quality Standards Subcommittee of the American Academy of      Neurology. Neurology. May 23 2000;54(10):1886-93. [Medline]. [Full Text].
  97. Scott JN, Rewcastle NB, Brasher PM, et al. Long-term glioblastoma      multiforme survivors: a population-based study. Can J Neurol Sci.      Aug 1998;25(3):197-201. [Medline].
  98. Sneed PK, Prados MD, McDermott MW, et al. Large effect of age on the      survival of patients with glioblastoma treated with radiotherapy and      brachytherapy boost. Neurosurgery. May 1995;36(5):898-903;      discussion 903-4. [Medline].
  99. Salmon I, Dewitte O, Pasteels JL, et al. Prognostic scoring in adult      astrocytic tumors using patient age, histopathological grade, and DNA      histogram type. J Neurosurg. May 1994;80(5):877-83. [Medline].
  100. Black PM. Brain tumors. Part 1. N Engl J Med. May 23      1991;324(21):1471-6. [Medline].
  101. Kaur G, Bloch O, Jian BJ, et al. A critical evaluation of cystic      features in primary glioblastoma as a prognostic factor for survival. J      Neurosurg. Oct 2011;115(4):754-9. [Medline].
  102. Black PM. Brain tumor. Part 2. N Engl J Med. May 30      1991;324(22):1555-64. [Medline].
  103. Bouvier-Labit C, Chinot O, Ochi C, Gambarelli D, Dufour H,      Figarella-Branger D. Prognostic significance of Ki67, p53 and epidermal      growth factor receptor immunostaining in human glioblastomas. Neuropathol      Appl Neurobiol. Oct 1998;24(5):381-8. [Medline].
  104. Bullard DE, Bigner DD. Applications of monoclonal antibodies in the      diagnosis and treatment of primary brain tumors. J Neurosurg. Jul      1985;63(1):2-16. [Medline].
  105. Burger PC, Green SB. Patient age, histologic features, and length of      survival in patients with glioblastoma multiforme. Cancer. May 1      1987;59(9):1617-25. [Medline].
  106. Burger PC, Heinz ER, Shibata T, Kleihues P. Topographic anatomy and CT      correlations in the untreated glioblastoma multiforme. J Neurosurg.      May 1988;68(5):698-704. [Medline].
  107. Burger PC, Scheithauer BW. Tumors of the central nervous system. In: Atlas      of tumor pathology. Washington, DC: Armed Forces Institute of      Pathology; 1994.
  108. Burger PC, Vogel FS, Green SB, Strike TA. Glioblastoma multiforme and      anaplastic astrocytoma. Pathologic criteria and prognostic implications. Cancer.      Sep 1 1985;56(5):1106-11. [Medline].
  109. Devaux BC, O'Fallon JR, Kelly PJ. Resection, biopsy, and survival in      malignant glial neoplasms. A retrospective study of clinical parameters,      therapy, and outcome. J Neurosurg. May 1993;78(5):767-75. [Medline].
  110. Dohrmann GJ, Farwell JR, Flannery JT. Glioblastoma multiforme in      children. J Neurosurg. Apr 1976;44(4):442-8. [Medline].
  111. Dropcho EJ, Soong SJ. The prognostic impact of prior low grade      histology in patients with anaplastic gliomas: a case-control study. Neurology.      Sep 1996;47(3):684-90. [Medline].
  112. Duerr EM, Rollbrocker B, Hayashi Y, et al. PTEN mutations in gliomas      and glioneuronal tumors. Oncogene. Apr 30 1998;16(17):2259-64. [Medline].
  113. Ekstrand AJ, Sugawa N, James CD, Collins VP. Amplified and rearranged      epidermal growth factor receptor genes in human glioblastomas reveal      deletions of sequences encoding portions of the N- and/or C-terminal      tails. Proc Natl Acad Sci U S A. May 15 1992;89(10):4309-13. [Medline]. [Full Text].
  114. Giordana MT, Bradac GB, Pagni CA, et al. Primary diffuse      leptomeningeal gliomatosis with anaplastic features. Acta Neurochir      (Wien). 1995;132(1-3):154-9. [Medline].
  115. Glantz MJ, Hoffman JM, Coleman RE, et al. Identification of early      recurrence of primary central nervous system tumors by      [18F]fluorodeoxyglucose positron emission tomography. Ann Neurol.      Apr 1991;29(4):347-55. [Medline].
  116. Greenberg MS. Tumor: Primary brain tumors. In: Handbook of      Neurosurgery. 4th ed. Lakeland, Fla: Greenberg Graphics; 1997:244-311.
  117. Herholz K, Pietrzyk U, Voges J, et al. Correlation of glucose      consumption and tumor cell density in astrocytomas. A stereotactic PET      study. J Neurosurg. Dec 1993;79(6):853-8. [Medline].
  118. Jafri NF, Clarke JL, Weinberg V, Barani IJ, Cha S. Relationship of      glioblastoma multiforme to the subventricular zone is associated with      survival. Neuro Oncol. Jan 2013;15(1):91-6. [Medline]. [Full Text].
  119. Kleihues P, Burger PC, Cavenee WK. Glioblastoma. In: WHO      Classification: Pathology and genetics of tumors of the nervous system.      ed. Lyon, France: International Agency for Research on Cancers;      1997:16-24.
  120. Korkolopoulou P, Christodoulou P, Kouzelis K, Hadjiyannakis M, Priftis      A, Stamoulis G, et al. MDM2 and p53 expression in gliomas: a multivariate      survival analysis including proliferation markers and epidermal growth      factor receptor. Br J Cancer. 1997;75(9):1269-78. [Medline]. [Full Text].
  121. Lang FF, Miller DC, Koslow M, Newcomb EW. Pathways leading to      glioblastoma multiforme: a molecular analysis of genetic alterations in 65      astrocytic tumors. J Neurosurg. Sep 1994;81(3):427-36. [Medline].
