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



Sexta-feira, 10.10.14

HCMV Arizona Center on Aging

HCMV Arizona Center on Aging

They discovered that while over time more and more cells of the immune system – particularly the T cells, a type of white blood cell critical in the immune system’s response to infection – concentrate on CMV, the T cells in charge of responding to other viruses were fewer in numbers and functionally impaired. Similar conclusions were reached by another group from Germany, led by Dr. Urs Karrer, and are published in the same issue of PloS Pathogens.

“The ongoing presence of CMV contributes to the defects of the aged immune system, helping to explain why older adults often are more prone to infectious diseases than young people,” said Nikolich-Zugich. “Future studies will allow us to understand the effect of persisting CMV infections on immune responses, which particularly is important for the efficiency of vaccination strategies.”

This work was supported in part by the U.S. Public Health Service grants AG20719 and AG23664 from the National Institutes of Health to Nikolich-Zugich and by the Collins Medical Trust and by the HGF-NG-VH-638 grants to Čiin-Šain. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Contacts

Media Contact

Jean Spinelli Arizona Health Sciences Center 520-626-7301 jeans@ahsc.arizona.edu

Research Article

Cytomegalovirus Infection Impairs Immune Responses and Accentuates T-cell Pool Changes Observed in Mice with Aging

Luka Cicin-Sain mail,

* E-mail: luka.cicin-sain@helmholtz-hzi.de (LCS); nikolich@email.arizona.edu (JNZ)

Affiliations: Department of Vaccinology and Applied Microbiology, Helmholtz Center for Infection Research, Braunschweig, Germany, Vaccine and Gene Therapy Institute and the Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon, United States of America

James D. Brien,

Affiliations: Vaccine and Gene Therapy Institute and the Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon, United States of America, Department of Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America

 

Jennifer L. Uhrlaub,

Affiliations: Vaccine and Gene Therapy Institute and the Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon, United States of America, Department of Immunobiology and the Arizona Center on Aging, University of Arizona College of Medicine, Tucson, Arizona, United States of America

Anja Drabig,

Affiliation: Department of Vaccinology and Applied Microbiology, Helmholtz Center for Infection Research, Braunschweig, Germany

Thomas F. Marandu,

Affiliation: Department of Vaccinology and Applied Microbiology, Helmholtz Center for Infection Research, Braunschweig, Germany

Janko Nikolich-Zugich mail

* E-mail: luka.cicin-sain@helmholtz-hzi.de (LCS); nikolich@email.arizona.edu (JNZ)

Affiliations: Vaccine and Gene Therapy Institute and the Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon, United States of America, Department of Immunobiology and the Arizona Center on Aging, University of Arizona College of Medicine, Tucson, Arizona, United States of America

 

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por cyto às 19:29

Sexta-feira, 10.10.14

HCMV charles coob

HCMV

By Charles Cobbs, M.D., neurosurgeon

Since returning to the San Francisco Bay Area in 2005, I have been fortunate to build a brain tumor research program at California Pacific Medical Center Research Institute (CPMCRI). My neurosurgical colleague at CPMC, Brian Andrews, M.D., had already begun a brain tumor clinical tumor board program that facilitated our growing interest in this area. Since the time of my neurosurgery residency at UC San Francisco (UCSF) in the 1990s, I had become interested in the most aggressive human brain tumors, called gliomas. Among these, glioblastoma multiforme (GBM) is traditionally associated with a survival of less than two years for most patients. After training at UCSF, I returned to join the Division of Neurosurgery faculty at UAB Medical School, in my home town of Birmingham, Alabama. There I received research awards and grants to study the associated inflammatory pathways that were known to accelerate progression of GBM in patients. During this time, I diverted some time to investigate a risky concept that brain tumors might not arise spontaneously from DNA mutations, rather that these tumors may be associated with a chronic infection and inflammation in the brain, which could gradually lead to a GBM developing over years. This concept was not even considered a reasonable possibility in the brain tumor community in 2000, the year I initiated the project. But many aspects of GBM patients suggested that their tumors could have a viral involvement. GBMs were more common in upper-middleclass individuals, as is the case of Hodgkin’s lymphoma, which is associated with Epstein-Barr virus (EBV). Furthermore, GBM patients were known to possess profound abnormalities in their immune function, but the relevance of this aspect of their cancer had never been clearly defined. Based on a hunch, we focused our efforts on potential viruses that could chronically infect brain cells in immunosuppressed patients, and this led me to focus on one particular virus called cytomegalovirus (CMV).

