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Espaço de publicação e discussão sobre oncologia. GBM IMMUNOTHERAPY ONCO-VIRUS ONCOLOGY CANCER CHEMOTHERAPY RADIOTHERAPY


Quarta-feira, 19.08.15

Unituxin (dinutuximab) granted EC Marketing Authorisation for treatment of childhood neuroblastoma

Unituxin (dinutuximab) granted EC Marketing Authorisation for treatment of childhood neuroblastoma

Published on August 17, 2015 at 7:21 AM ·

United Therapeutics Corporation (NASDAQ: UTHR) announced today that the European Commission (EC) has granted Marketing Authorisation for Unituxin™ (dinutuximab) for the treatment of high-risk neuroblastoma in patients aged 12 months to 17 years, who have previously received induction chemotherapy and achieved at least a partial response, followed by myeloablative therapy and autologous stem cell transplantation (ASCT). Unituxin is administered in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and isotretinoin.

Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence in the European Union of approximately 1500 patients, of whom 50% are diagnosed as having high-risk disease.

The European approval was based on demonstration of improved event-free survival (EFS) and overall survival (OS) in a multicenter, open-label, randomized trial (ANBL0032) sponsored by the US National Cancer Institute under a Cooperative Research and Development Agreement with United Therapeutics and conducted by the Children's Oncology Group (COG).

Trial design and results

The trial randomized (1:1) 226 patients to either the Unituxin/13-cis-retinoic acid (RA) arm or the RA alone arm. Patients in each arm received six cycles of treatment. The Unituxin/RA arm consisted of Unituxin in combination with granulocyte macrophage-colony stimulating factor and RA (cycles 1, 3, and 5), Unituxin in combination with interleukin-2 and RA (cycles 2 and 4), and RA (cycle 6). Patients were 11 months to 15 years of age (median age 3.8 years).

The major efficacy outcome measure was investigator-assessed EFS, defined as the time from randomization to the first occurrence of relapse, progressive disease, secondary malignancy or death. The primary intent-to-treat analysis found an improvement in EFS associated with dinutuximab immunotherapy plus isotretinoin as compared to isotretinoin alone. The two-year estimates of EFS were 66% among subjects receiving dinutuximab immunotherapy plus isotretinoin as compared with 48% in subjects receiving isotretinoin alone (log-rank test p = 0.033) although this difference did not reach formal statistical significance according to the pre-specified plan for interim analyses. In addition, OS was evaluated with 3 years of follow-up after the EFS analysis as a secondary endpoint with a significant improvement observed among ITT subjects randomly allocated to receive dinutuximab immunotherapy plus isotretinoin as compared with isotretinoin alone. The three-year estimates of OS were 80% compared with 67% among subjects receiving dinutuximab immunotherapy plus isotretinoin and isotretinoin alone, respectively (log-rank test p = 0.0165). Long-term overall survival was evaluated with five years of follow up after the EFS analysis and continued to demonstrate a survival advantage for patients who received dinutuximab immunotherapy compared to those who received isotretinoin alone. The five-year estimates of OS were 74% for dinutuximab immunotherapy compared to 57% for isotretinoin alone (log-rank test p = 0.030).

Frequently occurring adverse reactions

The most frequently occurring (more than 30% of patients) adverse reactions reported during the neuroblastoma studies were hypotension (67%), pain (66%), hypersensitivity (56%), pyrexia (53%), urticaria (49%), capillary leak syndrome (45%), anaemia (45%), hypokalaemia (41%), platelet count decreased (40%), hyponatraemia (37%), alanine aminotransferase increased (35%), decreased lymphocyte count (34%) and decreased neutrophil count (31%). Additional adverse reactions characteristic of an allergic response were also reported – including anaphylactic reaction (18%) and bronchospasm (4%).

Posology and method of administration

Unituxin is to be administered by intravenous infusion over five courses at a daily dose of 17.5 mg/m2. It is administered on days 4-7 during courses 1, 3 and 5 (each course lasting approximately 24 days) and on days 8-11 during courses 2 and 4 (each course lasting approximately 28 days).

The treatment regimen consists of Unituxin, GM-CSF, IL-2, and isotretinoin, administered over six consecutive courses.