  122. Lantos PL, VandenBerg SR, Kleihues P. Tumors of the nervous system.      In: Graham DI, Lantos PL, eds. Greenfield's Neuropathology. 6th ed.      London, England: Edward Arnold; 1998:583-879.
  123. Li J, Wang M, Won M, et al. Validation and simplification of the      Radiation Therapy Oncology Group recursive partitioning analysis      classification for glioblastoma. Int J Radiat Oncol Biol Phys. Nov      1 2011;81(3):623-30. [Medline].
  124. Libermann TA, Nusbaum HR, Razon N, et al. Amplification, enhanced      expression and possible rearrangement of EGF receptor gene in primary      human brain tumours of glial origin. Nature. Jan 10-18      1985;313(5998):144-7. [Medline].
  125. Macdonald DR, Cascino TL, Schold SC, Cairncross JG. Response criteria      for phase II studies of supratentorial malignant glioma. J Clin Oncol.      Jul 1990;8(7):1277-80. [Medline].
  126. Mahaley MS, Mettlin C, Natarajan N, et al. National survey of patterns      of care for brain-tumor patients. J Neurosurg. Dec      1989;71(6):826-36. [Medline].
  127. Newcomb EW, Cohen H, Lee SR, et al. Survival of patients with      glioblastoma multiforme is not influenced by altered expression of p16,      p53, EGFR, MDM2 or Bcl-2 genes. Brain Pathol. Oct 1998;8(4):655-67.      [Medline].
  128. Nigro JM, Baker SJ, Preisinger AC, et al. Mutations in the p53 gene      occur in diverse human tumour types. Nature. Dec 7      1989;342(6250):705-8. [Medline].
  129. Ohgaki H, Kleihues P. Genetic pathways to primary and secondary      glioblastoma. Am J Pathol. May 2007;170(5):1445-53. [Medline]. [Full Text].
  130. Ohgaki H, Kleihues P. Population-based studies on incidence, survival      rates, and genetic alterations in astrocytic and oligodendroglial gliomas.      J Neuropathol Exp Neurol. Jun 2005;64(6):479-89. [Medline].
  131. Ohgaki H, Watanabe K, Peraud A, et al. A case history of glioma      progression. Acta Neuropathol (Berl). May 1999;97(5):525-32. [Medline].
  132. Patronas NJ, Di Chiro G, Kufta C, et al. Prediction of survival in      glioma patients by means of positron emission tomography. J Neurosurg.      Jun 1985;62(6):816-22. [Medline].
  133. Pelloski CE, Ballman KV, Furth AF, Zhang L, Lin E, Sulman EP, et al.      Epidermal growth factor receptor variant III status defines clinically      distinct subtypes of glioblastoma. J Clin Oncol. Jun 1      2007;25(16):2288-94. [Medline]. [Full Text].
  134. Rich JN, Hans C, Jones B, et al. Gene expression profiling and genetic      markers in glioblastoma survival. Cancer Res. May 15      2005;65(10):4051-8. [Medline]. [Full Text].
  135. Shiras A, Bhosale A, Shepal V, Shukla R, Baburao VS, Prabhakara K, et      al. A unique model system for tumor progression in GBM comprising two      developed human neuro-epithelial cell lines with differential transforming      potential and coexpressing neuronal and glial markers. Neoplasia.      Nov-Dec 2003;5(6):520-32. [Medline]. [Full Text].
  136. van den Bent MJ, Hegi ME, Stupp R. Recent developments in the use of      chemotherapy in brain tumours. Eur J Cancer. Mar 2006;42(5):582-8. [Medline].
  137. von Deimling A, Louis DN, von Ammon K, et al. Association of epidermal      growth factor receptor gene amplification with loss of chromosome 10 in      human glioblastoma multiforme. J Neurosurg. Aug 1992;77(2):295-301.      [Medline].
  138. Watanabe K, Sato K, Biernat W, et al. Incidence and timing of p53      mutations during astrocytoma progression in patients with multiple biopsies.      Clin Cancer Res. Apr 1997;3(4):523-30. [Medline].
  139. Watanabe K, Tachibana O, Sata K, et al. Overexpression of the EGF      receptor and p53 mutations are mutually exclusive in the evolution of      primary and secondary glioblastomas. Brain Pathol. Jul      1996;6(3):217-23; discussion 23-4. [Medline].
  140. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med.      Jul 31 2008;359(5):492-507. [Medline]. [Full Text].
  141. Winger MJ, Macdonald DR, Cairncross JG. Supratentorial anaplastic      gliomas in adults. The prognostic importance of extent of resection and      prior low-grade glioma. J Neurosurg. Oct 1989;71(4):487-93. [Medline].
  142. Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS,      et al. Structural alterations of the epidermal growth factor receptor gene      in human gliomas. Proc Natl Acad Sci U S A. Apr 1      1992;89(7):2965-9. [Medline]. [Full Text].
  143. Wood JR, Green SB, Shapiro WR. The prognostic importance of tumor size      in malignant gliomas: a computed tomographic scan study by the Brain Tumor      Cooperative Group. J Clin Oncol. Feb 1988;6(2):338-43. [Medline].
  144. Zauberman A, Flusberg D, Haupt Y, Barak Y, Oren M. A functional      p53-responsive intronic promoter is contained within the human mdm2 gene. Nucleic      Acids Res. Jul 25 1995;23(14):2584-92. [Medline]. [Full Text].
  145. Zulch KJ. Brain Tumors: their biology and pathology. 3rd ed.      Berlin, Germany: Springer-Verlag; 1986.