CMV Virus

CMV is a member of the herpes virus family, akin to herpes simplex virus (HSV), EBV, herpes zoster virus (HSV), and Kaposi’s sarcoma virus (KSV). Both EBV and KSV were known at the time to cause cancers, so it seemed reasonable that CMV might possess the capacity to cause or promote GBM. By enlisting the assistance of a superb technician who possessed the necessary skill to detect very low levels of CMV infection in brain tumors, our group determined that nearly 100 percent of GBM were infected with CMV, and we published findings in the journal Cancer Research in 2002 (1).

 

Unfortunately, as with many discoveries that seemingly come from “left field,” this publication appeared to remain unnoticed for several years. Then a couple of research groups attempted to confirm the findings without using the extra-sensitive detection techniques that we had developed, and their efforts were unsuccessful, thus casting doubt on the validity of our findings. Undaunted, we were able to pursue a group at the National Cancer Institute (NCI) to support our work in this area through the NCI Special Projects in Oncology Research Excellence (SPORE) mechanism, and this funding facilitated confirmation of the presence of CMV in GBM by other well-established groups, including those at Duke University Medical Center and Karolinska Institute in Stockholm, Sweden. The Duke group, headed by Drs. John Sampson and Duane Mitchell, not only confirmed our initial observations of CMV in more than 95 percent of GBM but also determined that the presence of the virus in the tumor cells might represent a unique target for an anticancer immune response(2).

Cancer Immunotherapy

Cancer immunotherapy is an emerging area of great interest in the cancer research community, and the concept of inoculating a cancer patient with a vaccine that will cause his/her immune system to target the tumor cells has always held great promise. The difficulty with the concept stems from the paradox that tumor cells are a person’s own cells, so the question is what target can a cancer vaccine use that will kill tumor cells but not other cells in the patient’s body. With the discovery that CMV infection appears to occur in the GBM cells specifically, and not in the adjacent normal brain cells, Drs. Sampson and Mitchell hypothesized that GBM patients had lost their immunity to CMV, but if they could boost a GBM patient’s immune system so that it could “see” the CMV infection in the tumor, then the ensuing immune response may be able to target and eradicate infected tumor cells. Clinical trials were initiated in 2006 at Duke to do just this. Duke is now the leading single-center Phase I and Phase II trials of GBM vaccines that target CMV, and the preliminary results are very encouraging(3). At Karolinska Institute, another of our colleagues, Dr. Cecilia Soderberg-Naucler, was attempting to see whether use of an oral antiviral drug, valganciclovir, taken once a day in addition to the standard treatment of GBM—chemotherapy and radiation therapy—might be able to thwart the progression of the tumor. Dr. Soderberg-Naucler’s study has not been published, but the preliminary data suggest that patients who received the antiviral drug have had statistically increased survival compared to those receiving placebo.

CPMCRI Research

Our research group has made progress in understanding the role the virus plays in GBM biology and how more novel antiviral strategies might be used to target the virus in GBM. Dr. Liliana Soroceanu, who heads the laboratory efforts for our research at CPMCRI, has made this research progress possible. A native of Romania, Dr. Soroceanu joined CPMCRI in 2006 after finishing a postdoctoral fellowship at Genentech. Within months of joining our group, Dr. Soroceanu discovered that a key cell receptor in the development of GBM, called PDGFR, was the key human cellular receptor for CMV, and when the virus attaches to a cell, such as a tumor cell, this receptor is turned on and drives cancer-causing pathways. This seminal finding was published in the journal Nature (4). Further work in the lab has led to the concept that certain CMV genes, when expressed in human GBM cells, not only can drive the cells to grow faster but can cause dramatic alteration of normal growth-promoting and growth-arresting signals. Worldwide, investigations are leading to the novel concept that CMV is a tumor promoter in GBM. Most recently, this consensus was reached at a small international meeting organized by our group and funded by the Accelerate Brain Cancer Cure (ABC2) and National Brain Tumor Society (NBTS) in Washington, D.C. in March 2011. At this meeting, a panel of international experts in virology and oncology presented recent findings in the area of CMV and GBM, and wrote a meeting summary documenting the state of the art in the field. Our current efforts are aimed at initiating the first U.S. clinical trial using a novel, highly active antiviral drug against CMV for GBM therapy. We are planning a Phase I trial of the novel drug CMX001 for GBM. CMX001 is an orally available, highly potent antiviral drug that can penetrate brain tumor tissues. We plan to perform clinical trials to determine whether use of this drug is safe in the setting of radiation and chemotherapy in primary and recurrent GBM.