Source:

United Therapeutics Corporation

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por cyto às 12:08

Quarta-feira, 19.08.15

ImmunoCellular signs agreement with FDA for phase 3 registrational trial of cancer immunotherapy ICT-107

GLIOBASTOMA GBM

ImmunoCellular signs agreement with FDA for phase 3 registrational trial of cancer immunotherapy ICT-107

Published on August 13, 2015 at 8:32 AM ·

ImmunoCellular Therapeutics, Ltd. ("ImmunoCellular") (NYSE MKT: IMUC) announced today that it has reached agreement with the US Food and Drug Administration (FDA) on a Special Protocol Assessment (SPA) for the phase 3 registrational trial of its cancer immunotherapy ICT-107 to treat patients with newly diagnosed glioblastoma.

The phase 3 trial is designed as a randomized, double-blind, placebo-controlled study of about 400 HLA-A2 positive subjects, which will be conducted at about 120 sites in the US, Canada and the EU. The primary endpoint in the trial is overall survival, which the FDA and EU regulators have stated is the appropriate endpoint for registrational clinical studies in glioblastoma. Secondary endpoints include progression-free survival and safety, as well as overall survival in the two pre-specified MGMT subgroups. Patient enrollment is anticipated to begin in the late third quarter or early fourth quarter of 2015.

A Special Protocol Assessment is a written agreement between the sponsor company and the FDA on the design, clinical endpoints, size and statistical design of a clinical trial intended to form the primary basis of an efficacy claim in the marketing application, such as a biologic licensing application (BLA) or a new drug application (NDA). Final marketing approval depends upon the safety and efficacy results demonstrated in the phase 3 clinical program.

Andrew Gengos, ImmunoCellular's Chief Executive Officer Commented: "We are pleased to have achieved this important milestone, and think that successful completion of the SPA process adds meaningful validation to the ICT-107 phase 3 program and design, especially the use of the gold standard primary endpoint of overall survival. With this SPA in place, we think that ICT-107 is uniquely positioned in the field of immuno-oncology approaches being tested in glioblastoma. We are making significant progress toward establishing our clinical site network and obtaining the necessary institutional review board approvals. We are confident that we are on track to begin patient enrollment in the late third quarter or early fourth quarter of this year."

Source:

ImmunoCellular Therapeutics, Ltd.

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por cyto às 11:37

Quinta-feira, 23.07.15

Magnetic nanoparticles may hold key to bringing immunotherapy into successful clinical use

 

Magnetic nanoparticles may hold key to bringing immunotherapy into successful clinical use

Published on July 16, 2015 at 1:54 AM

In recent years, researchers have hotly pursued immunotherapy, a promising form of treatment that relies on harnessing and training the body's own immune system to better fight cancer and infection. Now, results of a study led by Johns Hopkins investigators suggests that a device composed of a magnetic column paired with custom-made magnetic nanoparticles may hold a key to bringing immunotherapy into widespread and successful clinical use. A summary of the research, conducted in mouse and human cells, appears online July 14 in the journal ACS Nano.

The Johns Hopkins team focused on training and rapidly multiplying immune system white blood cells known as T cells because of their potential as an effective weapon against cancer, according to Jonathan Schneck, M.D., Ph.D., a professor of pathology, medicine and oncology at the Johns Hopkins University School of Medicine's Institute for Cell Engineering. "The challenge has been to train these cells efficiently enough, and get them to divide fast enough, that we could use them as the basis of a therapy for cancer patients. We've taken a big step toward solving that problem," he says.

In a bid to simplify and streamline immune cellular therapies, Schneck, Karlo Perica, a recent M.D./Ph.D. graduate who worked in Schneck's lab, and others worked with artificial white blood cells. These so-called artificial antigen-presenting cells (aAPCs) were pioneered by Schneck's lab and have shown promise in activating laboratory animals' immune systems to attack cancer cells.

To do that, Perica explains, the aAPCs must interact with naive T cells already present in the body, awaiting instructions about which specific invader to target and battle. The aAPCs bind to specialized receptors on the T cells' surfaces and "present" them with distinctive proteins called antigens. This process activates the T cells to ward off a virus, bacteria or tumor, as well as to make more T cells.

In a previous study in mice, Schneck's team found that naive T-cells activated more effectively when multiple aAPCs bound to different receptors on the cells, and then were exposed to a magnetic field. The magnets brought the aAPCs and their receptors closer together, priming the T cells both to battle the target cancer and divide to form more activated cells.