Autoria e outros dados (tags, etc)

por cyto às 20:47

Terça-feira, 27.05.14

Perspectives on reprograming cancer-associated dendritic cells for anti-tumor therapies

Front. Oncol., 07 April 2014 | doi: 10.3389/fonc.2014.00072

Perspectives on reprograming cancer-associated dendritic cells for anti-tumor therapies

                        Fabian Benencia1,2,3,4*, Maria Muccioli4 and Mawadda Alnaeeli2,5

  • 1Biomedical Engineering Program, Russ College of Engineering and Technology, Ohio University, Athens, OH, USA
  • 2Diabetes Institute, Ohio University, Athens, OH, USA
  • 3Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
  • 4Molecular and Cell Biology Program, Ohio University, Athens, OH, USA
  • 5Department of Biological Sciences, Ohio University, Athens, OH, USA

In recent years, the relevance of the tumor microenvironment (TME) in the progression of cancer has gained considerable attention. It has been shown that the TME is capable of inactivating various components of the immune system responsible for tumor clearance, thus favoring cancer cell growth and tumor metastasis. In particular, effects of the TME on antigen-presenting cells, such as dendritic cells (DCs) include rendering these cells unable to promote specific immune responses or transform them into suppressive cells capable of inducing regulatory T cells. In addition, under the influence of the TME, DCs can produce growth factors that induce neovascularization, therefore further contributing to tumor development. Interestingly, cancer-associated DCs harbor tumor antigens and thus have the potential to become anti-tumor vaccines in situ if properly reactivated. This perspective article provides an overview of the scientific background and experimental basis for reprograming cancer-associated DCs in situ to generate anti-tumor immune responses.


Tumors are composed of cancerous cells and non-cancerous cells such as fibroblasts, endothelial cells, and infiltrating leukocytes. Together with non-cellular components (extracellular matrix proteins), this constitutes the tumor microenvironment (TME). The non-cellular components often support the growth and survival of cancer cells. Moreover, cancer cell growth and survival are influenced by the activation state and responses of infiltrating leukocytes. In particular, leukocytes such as macrophages, T cells, myeloid-derived suppressor cells (MDSCs), and dendritic cells (DCs) have all been shown to participate in tumor development in various settings. For instance, on one hand, chronic inflammation, either induced by infection (e.g., H. pylori, Hepatitis virus) or irritants (tobacco smoke, asbestos) constitutes an important risk factor for the development of cancer (14). On the contrary, tumor-infiltrating leukocytes, such as cytotoxic T cells can mediate an immune response against the tumor by recognizing tumor antigens and attacking tumor cells in a specific manner (5, 6). Indeed, this is the basis of cancer immunotherapies. Thus, immunosuppression is also able to support tumor growth. Furthermore, existing evidence supports that adaptive immune response influences the behavior of human tumors. In situ analysis of tumor-infiltrating immune cells may therefore be a valuable prognostic tool in the treatment of colorectal cancer and possibly other malignancies (7).

There are two main ways in which leukocytes can collaborate with tumor development (i.e., pro-tumorigenic processes): suppression of the anti-tumor immune response and production of growth factors. In particular, cancer-associated immune cells such as regulatory T cells (Treg) or MDSCs have been shown to directly inhibit the activity of specific anti-tumor cytotoxic T cell responses (8, 9). In addition, infiltrating inflammatory cells secrete a diverse repertoire of growth factors that can enhance cancer cell proliferation and survival directly [e.g., interleukin (IL)-6 and TNF-α] or by stimulating angiogenesis (1017). In this context, DCs are very interesting players, especially taking into account their ability to participate in both pro-tumorigenic and anti-tumor processes. For more detailed reviews on DCs in cancer biology and immunotherapy, please refer to Ref. (1821).