References

  1. Cobbs, C.S., et al. Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res 62, 3347-3350. (2002).
  2. Mitchell, D.A., et al. Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol 10,10-18 (2008).
  3. Sampson, J.H. & Mitchell, D.A. Is cytomegalovirus a therapeutic target in glioblastoma? Clin Cancer Res 17, 4619-4621.
  4. Soroceanu, L., Akhavan, A. & Cobbs, C.S. Plateletderived growth factor-alpha receptor activation is required for human cytomegalovirus infection. Nature 455, 391-395 (2008).

 

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por cyto às 19:21

Sexta-feira, 10.10.14

Human Cytomegalovirus (HCMV) induces Human Endogenous Retrovirus (HERV) transcription

Human Cytomegalovirus (HCMV) induces Human Endogenous Retrovirus (HERV) transcription

Alice Assinger1, Koon-Chu Yaiw1, Ingmar Göttesdorfer2, Christine Leib-Mösch2,3 and Cecilia Söderberg-Nauclér1*

Abstract

Background: Emerging evidence suggests that human cytomegalovirus (HCMV) is highly prevalent in tumours of different origin. This virus is implied to have oncogenic and oncomodulatory functions, through its ability to control host gene expression. Human endogenous retroviruses (HERV) are also frequently active in tumours of different origin, and are supposed to contribute as cofactors to cancer development. Due to the high prevalence of HCMV in several different tumours, and its ability to control host cell gene expression, we sought to define whether HCMV may affect HERV transcription.

Findings: Infection of 3 established cancer cell lines, 2 primary glioblastoma cells, endothelial cells from 3 donors and monocytes from 4 donors with HCMV (strains VR 1814 or TB40/F) induced reverse transcriptase (RT) activity in all cells tested, but the response varied between donors. Both, gamma retrovirus-related class I elements HERV-T, HERV-W, HERV-F and ERV-9, and beta retrovirus-related class II elements HML-2 - 4 and HML-7 - 8, as well as spuma-virus related class III elements of the HERV-L group were up-regulated in response to HCMV infection inGliNS1 cells. Up-regulation of HERV activity was more pronounced in cells harbouring active HCMV infection, but was also induced by UV-inactivated virus. The effect was only slightly affected by ganciclovir treatment and was not controlled by the IE72 or IE86 HCMV genes.

Conclusions: Within this brief report we show that HCMV infection induces HERV transcriptional activity in different cell types.

Keywords: Cytomegalovirus, Retrovirus, Reverse transcriptase, HERV, Cancer, Endothelial cells, Monocytes

Findings Human cytomegalovirus (HCMV) is a ubiquitous virus infecting 40-100% of the world’s population. It usually causes a mild or asymptomatic infection, but may cause severe and life-threatening disease in immunocompromised hosts [1]. Emerging evidence today implies that HCMV can be detected in very high prevalence in cancers of different origin e.g. glioblastoma, medulloblastoma , neuroblastoma, colon, breast and prostate cancer [2-10]. It is currently debated whether HCMV is oncogenic or oncomodulatory in human cancer, although it fulfills the modified criteria for Koch’s postulates for human tumour viruses [11,12]. Other viruses implied as tumour viruses include Epstein Barr virus (EBV), Hepatitis

B and C, human papillomavirus, human herpes virus8 (HHV-8), Merkel cell polyomavirus and human

T-lymphotropic virus type 1 (HTLV-1) and recently human endogenous retroviruses (HERV) [13-15].

HERVs and related retrotransposons constitute approximately8% of the human genome [16,17]. Most HERVs are defective and generally not considered to be infectious [16,18], but are transmitted vertically.

While they are known to be transcriptionally active during embryonic development, they are generally down-regulated in adult human tissues by epigenetic mechanisms such as DNA methylation or chromatin modifications [19,20]. However, induction of HERV transcription is possible under certain circumstances, and may have a possible role in some pathological conditions. For example, an increased prevalence of several HERVs in cancer has led to studies of a potential role of HERVs in tumour development (reviewed in[21,22]) and investigation into the idea that HERVs could be potential therapeutic targets as they represent

* Correspondence: cecilia.naucler@ki.se

1Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden

Full list of author information is available at the end of the article

© 2013 Assinger et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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por cyto às 19:16

Sexta-feira, 10.10.14

Cytomegalovirus might accelerate the development of glioblastoma

Cytomegalovirus might accelerate the development of glioblastoma

Published on June 1, 2013 at 9:51 AM · No Comments

inShare.0A virus that infects most Americans but that usually remains dormant in the body might speed the progression of an aggressive form of brain cancer when particular genes are shut off in tumor cells, new research shows. The animal study by researchers at the Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James) and at Dana Farber Cancer Institute suggests that cytomegalovirus (CMV) might significantly accelerate the development and progression of glioblastoma, a deadly form of brain cancer.