But naive T cells are as rare in the blood as a "needle in a haystack," Perica says. Because the ultimate goal is to harvest a patient's T cells from a blood sample, then train them and expand their numbers before putting them back into the patient, Schneck's research team looked to magnets as a potential way to separate the naive T cells from others in the blood.

The team mixed blood plasma from mice and, separately, humans with magnetic aAPCs bearing antigens from tumors. They then ran the plasma through a magnetic column. The tumor-fighting T cells bound to aAPCs and stuck to the sides of the column, while other cells washed straight through and were discarded. The magnetic field of the column activated the T cells, which were then washed off into a nourishing broth, or culture, to grow and divide. After one week, their numbers had expanded by an estimated 5,000 to 10,000 times. Because numbers of these cells could be expanded quickly enough to be therapeutically useful, the approach could open the door to individualized immunotherapy treatments that rely on a patient's own cells, says Perica.

Schneck says that the use of naive T cells could make the new technique useful for more patients than another immunotherapy now being tested, which relies on other white blood cells called tumor-infiltrating lymphocytes. Those cells are already "trained" to fight cancer, and researchers have shown some success isolating some of the cells from tumors, inducing them to divide, and then transferring them back into patients. But, Schneck says, not all patients are eligible for this therapy, because not all have tumor-infiltrating lymphocytes. By contrast, all people have naive T cells, so patients with cancer could potentially benefit from the new approach whether or not they have tumor-infiltrating lymphocytes.

"The aAPCs and magnetic column together provide the foundation for simplifying and streamlining the process of generating tumor-specific T cells for use in immunotherapy," says Juan Carlos Varela, M.D., Ph.D., a former member of Schneck's laboratory who is now an assistant professor at the Medical University of South Carolina.

The researchers found that the technique also worked with a mixture of aAPCs bearing multiple antigens, which they say could help combat the problem of tumors mutating to evade the body's defenses. "We get multiple shots on the goal," Schneck says.

While the team initially tested the new method only on cancer antigens, Schneck says it could also potentially work for therapies against chronic infectious diseases, such as HIV. He says that if further testing goes well, clinical trials of the technique could begin within a year and a half.

Source:

Johns Hopkins Medicine

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por cyto às 22:49

Terça-feira, 21.07.15

Scientists elucidate which mechanisms block natural killer cells and how this could be lifted

 

Scientists elucidate which mechanisms block natural killer cells and how this could be lifted

Published on July 8, 2015 at 12:00 PM 

Natural killer cells of the immune system can fend off malignant lymphoma cells and thus are considered a promising therapeutic approach. However, in the direct vicinity of the tumor they lose their effect. Scientists of Helmholtz Zentrum München have now elucidated which mechanisms block the natural killer cells and how this blockade could be lifted. The results were recently published in the European Journal of Immunology.

Natural killer cells (NK cells) are part of the immune system and provide an innate immunity against exogenous and altered endogenous structures. This also appears to apply to tumor cells, against which the body could develop immunity as it does against pathogens, e.g. against viruses. Tumors of the lymph nodes, called lymphomas, are malignant neoplasms that originate from the B cells or T cells of the lymphatic system. B cell lymphomas are very difficult to treat - which is why innovative approaches to therapy are needed. Earlier studies have shown that NK cells have the potential to attack B lymphoma cells and are therefore considered a possible approach to new treatment strategies. In the living organism, however, tumor control by NK cells has been found to be clearly limited.

NK cells become functionally impaired in the tumor microenvironment

In their experiments, the team led by Prof. Dr. Ralph Mocikat of the Institute of Molecular Immunology (IMI) at Helmholtz Zentrum München, found that the NK cells in the immediate vicinity of the tumor showed reduced function. If the cells were placed in a normal environment, their function could be restored within a few hours. This suggests that the factors responsible for the inactivation of the NK cells derive from the tumor itself.

An inflammatory cytokine inactivates NK cells - altered surface molecules block immune activation

The scientists engaged in the research project identified two important tumor-specific factors that are associated with impaired NK cell function. First, a specific inflammatory cytokine (IL-10) is indirectly involved in the inactivation of NK cells. Second, the tumor cells develop protective mechanisms against the NK cells. Thus, the research group showed that specific surface molecules of the tumor cells (NKG2D ligands) which NK cells could bind are down-regulated. Consequently, the NK cells lack an important activation mechanism and are no longer able to carry out cytotoxic activity. Despite the inhibitory strategies of the tumor cells, at an early stage the NK cells produce the cytokine interferon-gamma (IFN-γ), the scientists reported. IFN-γ is essential to activate further immune responses that support the fight against the tumor.