Immune Properties of Dendritic Cells

Dendritic cells scan peripheral tissues where they recognize, take up, and process antigens and then migrate to lymphoid organs to present antigenic peptides to naive T lymphocytes in the context of major histocompatibility molecules (MHC) (13, 2224). During this process, DCs become activated, upregulating MHC class II molecules and co-stimulatory molecules such as CD40, CD80, CD86, or OX40L. Upon activation, DCs typically show a decrease in their phagocytic capability, an augment in their efficacy to present processed antigens in the context of MHC molecules, and consequently an improved capability to activate T cells. Through the expression of both MHC class I and II molecules, DCs are able to activate antigen-specific CD8+ T cytotoxic and CD4+ T helper lymphocytes respectively (2527). By means of various signals, DCs do not only activate specific T cells, but also drive their differentiation into distinct subsets and even can imprint a migration pattern on these cells toward particular organs or tissues (28). Depending on the stimulus and tissue microenvironment, activated DCs produce an array of cytokines including IL-6, IL-12, IFN-γ, and TNF-α, in addition to several chemokines such as CCL2, CCL3, and CCL5 (29), and thus can play a critical role in shaping the cytokine milieu and leukocyte recruitment and activation.

Dendritic cells are a diverse group of professional antigen-presenting cells that link innate and adaptive immune systems. Several distinct subsets of DCs have been identified and broadly subcategorized into conventional (cDCs) and plasmacytoid (pDCs) (30). Each subset is considered functionally unique, with different TLR expression profiles, response, and outcomes leading to activation of alternate branches of the immune system. For instance, mDC express TLR-2, -4, and -5 whose activation induces IL-12 and IL-6 production. In contrast, pDCs express TLR-7 and -9 ligation resulting in a strong type-I interferon namely IFN-α and are critical players in the innate anti-viral response (31). Such subset differences may have critical implications in success or failure of reprograming cancer-associated DCs in situ to generate anti-tumor immune responses.

Characteristics of Cancer-Associated DCs

The presence of DCs in the stroma of various types of cancer has been well-established (11, 3235). Interestingly, often these cells do not exert a positive immune influence but act as co-conspirators of tumor growth by inducing regulatory T cell expansion, or directly suppressing T cell responses. These cancer-associated DCs, albeit carrying tumor antigen as we have previously shown (36), express low levels of co-stimulatory molecules (37). Thus, upon encounter with antigen-specific naïve T cells, they can induce an anergic state in these cells favoring tumor immune-escape. This DC phenotype could be caused by products generated by cancer cells or non-cancer cells present in the microenvironment of the tumor. For example, tumor-associated cytokines such as vascular endothelial growth factor (VEGF), IL-10, prostaglandin E-2 (PGE2), and transforming growth factor (TGF)-β can profoundly affect the nature of DCs (38, 39). Indeed, we have previously shown that DCs that were co-opted by the mouse tumors upon injection, acquired angiogenic properties (10). As we have recently reported, the particular characteristics of the extracellular matrix components can also shape the immune properties of these cells (40). Importantly, tumor factors usually exert a systemic effect as previously described (41, 42). For example, it has been demonstrated that VEGF induces a potent systemic effect on both primary and secondary immune organs (41). Therefore, DCs at lymphoid organs can be influenced by tumor factors and/or immunosuppressive leukocytes that can affect their properties (43).

Cancer-associated DCs can also contribute to tumor development by producing factors that promote angiogenesis (44). In the mouse model, we have recently shown that myeloid DCs are able to produce an array of angiogenic molecules in vitro, including matrix metalloproteases, VEGF, angiogenin, heparanase, and basic fibroblast growth factors among others (40). We have also previously shown that DC precursors participate in tumor progression and angiogenesis in a mouse model of ovarian cancer (10). Moreover, depletion of cancer-associated DCs in vivo was found to reduce tumor growth and decrease angiogenesis in a mouse model of ovarian cancer (45, 46). Not surprisingly, in the same way DCs contributed to angiogenesis in the Lewis lung carcinoma model (47). In humans, cancer-associated DCs have also been shown to produce angiogenic factors and promote neovascularization in the TME (11, 35, 48).

Collectively, these studies provide ample evidence in support of tumors’ capability to reprogram the biology of DCs, inducing them to exert immunosuppressive or angiogenic effects, favoring tumor growth and survival.

Reprograming Cancer-Associated DC to Induce Anti-Tumor Immunity

The “immune paralysis” of cancer-associated DCs can be overcome in an experimental setting by blocking IL-10R while simultaneously activating specific pattern recognition receptors (PRRs). Upon treatment, the cells regain their ability to activate antigen-specific T cells (10, 49, 50). Considering that cancer-associated DCs can harbor tumor antigen, a compelling strategy would be to reprogram them in vivo. Thus, these cells will be transformed into effective antigen-presenting cells capable of promoting anti-tumor immunity and combating tumor growth.

In the mouse model, targeted delivery of antigens to DCs via specific molecules expressed on the DC surface has been investigated. For example, antibodies specific to these surface molecules have been fused with antigens in order to induce an immune response mediated by specific DC populations. Targeting ovalbumin to CD205 and 33D1 molecules on the surface of DCs in vivo helped to markedly enhance and qualitatively direct the antigen-presenting properties of CD8+ and CD8− DC subpopulations of splenic DCs. This difference in antigen processing is suggested to be intrinsic to the DC subsets in association with increased expression of proteins involved in MHC processing (51). Likewise, immunization strategies have been designed using antibody–tumor antigen fusion proteins targeting DCs via CD205 (52) or CD11c (53). In addition, antibodies specific to DC surface molecules have been used to coat liposomes or nanoparticles to deliver antigens and inflammatory compounds to DCs in situ in a mouse model (54) or to target human DCs (55). Other strategies involve the design of antigen-carrying lentiviral vectors capable of selectively binding to DCs (56).