The virus by itself does not cause cancer, the study suggests, but it might influence tumor development when changes occur that silence two genes called p53 and Nf1 in tumor cells. These genes are protective "tumor suppressor" genes that normally cause cells to die before they become malignant. But cancer-related changes can silence them, enabling malignant cells to survive, multiply and form tumors.

The findings are published in the journal Cancer Research. Some 50 to 80 percent of Americans become infected with CMV by age 40. The virus is transmitted by contact with infected saliva and other body fluids, and through sexual contact. Most people are infected early in life and then the virus remains dormant.

"CMV has been detected in many cancer types, suggesting that it might be reactivated when cancer occurs in the body," says co-corresponding author and researcher Dr. Chang-Hyuk Kwon, assistant professor of neurological surgery, at the OSUCCC - James and at the Dardinger Center for Neuro-oncology and Neurosciences.

 

The researchers also learned that CMV stimulates tumor-cell proliferation by activating a biochemical cell pathway called STAT3. In healthy cells, STAT3 plays an important role in controlling cell proliferation.

"Our data indicate that CMV contributes to glioblastoma when already-mutated cancer cells proliferate using the STAT3 signaling pathway," Kwon says. "We believe that CMV's action occurs in the tumor's cells of origin early in tumor initiation."

The findings raise questions about how cancer is studied, says co-corresponding author Dr. E. Antonio Chiocca, chairman of neurosurgery at the Brigham and Women's Hospital and surgical director for the Center for Neuro-oncology at Dana-Farber Cancer Institute in Boston.

"First, we usually study cancer in models that are virus-free, but our findings suggest that CMV might play a significant role in human cancers," he says.

"Secondly, anti-viral therapy against CMV might now be justified for human cancers, and immune responses to such cancer-modulating viruses should be carefully studied," Chiocca says.

About 18,500 new cases of glioblastoma multiforme are expected annually in the U.S., and 12,760 Americans are expected to die of the disease.

Kwon, Chiocca and their colleagues conducted the study using two mouse models infected with murine CMV (MCMV). One model developed glioblastoma spontaneously; the other received implants of human glioblastoma cells. Key technical findings include:

  • MCMV-infected mice with genetic mutations in p53 and NF1 in their brain cells that predisposed them to spontaneous glioblastoma had shorter survival than non-MCMV-infected mice with the same mutations;
  • Implanting human gliomas into the brains of MCMV-infected animals significantly shortened their survival compared with controls;
  • MCMV infection increased levels of activated STAT3 in neural stem cells, the cells in which glioblastoma is thought to originate;
  • Human CMV increased STAT3 activation and proliferation of patient-derived glioblastoma cells; a STAT3 inhibitor reversed this effect in cell and animal models.
  • Cytomegalovirus (CMV) infects most middle-aged Americans, and it is often associated with an aggressive form of brain cancer; whether it plays a role in the cancer is unknown;
  • This study indicates that, in mice, a mouse CMV can speed the tumor's growth when two protective genes called p53 and NF1 are mutated in neural stem cells of the brain.
  • The findings suggest that viruses might influence cancer progression, and that anti-viral therapy might improve the treatment of these aggressive brain tumors.

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por cyto às 18:55

Sexta-feira, 10.10.14

Research SHENK LABS PRINCETON

Research SHENK LABS PRINCETON

 

Research: Human cytomegalovirus replication and pathogenesis

Cytomegaloviruses are members of the herpes virus family. Human cytomegalovirus (HCMV) infections are widespread and subclinical in the vast majority of cases, but the virus exhibits increased virulence in the very young and old and in immunocompromised individuals. Congenital infections cause life-long disabilities in a significant number of children. Transplant recipients, cancer patients, and AIDS patients, all of whom can exhibit decreased immune function, suffer a variety of clinical manifestations resulting from cytomegalovirus infection, including mononucleosis and pneumonia. There are also suggestions in the literature that HCMV might serve as a cofactor in certain cancers, atherosclerosis and immune senescence. The HCMV particle carries a viral genome comprised of linear double-stranded DNA that encodes more than 200 proteins, 23 microRNAs and a variety of additional non-coding RNAs. We study molecular mechanisms underlying HCMV replication and pathogenesis.