Immunotherapy possible using NK cells - with optimization potential

"Our results show that the transfer of NK cells is a possible strategic option to treat B cell lymphoma. According to our findings, this therapeutic approach can be optimized when transferred NK cells are already activated in vitro prior to their injection, thus bypassing the missing activation potential in the tumor microenvironment. An additional injection of IFN-γ or of antibodies against IL-10 could further support the immune activity," said study leader Mocikat.

Source:

Helmholtz Zentrum München - German Research Center for Environmental Health

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por cyto às 18:20

Terça-feira, 21.07.15

Novel cancer drug candidate developed in Singapore advances into clinical trials

 

Novel cancer drug candidate developed in Singapore advances into clinical trials

Published on July 17, 2015 at 2:01 AM

A made-in-Singapore cancer drug has advanced into clinical trials, charting a milestone in Singapore's biomedical sciences initiative that will go towards improving the lives of cancer patients in Singapore, and worldwide. The Agency for Science, Technology and Research (A*STAR) and Duke-National University of Singapore Graduate Medical School (Duke-NUS) today announced the start of a Phase I clinical trial of novel cancer drug candidate, ETC-159. This is the first publicly-funded drug candidate discovered and developed in Singapore to advance into first-in-human trials, and will target a range of cancers. Overall, cancer is the leading cause of death in Singapore, accounting for 30 percent of deaths in 2013. Cancer has also resulted in 8.2 million deaths world-wide .

ETC-159 targets a number of cancers including colorectal, ovarian and pancreatic cancers which contribute to a significant proportion of Singapore's cancer burden. These cancers are linked to a group of cell signalling pathways known as Wnt signalling, that have been identified to promote cancer growth and spread when elevated or dysregulated. As ETC-159 is an inhibitor of these pathways, it could suppress cancer proliferation and prevent cancer progression.

This drug candidate therefore offers a promising novel and targeted cancer therapy that could shape future cancer therapeutic strategies.

ETC-159 was discovered and developed through a collaboration between A*STAR's Experimental Therapeutics Centre (ETC), Drug Discovery and Development (D3) unit and Duke-NUS since 2009. This was based on the discovery work of Prof David Virshup from Duke-NUS, who has continued to contribute to the development of the drug candidate.

The Phase I clinical trial will evaluate the safety and tolerability of ETC-159 in advanced solid tumours of up to 58 patients. The first patient was dosed on 18 June 2015.

Dr Benjamin Seet, Executive Director of A*STAR's Biomedical Research Council, said, "This breakthrough, which closely follows local company MerLion Pharmaceuticals' recent success in obtaining FDA approval for one of its drugs, marks an inflection point in Singapore's biomedical sciences initiative. Despite the protracted process of drug discovery and development, I am confident that we will see more locally developed drugs in the pipeline being tested and implemented."

Prof Ranga Rama Krishnan, Chairman of the National Medical Research Council (NMRC), Singapore, said, "The first dosing of a drug developed by A*STAR based on a scientific discovery by Duke-NUS researchers, is an example of the terrific and exciting progress that has been made when different entities come together to work on a common problem. This will lead to developing new treatments that can benefit patients in Singapore and beyond."

Prof Alex Matter, Chief Executive Officer of ETC and D3 said, "The discovery and subsequent development of this drug candidate marks a major breakthrough in cancer therapeutics. It also demonstrates the world-class drug discovery and development capabilities we have built up at ETC and D3, complemented by valued partners like Duke-NUS. We will continue to strengthen these capabilities and partnerships to continue developing a pipeline of promising drug candidates and advancing them into the clinic."

Prof David Virshup, inaugural Director of the Programme in Cancer and Stem Cell Biology at Duke-NUS, said, "As the drug candidate provides a targeted cancer therapy, it could potentially minimise side effects and make cancer treatments more bearable for cancer patients. This is a major milestone that was made possible by Singapore's ongoing investment in basic and translational biomedical research to address unmet medical needs. It is fitting that Singaporeans might be the first to benefit from this Singapore-developed drug."

A*STAR's ETC and Duke-NUS are the primary drivers of the discovery and development of the drug candidate. D3 joined the collaboration in 2013 to bring the project forward to achieve proof of concept in humans.