Evidence that phenotype of cancer-associated DCs can be altered in vivo is found in human clinical trials. Anti-tumor therapies using anti-VEFG antibodies, alone or in combination with other drugs, have been evaluated in preclinical and clinical studies (5760). Interestingly, tumor patients treated with anti-VEGF antibody showed decreased levels of immunosuppressive DCs (61). Similarly, it has been demonstrated that the endothelial cell-produced antiangiogenic cytokine vascular endothelial growth inhibitor induces DC maturation (62). On the other hand, further highlighting the complexity of DC modulation by the TME, cancer patients treated with VEGF-trap [a fusion protein of extracellular domains of VEGF receptor(R)-1 and -2, which can capture all VEGF isoforms] did not show a significant improvement in their immune response, despite a significant increase in the proportion of activated DCs (63). Thus, therapies directly focused on targeting DC in vivo must be designed to enhance this effect.

Pioneering research has been performed by the Conejo-Garcia group aimed at reprograming cancer-associated DCs in order to generate a vaccine in situ (64). For these studies, a mouse model of ovarian cancer was used. Ovarian cancer characteristically exhibits metastasis within the peritoneal cavity, and is thus an excellent target for localized immunotherapies (65). In a mouse model of ovarian cancer ascites, the group showed that intraperitoneal co-delivery of TLR3 ligands and CD40-activating antibodies induced up-regulation of co-stimulatory molecules in cancer-associated DCs together with increased antigen presentation and anti-tumor T cell response (66). A more focused strategy involved directly targeting cancer-associated DCs with nanoparticles carrying pre-miRNA oligonucleotides that were able to reprogram these immunosuppressive cells into promoters of anti-tumor immune response by increasing miR-155 activity in the targeted cells (67). In addition, similar results were obtained when cancer-associated DCs were targeted by linear polyethylenimine nanoparticles encapsulating non-viral siRNA. These particles were avidly engulfed by the cells, activating them through TLR5 and inducing a potent anti-tumor immune response (64). Lastly, an alternative procedure to activate cancer-associated DCs in situ was recently reported. As described by Baird et al. (68), intratumoral administration of an avirulent strain of Toxoplasma gondii in a model of ovarian cancer specifically infected cancer-associated DCs (68). These cells reversed their immunosuppressive status and were able to activate a robust anti-tumor T cell response. Finally, future studies will also need to focus on enhancing the migratory capability of reprogramed DCs toward lymph nodes in order to generate a robust T cell response.


Dendritic cells comprise a population of leukocytes with the capability of activating specific immune responses to promote immunity or induce tolerance. They capture, process, and present antigens thereby activating T cells that carry cognate receptors for these presented antigens. Consequently, DCs serve vital function in initiating adaptive immunity and orchestrating the immune response outcome. The TME can exert undesirable effects on DCs by either rendering them unable to promote specific immune responses, or transforming them into suppressive cells capable of inducing regulatory T cells collectively creating significant obstacles and challenges in cancer immunotherapy. However, ample evidence supports the feasibility to overcome the immune paralysis of cancer-associated DCs. Herein, we summarized our perspective overview of cancer-associated DCs reprograming in situ to generate anti-tumor immune responses that will orchestrate a desirable outcome by halting tumor growth and survival. Knowledge of TME, DC biology, and DC response to specific signals will promote the discovery of new strategies for the reprograming of cancer-associated DCs. The fact that cancer-associated DCs harbor tumor antigens also opens up the tantalizing possibility of reprograming these cells in vivo, thus inducing a de facto patient personalized vaccine. Using innovative approaches to target DCs is vital, and these types of studies will be important in revealing the most effective strategies to overcome setbacks that troubled the field for so long, subsequently helping advance anti-tumor immunotherapy.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This work was supported in part by the NIH under Grant R15 CA137499-01 (Fabian Benencia), the RSAC grant (RP1206) from the Heritage College of Osteopathic Medicine, OU (Fabian Benencia) and a SEA grant from Ohio University (Maria Muccioli). Maria Muccioli was supported by the MCB program (OU).


1. Ruegg C. Leukocytes, inflammation, and angiogenesis in cancer: fatal attractions. J Leukoc Biol (2006) 80:682–4. doi: 10.1189/jlb.0606394

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

2. Peek RM Jr, Crabtree JE. Helicobacter infection and gastric neoplasia. J Pathol (2006) 208:233–48. doi:10.1002/path.1868

CrossRef Full Text

3. Szabo E, Paska C, Kaposi Novak P, Schaff Z, Kiss A. Similarities and differences in hepatitis B and C virus induced hepatocarcinogenesis. Pathol Oncol Res (2004) 10:5–11. doi:10.1007/BF02893401

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

4. Williams MD, Sandler AB. The epidemiology of lung cancer. Cancer Treat Res (2001) 105:31–52. doi:10.1007/978-1-4615-1589-0_2

CrossRef Full Text

5. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med (2003) 348:203–13. doi:10.1056/NEJMoa020177

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

6. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell (2010) 140:883–99. doi:10.1016/j.cell.2010.01.025

CrossRef Full Text

7. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science (2006) 313:1960–4. doi:10.1126/science.1129139