When the virus infects a fibroblast, epithelial cell or endothelial cell, it actively replicates and generates infectious progeny. We have studied the HCMV life cycle by using a mixture of genetic, biochemical, proteomic and metabolomic approaches. One area of special interest to us has been the identification of mechanisms by which the virus blocks defensive responses of the host cell, an area where the HCMV pUL38 protein plays a major role. We constructed a mutant virus unable to express pUL38 and found that it failed to efficiently express all viral genes tested and infected cells died of apoptosis before the viral replication cycle was completed. Using proteomic technology we discovered that pUL38 binds to the cellular tuberous sclerosis protein complex (TSC). This is a tumor suppressor complex that interprets stress signals and modulates the activity of mTOR, which in turn controls translation, fatty acid synthesis and many other vital processes in the cell. The pUL38 protein blocks the ability of TSC to respond to upstream signals, allowing the virus to continue to utilize cellular biosynthetic systems in spite of inducing a strong stress response. We have further probed the HCMV-host cell interaction by studying how metabolism is altered by infection. This work has revealed that HCMV induces glycolysis, nucleotide synthesis, citric acid cycle flux and lipid biosynthesis. Inhibition of the committed step of fatty acid synthesis and elongation, acetyl-CoA carboxylase, blocks HCMV replication, so we performed an siRNA screen and identified a substantial number of enzymes that sponsor fatty acid and lipid biosynthesis and are needed for successful virus replication. We are now working to elucidate how these enzymes are regulated, and one approach we have employed is to knock down each of the cell-coded kinases and test how the loss of function influences HCMV replication. This approach has identified several kinases that modulate the cell metabolome following infection. Most recently, we discovered that each of the seven human sirtuins is an HCMV restriction factor. Sirtuins are NAD+-dependent protein deacetylases, and we have begun to identify cellular targets of sirtuins that are critical for their anti-viral activity.

When HCMV infects a bone marrow stem cell or a monocyte, it doesn’t replicate. Rather, it enters a state of quiescence termed latency. We have developed and validated two cell culture models for latency. Using these models, we have discovered that the virus transiently expresses a large number of viral products after infecting these cells, but after several days the viral genome becomes quiescent. A small number of viral proteins that continue to be expressed, including pUL138, a protein whose role in latency was first identified in our latency models. Others have shown that it controls the expression of at least one cell surface protein, and we are now following this clue by characterizing the cell surface proteome of uninfected monocytes as compared to monocytes harbouring latent HCMV. Our early results show that they are remarkably different!

 

 

 