D3 has obtained ethics and regulatory approval for this trial from the SingHealth Centralised Institutional Review Board (CIRB) and the Singapore Health Sciences Authority (HSA) respectively. The first two sites for the trial are the National Cancer Centre Singapore (NCCS) and the National University Hospital (NUH), Singapore. Trial sites in the United States will be opened as the trial progresses.

Source:

Biomedical Sciences Institutes (BMSI)

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por cyto às 18:15

Terça-feira, 21.07.15

Ludwig, CRI launch clinical trials to evaluate immunotherapies for treatment of GBM and solid tumors

 

Ludwig, CRI launch clinical trials to evaluate immunotherapies for treatment of GBM and solid tumors

Published on July 8, 2015 at 11:50 PM 

Ludwig Cancer Research (Ludwig) and the Cancer Research Institute (CRI) have launched clinical trials evaluating an immunotherapy for the treatment of the brain cancer glioblastoma multiforme (GBM), and a combination of immunotherapies for a variety of solid tumors.

The trials are being conducted through the CVC Clinical Trials Network in collaboration with MedImmune, the global biologics research and development arm of AstraZeneca. The CVC Clinical Trials Network -- jointly managed by Ludwig and CRI -- is a coordinated global network of basic and clinical immunologists with expertise in devising and developing immunotherapies for the treatment of cancer. The CVC Clinical Trials Network is led by Jedd Wolchok, Ludwig member and director of the Ludwig Collaborative Laboratory at Memorial Sloan Kettering Cancer Center, as well as associate director of the CRI Scientific Advisory Council.

The GBM trial is a nonrandomized, multicenter Phase 2 trial testing the effects of MedImmune's checkpoint blockade antibody durvalumab (MEDI4736) in patients with GBM, which is the most aggressive and deadly type of adult brain cancer. The study will be conducted using three cohorts of patients - newly diagnosed, recurrent patients and those with tumors which have become unresponsive to standard treatment of care.

"GBM is an inevitably lethal cancer that has so far eluded every therapy in the pharmaceutical arsenal," said Jonathan Skipper, Ludwig's executive director of technology development. "We are hopeful that adding a promising immunotherapy to the treatment regimen for this brain cancer will yield significant benefits for patients who today have a median life expectancy of roughly 15 months, even with the best treatment available."

Durvalumab is an investigational human monoclonal antibody directed against programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumors avoid detection by the immune system. Durvalumab blocks these signals, countering the tumor's immune-evading tactics. The antibody belongs to an emerging class of immunotherapies commonly referred to as checkpoint inhibitors because they remove checks the body places on immune activation.

"Checkpoint inhibitors have deservedly stirred considerable excitement in the oncology community as their application yields notable results against a growing variety of cancers," said Adam Kolom, managing director of CRI's venture fund and Clinical Accelerator, which organizes and provides philanthropic funding and clinical resources for this and other promising immunotherapy trials. "This will be the first time the immunotherapeutic agent will be tested against this difficult-to-treat cancer, and its outcomes are eagerly anticipated by the GBM patient community."

The other trial, which Ludwig and CRI launched in 2013, is a Phase 1 nonrandomized multicenter trial evaluating the combination of durvalumab with another checkpoint blockade therapy (tremelimumab, anti-CTLA-4) for the treatment of a variety of advanced solid tumors including ovarian cancer, non-small cell lung cancer, colorectal cancer, head and neck cancer, cervical cancer and kidney cancer.

Both clinical trials, which are now under way, are part of a larger clinical research program supported by Ludwig and CRI to speed the evaluation of novel cancer immunotherapies, alone or in combination with other cancer drugs. All of the studies will include collection of genetic and immunologic data derived from clinical samples obtained from patients. Such information will provide clues to the impact of the evaluated therapies and suggest refined or new strategies for treating cancer.

Source:

Ludwig Institute for Cancer Research

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por cyto às 18:12

Terça-feira, 21.07.15

Patients' own genetically engineered immune cells show significant success against multiple myeloma

 

Patients' own genetically engineered immune cells show significant success against multiple myeloma

Published on July 21, 2015 at 2:37 AM 

In recent years, immunotherapy has emerged as a promising treatment for certain cancers. Now this strategy, which uses patients' own immune cells, genetically engineered to target tumors, has shown significant success against multiple myeloma, a cancer of the plasma cells that is largely incurable. The results appeared in a study published online today in Nature Medicine.