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

8. Condamine T, Gabrilovich DI. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol (2011) 32:19–25. doi:10.1016/

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

9. Teng MW, Ritchie DS, Neeson P, Smyth MJ. Biology and clinical observations of regulatory T cells in cancer immunology. Curr Top Microbiol Immunol (2011) 344:61–95. doi:10.1007/82_2010_50

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

10. Conejo-Garcia JR, Benencia F, Courreges MC, Kang E, Mohamed-Hadley A, Buckanovich RJ, et al. Tumor-infiltrating dendritic cell precursors recruited by a beta-defensin contribute to vasculogenesis under the influence of Vegf-A. Nat Med (2004) 10:950–8. doi:10.1038/nm1097

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

11. Curiel TJ, Cheng P, Mottram P, Alvarez X, Moons L, Evdemon-Hogan M, et al. Dendritic cell subsets differentially regulate angiogenesis in human ovarian cancer. Cancer Res (2004) 64:5535–8. doi:10.1158/0008-5472.CAN-04-1272

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

12. Ribatti D. The paracrine role of Tie-2-expressing monocytes in tumor angiogenesis. Stem Cells Dev (2009) 18:703–6. doi:10.1089/scd.2008.0385

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

13. Riboldi E, Musso T, Moroni E, Urbinati C, Bernasconi S, Rusnati M, et al. Cutting edge: proangiogenic properties of alternatively activated dendritic cells. J Immunol (2005) 175:2788–92.

Pubmed Abstract | Pubmed Full Text

14. Conejo-Garcia JR, Buckanovich RJ, Benencia F, Courreges MC, Rubin SC, Carroll RG, et al. Vascular leukocytes contribute to tumor vascularization. Blood (2005) 105:679–81. doi:10.1182/blood-2004-05-1906

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

15. Gough PJ, Gomez IG, Wille PT, Raines EW. Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice. J Clin Invest (2006) 116:59–69. doi:10.1172/JCI25074

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

16. Luo JL, Maeda S, Hsu LC, Yagita H, Karin M. Inhibition of NF-kappaB in cancer cells converts inflammation-induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression. Cancer Cell (2004) 6:297–305. doi:10.1016/j.ccr.2004.08.012

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

17. Yang H, Bocchetta M, Kroczynska B, Elmishad AG, Chen Y, Liu Z, et al. TNF-alpha inhibits asbestos-induced cytotoxicity via a NF-kappaB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis. Proc Natl Acad Sci U S A (2006) 103:10397–402. doi:10.1073/pnas.0604008103

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

18. Schuler G. Dendritic cells in cancer immunotherapy. Eur J Immunol (2010) 40:2123–30. doi:10.1002/eji.201040630

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

19. Steinman RM, Banchereau J. Taking dendritic cells into medicine. Nature (2007) 449:419–26. doi:10.1038/nature06175

CrossRef Full Text

20. Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer (2012) 12:265–77. doi:10.1038/nrc3258

CrossRef Full Text

21. Palucka K, Ueno H, Roberts L, Fay J, Banchereau J. Dendritic cell subsets as vectors and targets for improved cancer therapy. Curr Top Microbiol Immunol (2011) 344:173–92. doi:10.1007/82_2010_48

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

22. Timmerman JM, Levy R. Dendritic cell vaccines for cancer immunotherapy. Annu Rev Med (1999) 50:507–29. doi:10.1146/

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

23. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature (1998) 392:245–52. doi:10.1038/32588

CrossRef Full Text

24. Palucka K, Banchereau J. Dendritic-cell-based therapeutic cancer vaccines. Immunity (2013) 39:38–48. doi:10.1016/j.immuni.2013.07.004

CrossRef Full Text

25. Kapsenberg ML. Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol (2003) 3:984–93. doi:10.1038/nri1246

CrossRef Full Text

26. Kadowaki N. Dendritic cells: a conductor of T cell differentiation. Allergol Int (2007) 56:193–9. doi:10.2332/allergolint.R-07-146

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

27. Cahalan MD, Parker I. Close encounters of the first and second kind: T-DC and T-B interactions in the lymph node. Semin Immunol (2005) 17:442–51. doi:10.1016/j.smim.2005.09.001

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

28. Kalinski P. Dendritic cells in immunotherapy of established cancer: roles of signals 1, 2, 3 and 4. Curr Opin Investig Drugs (2009) 10:526–35.

Pubmed Abstract | Pubmed Full Text

29. Morelli AE, Zahorchak AF, Larregina AT, Colvin BL, Logar AJ, Takayama T, et al. Cytokine production by mouse myeloid dendritic cells in relation to differentiation and terminal maturation induced by lipopolysaccharide or CD40 ligation. Blood (2001) 98:1512–23. doi:10.1182/blood.V98.5.1512

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

30. Shortman K, Liu YJ. Mouse and human dendritic cell subtypes. Nat Rev Immunol (2002) 2:151–61. doi:10.1038/nri746

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

31. Kaisho T, Akira S. Regulation of dendritic cell function through toll-like receptors. Curr Mol Med (2003) 3:759–71. doi:10.2174/1566524033479366