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por cyto às 18:52

Sexta-feira, 10.10.14

A new compound that majorly boosts the effectiveness of immunotherapy

A new compound that majorly boosts the effectiveness of immunotherapy

Posted on September 3, 2013 | Leave a comment

Immunotherapy is one of the more hopeful approaches to cancer treatment, insofar as it uses highly specific monoclonal antibodies against specific types of cancer. Several antibodies are in clinical use, and many more are being developed. But immunotherapy is not always fully effective – yet. I report here on a compound has been developed that enormously increases the effectiveness of immunotherapy, working like an adjuvant. When you reach the bottom of this blog you will be convinced that we are on the threshold of a major advance in cancer treatment. One of the keys to immunotherapy involves the stimulation of macrophages to consume antibody-bound cancer cells. Macrophages have evolved the ability to recognize cancer cells and destroy them. However, cancer cells have evolved counter-mechanisms to evade detection by macrophages, so they continue to live. That mechanism even makes it difficult for antibodies raised against specific cancer cell surface molecules to successfully eliminate the cancer cell population. In a recent study from Stanford medical school, researchers have learned to interfere with the evasion mechanism, and have increased the potential for successful immunotherapy with a wide variety of cancers.(1) Many cancer cells overexpress a ubiquitous cell surface protein known as CD47, a member of the immunoglobulin superfamily. It functions in apoptosisproliferationadhesion, and migration, among other cell processes. The cell surface of macrophages has a protein, SIRP-a, or Signal Response Protein-alpha, which, when bound to CD47, prevents the macrophage from enveloping, incorporating and digesting the cancer cell, a process called phagocytosis. The Stanford researchers show that a molecule that interferes with the binding of C47 to SIRP-a allows the macrophages to phagocytize and eliminate cancer cells. The interfering molecule is brilliantly simple, works well, and heralds the possibility of other drugs that could work in a similar manner. The researchers reasoned that if the SIRP-a molecule binds to CD47, they could isolate that fragment of the whole SIRP-a molecule that binds to C47, and when added back to cells it should compete with the SIRP-a attached to macrophages. That could prevent macrophages from being inhibited, enabling them to phagocytose cancer cells. It turned out to be a little more complicated than that, but in an advantageous way. First, by using a selection scheme which is not necessary to discuss here, they were able to construct a SIRP-a fragment that binds to CD47 a hundred times better than the natural fragment. It was this molecule, which they called CV1, that was used for further experiments. CV1 was added to a mixture of fluorescent human lymphoma cells together with human macrophages, and the macrophages were assayed for phagocytosis. Perhaps unexpectedly, phagocytosis was not stimulated, relative to control mixtures of cells. However, when the CV1 was fused to the Fc chain of an immunoglobulin (the constant region base of an antibody), phagocytosis was stimulated. This led the investigators to suppose that CV1 would enhance phagocytosis of cancer cells in the presence of tumor-specific antibodies. That turned out to be the case. After successful in vitro tests, and toxicity tests in both mice and primates, the investigators jumped to a test in live mice, a test with clinical implications. They engrafted Raji lymphoma cells subcutaneously into mice lacking B cells, T cells, and Natural Killer cells while retaining macrophages. For three weeks, from days 8 to 29, the mice were injected daily with 200 ug of CV1 plus 200 ug of Rituximab, a commercially developed monoclonal antibody approved for treatment of B-cell Non-Hodgkin lymphoma. These were compared to mice treated with saline alone, or with CV1 alone or with Rituximab alone.  Each treatment group consisted of 10-15 mice. The findings were stunning. Large tumors developed in all of the mice – except for those mice treated with both CV1 and Rituximab. There was a modest reduction in tumor size in the groups treated with CV1 alone or with Rituximab alone, but in the mice treated with combination therapy tumors were either very small or in most cases, not detectable (a bioluminescence assay was used). The effect continued even after treatment was over. Even more significant, the combination therapy had a major impact on longevity. Mice treated with saline alone or CV1 alone did not survive more than 40 days. Survival for most mice treated with Rituximab was slightly longer, with about 10 percent living for about 3 months. But 75% of the mice treated with combination therapy were still alive at 250 days. Similar results were obtained with another type of cancer and a different monoclonal antibody.  

The authors tell us clearly what all of this means: “We have developed reagents that broadly enhance the efficacy of tumor-specific antibodies, and thus, could be used as UNIVERSAL (emphasis mine) adjuvants to antibody therapies”. In other words, this one reagent, CV1, could be used with a number of different cancers and a number of different antibodies. These data bursts open the doors for the widespread and successful use of immunotherapy. I suspect that drug companies will be quickly screening for small molecule compounds that can also inhibit the interactions between CD47 and SIRP-a, drugs that might be easier and less expensive to produce, but with similar effectiveness to CV1. Of course, these experiments were done with mice, and we must wait for the human clinical test to see whether CV1 will be useful in cancer treatment. If it is, as expected, we will be witness to a major leap in the efficacy and safety of treatments for cancer, and possibly years of additional healthy life for the hundreds of thousand of people who now succumb to cancer.

1.         Weiskopf K, Ring A, Ho C, Volkmer J-P, Levin A, Volkmer A, Özkan E, Fernhoff N, van de Rijn M, Garcia K. 2013. Engineered SIRP-α variants as immunotherapeutic adjuvants to anticancer antibodies. Science 341:88-91.

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por cyto às 18:29

Sexta-feira, 10.10.14

Northwest Bio And The Curious Relationship With Cognate BioServices

Northwest Bio And The Curious Relationship With Cognate BioServices

Jul. 17, 2014 6:55 PM ET  |  157 comments  |  About: Northwest Biotherapeutics, Inc. (NWBO) by: Biotech Hawk

Summary

  • NWBO granted $20-$70 million in equity to a contractor controlled by its CEO in Q1 2014.
  • The contractor appears to be wildly overinflating service fees to NWBO.
  • NWBO does not segregate financial duties to assure internal controls.