Patients received an infusion of altered immune cells known as T-cells - roughly 2.4 billion of them - after undergoing a stem cell transplantation of their own stem cells. In 16 of 20 patients with advanced disease, there was a significant clinical response. The scientists found that the T-cell therapy was generally well-tolerated and that modified immune cells traveled to the bone marrow, where myeloma tumors typically are found, and showed a long-term ability to fight the tumors. Relapse was generally associated with a loss of the engineered T-cells.

"This study suggests that treatment with engineered T-cells is not only safe but of potential clinical benefit to patients with certain types of aggressive multiple myeloma," says first author Aaron P. Rapoport, MD, the Gary Jobson Professor in Medical Oncology at the University of Maryland School of Medicine. "Our findings provide a strong foundation for further research in the field of cellular immunotherapy for myeloma to help achieve even better results for our patients."

The trial is the first published use of genetically modified T-cells for treating patients with multiple myeloma. The approach has been used to treat leukemia as well as lymphoma, according to Dr. Rapoport, who is the Director of the Blood and Marrow Transplant Program at the University of Maryland Marlene and Stewart Greenebaum Cancer Center.

More than 77,000 people in the United States have multiple myeloma, with about 24,000 new cases diagnosed each year. Patients are treated with chemotherapy and in many cases an autologous stem cell transplant, but long-term response rates are low, and median survival is three to five years.

"The majority of patients who participated in this trial had a meaningful degree of clinical benefit," Dr. Rapoport notes. "Even patients who later relapsed after achieving a complete response to treatment or didn't have a complete response had periods of disease control that I believe they would not have otherwise experienced. Some patients are still in remission after nearly three years."

The research is a collaboration between the University of Maryland School of Medicine, the Perelman School of Medicine at the University of Pennsylvania and Adaptimmune, a clinical stage biopharmaceutical company which owns the core T-cell receptor technology and funded the study. Dr. Rapoport and co-authors Edward A. Stadtmauer, MD, of the University of Pennsylvania Abramson Cancer Center, and Gwendolyn K. Binder-Scholl, PhD, of Adaptimmune, contributed equally to the research. Dr. Rapoport is the study's principal investigator.

In the clinical study, patients' T-cells were engineered to express an affinity-enhanced T-cell receptor (TCR) specific for a type of tumor antigen, or protein, known as a cancer-testis antigen (CT antigen). The target CT antigens were NY-ESO-1 and LAGE-1. Up to 60 percent of advanced myelomas have been reported to express NY-ESO-1 and/or LAGE-1, which correlates to tumor proliferation and poorer outcomes. According to Adaptimmune, the trial is the first published study of lentiviral vector mediated TCR gene expression in humans.

Of the 20 patients treated, 14 (70 percent) had a near complete or complete response three months after treatment. Median progression-free survival was 19.1 months and overall survival was 32.1 months. Two patients had a very good partial response three months post treatment. Half the patients were treated at the University of Maryland Greenebaum Cancer Center and half at the University of Pennsylvania Abramson Cancer Center. Researchers note that the response rate was better than would be expected for a standard autologous stem cell transplant. In addition, patients did not experience side effects which have been associated with another type of genetically engineered T-cells (chimeric antigen receptors, or CARS) used to treat other cancers.

The study was originally developed by Carl H. June, MD, of the University of Pennsylvania Abramson Cancer Center, and Dr. Rapoport, who have been research collaborators for 18 years.

"Multiple myeloma is a treatable but largely incurable cancer. This study reveals the promise that immunotherapy with genetically engineered T-cells holds for boosting the body's ability to attack the cancer and provide patients with better treatments and control of their disease," says E. Albert Reece, MD., PhD, MBA, vice president for medical affairs at the University of Maryland and the John Z. and Akiko K. Bowers Distinguished Professor and dean of the University of Maryland School of Medicine. "This trial is also an excellent example of significant scientific advances that result from collaborations between academic medical institutions and private industry."

Source:

University of Maryland Medical Center

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por cyto às 18:10

Terça-feira, 21.07.15

clinical study data on ImmunTraCkeR assay in the Journal for ImmunoTherapy of Cancer

 

ImmunID announces publication of clinical study data on ImmunTraCkeR assay in the Journal for ImmunoTherapy of Cancer

Published on July 8, 2015 at 10:02 AM 

ImmunID today announced the publication of a short report in the Journal for ImmunoTherapy of Cancer (JITC) showing that the analysis of peripheral T cell receptor diversity using the company's ImmunTraCkeR® assay is associated with clinical outcomes following Ipilimumab treatment in metastatic melanoma. Results from the study, conducted at Memorial Sloan Kettering Cancer Center, were first presented at the SITC 2014 Annual Meeting.