CrossRef Full Text

32. Baleeiro RB, Anselmo LB, Soares FA, Pinto CA, Ramos O, Gross JL, et al. High frequency of immature dendritic cells and altered in situ production of interleukin-4 and tumor necrosis factor-alpha in lung cancer. Cancer Immunol Immunother (2008) 57:1335–45. doi:10.1007/s00262-008-0468-7

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

33. Shurin MR, Shurin GV, Lokshin A, Yurkovetsky ZR, Gutkin DW, Chatta G, et al. Intratumoral cytokines/chemokines/growth factors and tumor infiltrating dendritic cells: friends or enemies? Cancer Metastasis Rev (2006) 25:333–56. doi:10.1007/s10555-006-9010-6

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

34. Whiteside TL. The role of immune cells in the tumor microenvironment. Cancer Treat Res (2006) 130:103–24. doi:10.1007/0-387-26283-0_5

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

35. Mantovani A, Sozzani S, Locati M, Schioppa T, Saccani A, Allavena P, et al. Infiltration of tumours by macrophages and dendritic cells: tumour-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Novartis Found Symp (2004) 256:137–45; discussion 146–138, 259–169. doi:10.1002/0470856734.ch10

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

36. Benencia F, Courreges MC, Fraser NW, Coukos G. Herpes virus oncolytic therapy reverses tumor immune dysfunction and facilitates tumor antigen presentation. Cancer Biol Ther (2008) 7:1194–205. doi:10.4161/cbt.7.8.6216

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

37. Gabrilovich DI, Ishida T, Nadaf S, Ohm JE, Carbone DP. Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin Cancer Res (1999) 5:2963–70.

38. Liu K, Victora GD, Schwickert TA, Guermonprez P, Meredith MM, Yao K, et al. In vivo analysis of dendritic cell development and homeostasis. Science (2009) 324:392–7. doi:10.1126/science.1170540

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

39. Cubillos-Ruiz JR, Rutkowski M, Conejo-Garcia JR. Blocking ovarian cancer progression by targeting tumor microenvironmental leukocytes. Cell Cycle (2010) 9:260–8. doi:10.4161/cc.9.2.10430

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

40. Sprague L, Muccioli M, Pate M, Meles E, McGinty J, Nandigam H, et al. The interplay between surfaces and soluble factors define the immunologic and angiogenic properties of myeloid dendritic cells. BMC Immunol (2011) 12:35. doi:10.1186/1471-2172-12-35

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

41. Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med (1996) 2:1096–103. doi:10.1038/nm1096-1096

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

42. McAllister SS, Gifford AM, Greiner AL, Kelleher SP, Saelzler MP, Ince TA, et al. Systemic endocrine instigation of indolent tumor growth requires osteopontin. Cell (2008) 133:994–1005. doi:10.1016/j.cell.2008.04.045

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

43. Sharma MD, Baban B, Chandler P, Hou DY, Singh N, Yagita H, et al. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J Clin Invest (2007) 117:2570–82. doi:10.1172/JCI31911

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

44. Sozzani S, Rusnati M, Riboldi E, Mitola S, Presta M. Dendritic cell-endothelial cell cross-talk in angiogenesis. Trends Immunol (2007) 28:385–92. doi:10.1016/

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

45. Bak SP, Walters JJ, Takeya M, Conejo-Garcia JR, Berwin BL. Scavenger receptor-A-targeted leukocyte depletion inhibits peritoneal ovarian tumor progression. Cancer Res (2007) 67:4783–9. doi:10.1158/0008-5472.CAN-06-4410

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

46. Huarte E, Cubillos-Ruiz JR, Nesbeth YC, Scarlett UK, Martinez DG, Buckanovich RJ, et al. Depletion of dendritic cells delays ovarian cancer progression by boosting antitumor immunity. Cancer Res (2008) 68:7684–91. doi:10.1158/0008-5472.CAN-08-1167

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

47. Fainaru O, Adini A, Benny O, Adini I, Short S, Bazinet L, et al. Dendritic cells support angiogenesis and promote lesion growth in a murine model of endometriosis. FASEB J (2008) 22:522–9. doi:10.1096/fj.07-9034com

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

48. Coukos G, Benencia F, Buckanovich RJ, Conejo-Garcia JR. The role of dendritic cell precursors in tumour vasculogenesis. Br J Cancer (2005) 92:1182–7. doi:10.1038/sj.bjc.6602476

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

49. Vicari AP, Chiodoni C, Vaure C, Ait-Yahia S, Dercamp C, Matsos F, et al. Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J Exp Med (2002) 196:541–9. doi:10.1084/jem.20020732

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

50. Osterbur J, Sprague L, Muccioli M, Pate M, Mansfield K, McGinty J, et al. Adhesion to substrates induces dendritic cell endothelization and decreases immunological response. Immunobiology (2013) 218:64–75. doi:10.1016/j.imbio.2012.02.003

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

51. Dudziak D, Kamphorst AO, Heidkamp GF, Buchholz VR, Trumpfheller C, Yamazaki S, et al. Differential antigen processing by dendritic cell subsets in vivo. Science (2007) 315:107–11. doi:10.1126/science.1136080

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

52. Wang B, Kuroiwa JM, He LZ, Charalambous A, Keler T, Steinman RM. The human cancer antigen mesothelin is more efficiently presented to the mouse immune system when targeted to the DEC-205/CD205 receptor on dendritic cells. Ann N Y Acad Sci (2009) 1174:6–17. doi:10.1111/j.1749-6632.2009.04933.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