A lot has been written lately regarding Northwest Biotherapeutics (NASDAQ:NWBO) - from missing trial data to premature announcement of immature trial data to potential links to illicit stock promotions. All this noise caught my interest so I decided to take a closer look at NWBO, a NASDAQ-listed company developing autologous cell therapies to treat cancer.

After analyzing NWBO's latest 10-K, and then doing a bit more reading of previous filings, I was left with a lot of questions about the arrangements between NWBO and its contract manufacturer Cognate BioServices, as well as the control of both companies by NWBO's CEO.

I emailed a list of questions (see below) to the company. A company representative emailed me back and offered to discuss the questions by phone, but he is unfortunately traveling until next week, he could not arrange for anyone else to speak with me, and has not responded to the actual questions I have posed in writing. If I do receive responses to my questions, I will pass them along as soon as possible.

How much does Northwest pay for manufacturing services?

As best as I can understand from the filings, NWBO has two ongoing clinical trials - a Phase III glioblastoma study that has been recruiting patients for many years and a 60-patient Phase I/II trial of DCVax-Direct® (the phase I portion completed recruitment this week). In 2013, NWBO reported R&D expenses of $43.9 million, $25.4 million of which was due to its contract manufacturer Cognate BioServices (Cognate), according to NWBO's 10-K (See section 9 on Related Party Transactions).

While clinical trials and autologous cell manufacturing are certainly expensive undertakings, these sums seemed extraordinary to me for a small cap company with only two ongoing trials. As a rough comparison, a competitor company also trialing a costly autologous cell therapy, ImmunoCellular Therapeutics (NYSEMKT:IMUC), recruited 278 patients into a Phase II glioblastoma trial during the years 2011 and 2012, reporting trial data in 2013. According to IMUC filings, its R&D expenses for these three years were $5 million, $7.7 million, and $5.3 million, a total of $18 million during the course of that trial.

Not only did NWBO ring up quite a tab with its contract manufacturer during 2013, the company delivered quite a valuable chunk of consideration to Cognate in the first quarter of 2014. As reported on pages 48-49 of its 10-K, for "Milestone and Initiation" payments under four separate contracts with NWBO, Cognate received 5,101,366 shares of NWBO common stock and 2,434,011 warrants with a $4 strike price. Given the range of NWBO share prices ($3.84-$10.64) during the first quarter, this consideration would be worth somewhere between $19.6 million and $70.4 million.

While Cognate appears to have agreed to a 30-month lockup of the shares granted during the first quarter, the lockup did not come for free. Cognate receives an additional 15% warrant coverage for each six months of the lockup.

But that's not all. As excerpted from the 10-K: "the amounts paid by [NWBO] in shares and warrants under each of the Cognate Agreements will be subject to adjustment on a most favored nation basis relative to the terms provided by us to any other investor or creditor during the term of such Agreement..." and "...the lock-up terms are subject to the same most favored nation treatment..."

Is Cognate such a special contract manufacturer to deserve this level of consideration and "most favored nation" status? Let's look at another rough comparison. Progenitor Cell Therapies, a contract manufacturer of similar products to Cognate, is a wholly owned subsidiary of publicly traded NeoStem, Inc. (NASDAQ:NBS). Though NBS does not break out revenues of Progenitor Cell Therapies in its filings, total revenues for NBS in 2012 and 2013 were both approximately $14.5 million per year (assumed to be primarily due to Progenitor operations). And by comparing filings, it would appear that Progenitor does a lot more work for that $14.5 million per year than Cognate provides to NWBO. Progenitor has two GMP facilities and has served over 100 clients (biotech company projects) in its 15 year history. As far as the Cognate business, it's a bit difficult to ascertain how busy the company is from its website. The last news update is from 2009.

While it is very difficult to ascertain from SEC filings, my best guess is that over the three year period from 2011 to 2013, NWBO delivered between $60 million and $100 million worth of equity in addition to tens of millions in cash to Cognate. This is for services along the lines for which IMUC probably paid about $6 million to $10 million over the same three year period (a guess that about 35-55% of IMUC R&D costs were spent on manufacturing). And over the same three year period, NBS total revenues were about $39 million, covering a number of projects for various companies. Granted, this is never an apples-to-apples comparison, but the difference in numbers is staggering.