Study results suggest that ImmunTraCkeR® may ultimately be used as a companion diagnostic for immune checkpoint agents, to determine eligibility to the treatment.

"We are delighted to have been selected by the JITC editorial board for publication. ImmunID's mission is to add precision to the immuno-oncology revolution by personalizing immunotherapy. A large multicenter study is currently underway (Predict-ID Melanoma, France) with the aim to validate prediction capabilities of ImmunTraCkeR® for response to immune checkpoint inhibitors. This is an area of high unmet medical need and could be game-changing for patients," said Bernhard Sixt, ImmunID's Chairman and Chief Executive Officer.

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por cyto às 18:06

Terça-feira, 21.07.15

Single molecule appears to be central regulator driving cancer metastasis

 

Single molecule appears to be central regulator driving cancer metastasis

Published on July 14, 2015 at 6:21 AM · 

Cancer is a disease of cell growth, but most tumors only become lethal once they metastasize or spread from their first location to sites throughout the body. For the first time, researchers at Thomas Jefferson University in Philadelphia report a single molecule that appears to be the central regulator driving metastasis in prostate cancer. The study, published online July 13th in Cancer Cell, offers a target for the development of a drug that could prevent metastasis in prostate cancer, and possibly other cancers as well.

"Finding a way to halt or prevent cancer metastasis has proven elusive. We discovered that a molecule called DNA-PKcs could give us a means of knocking out major pathways that control metastasis before it begins," says Karen Knudsen, Ph.D., Director of the Sidney Kimmel Cancer Center at Thomas Jefferson University, the Hilary Koprowski Professor and Chair of Cancer Biology, Professor of Urology, Radiation Oncology, and Medical Oncology at Jefferson.

Metastasis is thought of as the last stage of cancer. The tumor undergoes a number of changes to its DNA - mutations - that make the cells more mobile, able to enter the bloodstream, and then also sticky enough to anchor down in a new location, such as the bone, the lungs, the liver or other organs, where new tumors start to grow. Although these processes are fairly well characterized, there appeared to be many non-overlapping pathways that ultimately lead to these traits.

Now, Dr. Knudsen and colleagues have shown that one molecule appears to be central to many of the processes required for a cancer to spread. That molecule is a DNA repair kinase called DNA-PKcs. The kinase rejoins broken or mutated DNA strands in a cancer cell, acting as a glue to the many broken pieces of DNA and keeping alive a cell that should normally self-destruct. In fact, previous studies had shown that DNA-PKcs was linked to treatment resistance in prostate cancer, in part because it would repair the usually lethal damage to tumors caused by radiation therapy and other treatments. Importantly, Dr. Knudsen's work showed that DNA-PKcs has other, far-reaching roles in cancer.

The researchers showed that DNA-PKcs also appears act as a master regulator of signaling networks that turn on the entire program of metastatic processes. Specifically, the DNA-PKcs modulates the Rho/Rac enzyme, which allows many cancer cell types to become mobile, as well as a number of other gene networks involved in other steps in the metastatic cascade, such as cell migration and invasion.

In addition to experiments in prostate cancer cell lines, Dr. Knudsen and colleagues also showed that in mice carrying human models of prostate cancer, they could block the development of metastases by using agents that suppress DNA-PKcs production or function. And in mice with aggressive human tumors, an inhibitor of DNA-PKcs reduced overall tumor burden in metastatic sites.

In a final analysis that demonstrated the importance of DNA-PKcs in human disease, the researchers analyzed 232 samples from prostate cancer patients for the amount of DNA-PKcs those cells contained and compared those levels to the patients' medical records. They saw that a spike in the kinase levels was a strong predictor of developing metastases and poor outcomes in prostate cancer. They also showed that DNA-PKcs was much more active in human samples of castrate-resistant prostate cancer, an aggressive and treatment-resistant form of the disease.

"These results strongly suggest that DNA-PKcs is a master regulator of the pathways and signals that lead to the development of metastases in prostate cancer, and that high levels of DNA-PKcs could predict which early stage tumors may go on to metastasize," says Dr. Knudsen.