53. Wei H, Wang S, Zhang D, Hou S, Qian W, Li B, et al. Targeted delivery of tumor antigens to activated dendritic cells via CD11c molecules induces potent antitumor immunity in mice. Clin Cancer Res (2009) 15:4612–21. doi:10.1158/1078-0432.CCR-08-3321

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

54. Faham A, Altin JG. Antigen-containing liposomes engrafted with flagellin-related peptides are effective vaccines that can induce potent antitumor immunity and immunotherapeutic effect. J Immunol (2010) 185:1744–54. doi:10.4049/jimmunol.1000027

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

55. Cruz LJ, Tacken PJ, Fokkink R, Joosten B, Stuart MC, Albericio F, et al. Targeted PLGA nano but not microparticles specifically deliver antigen to human dendritic cells via DC-SIGN in vitro. J Control Release (2010) 144:118–26. doi:10.1016/j.jconrel.2010.02.013

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

56. Hu B, Dai B, Wang P. Vaccines delivered by integration-deficient lentiviral vectors targeting dendritic cells induces strong antigen-specific immunity. Vaccine (2010) 28:6675–83. doi:10.1016/j.vaccine.2010.08.012

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

57. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev (2004) 25:581–611. doi:10.1210/er.2003-0027

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

58. Ferrara N. VEGF as a therapeutic target in cancer. Oncology (2005) 69(Suppl 3):11–6. doi:10.1159/000088479

CrossRef Full Text

59. Kenny PA, Lee GY, Bissell MJ. Targeting the tumor microenvironment. Front Biosci (2007) 12:3468–74. doi:10.2741/2327

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

60. Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol (2005) 23:1028–43. doi:10.1200/JCO.2005.01.186

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

61. Osada T, Chong G, Tansik R, Hong T, Spector N, Kumar R, et al. The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients. Cancer Immunol Immunother (2008) 57:1115–24. doi:10.1007/s00262-007-0441-x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

62. Tian F, Grimaldo S, Fujita M, Cutts J, Vujanovic NL, Li LY. The endothelial cell-produced antiangiogenic cytokine vascular endothelial growth inhibitor induces dendritic cell maturation. J Immunol (2007) 179:3742–51.

Pubmed Abstract | Pubmed Full Text

63. Fricke I, Mirza N, Dupont J, Lockhart C, Jackson A, Lee JH, et al. Vascular endothelial growth factor-trap overcomes defects in dendritic cell differentiation but does not improve antigen-specific immune responses. Clin Cancer Res (2007) 13:4840–8. doi:10.1158/1078-0432.CCR-07-0409

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

64. Cubillos-Ruiz JR, Engle X, Scarlett UK, Martinez D, Barber A, Elgueta R, et al. Polyethylenimine-based siRNA nanocomplexes reprogram tumor-associated dendritic cells via TLR5 to elicit therapeutic antitumor immunity. J Clin Invest (2009) 119:2231–44. doi:10.1172/JCI37716

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

65. Lengyel E. Ovarian cancer development and metastasis. Am J Pathol (2010) 177:1053–64. doi:10.2353/ajpath.2010.100105

CrossRef Full Text

66. Scarlett UK, Cubillos-Ruiz JR, Nesbeth YC, Martinez DG, Engle X, Gewirtz AT, et al. In situ stimulation of CD40 and Toll-like receptor 3 transforms ovarian cancer-infiltrating dendritic cells from immunosuppressive to immunostimulatory cells. Cancer Res (2009) 69:7329–37. doi:10.1158/0008-5472.CAN-09-0835

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

67. Cubillos-Ruiz JR, Baird JR, Tesone AJ, Rutkowski MR, Scarlett UK, Camposeco-Jacobs AL, et al. Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against ovarian cancer. Cancer Res (2012) 72:1683–93. doi:10.1158/0008-5472.CAN-11-3160

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

68. Baird JR, Fox BA, Sanders KL, Lizotte PH, Cubillos-Ruiz JR, Scarlett UK, et al. Avirulent Toxoplasma gondii generates therapeutic antitumor immunity by reversing immunosuppression in the ovarian cancer microenvironment. Cancer Res (2013) 73:3842–51. doi:10.1158/0008-5472.CAN-12-1974

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Keywords: tumor microenvironment, dendritic cells, vaccines, angiogenesis, targeted delivery

Citation: Benencia F, Muccioli M and Alnaeeli M (2014) Perspectives on reprograming cancer-associated dendritic cells for anti-tumor therapies. Front. Oncol. 4:72. doi: 10.3389/fonc.2014.00072

Received: 10 January 2014; Paper pending published: 26 January 2014;
Accepted: 21 March 2014; Published online: 07 April 2014.

Edited by:

Jozsef Dudas, Innsbruck Medical University, Austria

Reviewed by:

Daniel Benitez-Ribas, CIBERehd, Spain
Nikolaus Romani, Innsbruck Medical University, Austria

Copyright: © 2014 Benencia, Muccioli and Alnaeeli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Fabian Benencia, Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, ARC 202c, Athens, OH 45701, USA e-mail:


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