"The finding that DNA-PKcs is a likely driver of lethal disease states was unexpected, and the discovery was made possible by key collaborations across academia and industry," explains Dr. Knudsen. Key collaborators on the study, in addition to leaders of the Sidney Kimmel Cancer Center's Prostate Program, included the laboratories of Felix Feng (University of Michigan), Scott Tomlins (University of Michigan), Owen Witte (UCLA), Cory Abate-Shen (Columbia University), Nima Sharifi (Cleveland Clinic) and Jeffrey Karnes (Mayo Clinic), and contributions from GenomeDx.

Although not all molecules are easily turned into drugs, at least one pharma company has already developed a drug that inhibits DNA-PKcs, and is currently testing it in a phase 1 study (NCT01353625). "We are enthusiastic about the next step of clinical assessment for testing DNA-PKcs inhibitors in the clinic. A new trial will commence shortly using the Celgene CC-115 DNA-PKcs inhibitor. This new trial will be for patients advancing on standard of care therapies, and will be available at multiple centers connected through the Prostate Cancer Clinical Trials Consortium, of which we are a member," explained Dr. Knudsen.

"Although the pathway to drug approval can take many years, this new trial will provide some insight into the effect of DNAP-PKcs inhibitors as anti-tumor agents. In parallel, using this kinase as a marker of severe disease may also help identify patients whose tumors will develop into aggressive metastatic disease, so that we can treat them with more aggressive therapy earlier," says Dr. Knudsen. "Given the role of DNA-PKcs in DNA repair as well as control of tumor metastasis, there will be challenges in clinical implementation, but this discovery unveils new opportunities for preventing or treating advanced disease."

Source:

Thomas Jefferson University

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por cyto às 18:05

Terça-feira, 21.07.15

Isis Innovation, Ludwig Cancer Research announce launch of new cancer immunotherapy spinout

 

Isis Innovation, Ludwig Cancer Research announce launch of new cancer immunotherapy spinout

Published on July 9, 2015 at 7:30 AM 

Isis Innovation, the University of Oxford's technology commercialisation company, and Ludwig Cancer Research are proud to announce the launch of a new spinout company, iOx Therapeutics. iOx Therapeutics will develop a novel cancer immunotherapy discovered through a collaboration between Ludwig Cancer Research and Professor Vincenzo Cerundolo, the director of the MRC Human Immunology Unit within the University of Oxford's Weatherall Institute of Molecular Medicine.

Since 2003, Professor Cerundolo, supported by funding from Ludwig Cancer Research, has led a research team working in collaboration with Professor Gurdyal Besra and Dr. Liam Cox of the University of Birmingham and Professor Richard Schmidt of the University of Konstanz. This team discovered multiple synthetic lipid compounds, now under development by iOx, which activate iNKT cells. A large body of evidence suggests that iNKT cells play an important role in anti-tumour immune responses and could prove highly effective in combination with other immunotherapies.

"Preclinical studies of our iNKT-activating compounds have been extremely promising," said Professor Cerundolo. "We've been able to show that these molecules can halt the progression of tumours in animal models. I am very excited to see them moving toward the clinic, and gratified that our research could prove to be of benefit to cancer patients."

"The new immune checkpoint inhibitors recently approved by regulatory agencies, such as anti-PD-1 antibodies, sabotage the strategies used by tumour cells to suppress the immune system and so induce potent anti-tumour immune responses in many patients," said Dr. Jonathan Skipper, Ludwig's executive director of technology development. "There is good reason to expect that iOX's iNKT agonists could significantly improve these responses, and we look forward to seeing the results of their clinical evaluation."

The company has discussed plans for a first human trial with the UK Medicines and Healthcare products Regulatory Agency. The trial will be run by Professor Mark Middleton, director of the Oxford Experimental Cancer Medicine Centre at Oxford University Hospitals NHS Trust.

Jim Mellon, an Oxford alumnus, has invested in the company through SalvaRx, an oncology-focused investment vehicle that provides capital and drug development expertise to support emerging technologies and companies.

Isis Innovation Head of Technology Transfer, Life Sciences Dr. Adam Stoten said, "The field of cancer immunotherapy is moving forward with unprecedented momentum and we're delighted to support Professor Cerundolo and his team in their goal of finding new and better cancer treatments."

Source:

Ludwig Institute for Cancer Research

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