A closer look at the Northwest-Cognate relationship

As excerpted from the notes on page 47 the latest 10-K: "Ms. Powers [NWBO CEO and Chairperson] has voting and dispositive power over the securities owned by ... Cognate BioServices, Inc." All of Cognate's shares in NWBO are included in the calculation of Ms. Powers' beneficial ownership of NWBO. While I cannot say definitively that Ms. Powers owns Cognate BioServices, it is quite clear she is the beneficial owner of at least a controlling stake of Cognate.

So, in addition to Ms. Powers' regular compensation (which, by the way included 14.2 million in-the-money options granted in 2011 worth about $9.26 million at that time), NWBO has directed tens of millions of dollars of business to a contractor she controls (and appears to own a significant part of) under agreements with "most favored nation" clauses? This disclosure made me want to take a closer look at these contractual relationships.

Can you believe the four agreements for contract manufacturing services between NWBO and Cognate have been granted Confidential Treatment by the SEC? The fees payable under these contracts are redacted in the filings! From that which we can see in the filings, in addition to the high fees and favorable stock grants to Cognate, NWBO is responsible for all of Cognate's capital expenses in the event it needs to scale up and, should NWBO stop certain projects early, $3 or $5 million penalties payable to Cognate.

It is curious to note in the NWBO press release this week announcing the completion of the Phase I portion of its DCVax-Direct® trial that: "[NWBO] and its manufacturing partner, Cognate BioServices, are also expanding the manufacturing capacity for DCVax-Direct." Given that the phase II part of this trial will enroll only 24 patients, as compared to the 36 patients enrolled in phase I, it is not clear why additional scale up activities would be necessary. Perhaps given that NWBO is to pay for all of Cognate's capital expenses, this is just an excuse to shovel more cash and stock to Cognate?

If all this were not bad enough - and remember that is only the first quarter of 2014 - here are a few other tidbits from SEC filings over the past few years:

  • In September 2013, NWBO put $4.5 million into a custodian account shared with Cognate (who contributed $2 million). Supposedly, these funds were to be made available for a potential acquisition that did not go forward. So the $4.5 million was directed to Cognate to settled accounts payable. (Page F-14 of latest 10-K)
  • In July 2013, NWBO settled $11.6 million of accounts payable to Cognate by delivering 4.7 million shares of common stock. Given the average price during July 2013 of NWBO stock of about $3.55, the value of this payoff was about $16.7 million - an extra $5 million over the amounts due to Cognate. (Page 37 of latest 10-K)
  • In October 2012, in a similar fashion, NWBO granted equity to Cognate valued at a $10.6 million to settle a $7.5 million debt. (Page 49 of the 10-K for 2012)
  • In November 2011, NWBO granted Cognate 46 million shares (worth about $16.56 million based on approximate trading prices during that month) to settle a $9.2 million debt. (Page 48 of the 10-K for 2011)

In the interest of brevity, I have only highlighted a few of the unusual transactions between Cognate and NWBO. Readers are encouraged to read SEC filings from the past years and investigate more for themselves.

Governing related-party transactions

Of course, just because NWBO and Cognate are considered related parties does not mean that something unethical is going on. But public companies must be very careful to appropriately govern related party transactions and, I believe, be more transparent about the nature of such transactions. Unfortunately, in the case of NWBO, Ms. Powers just so happens to be both the "Principal Executive Officer" as well as the "Principal Financial and Accounting Officer." Strangely, NWBO auditors noted in the 10-K that "[NWBO] audit included consideration of internal control over financial reporting as a basis for designing audit procedures that are appropriate in the circumstances, but not for the purpose of expressing an opinion on the effectiveness of the Company's internal control over financial reporting. Accordingly, we express no such opinion." $175,000 in audit fees incurred during 2013 and there is no opinion on internal control? Not a lot of comfort to shareholders, in my opinion.

Life as a development-stage biotech company is hard. Many years of financial losses and a high risk of failure are a part of life in the industry. I am generally sympathetic to biotech companies with ugly balance sheets as a result of financings on unfavorable terms. I understand that sometimes stock is all that these companies have to compensate employees and contractors when cash is in short supply.

But this is no excuse to allow the types of transactions that have transpired at NWBO. How does the board allow the CEO to incur what appears to be wildly overinflated fees from a contractor controlled by the same CEO? And when NWBO can't pay the invoices to that contractor, they compensate with stock grants valued significantly higher than the already inflated expenses.

After doing my homework on NWBO, I thought about possible trading strategies to capitalize on my insight. Given that the CEO controls over 50% of the stock, I came to the conclusion that trying to take a serious position would be difficult. Nonetheless, I did buy (and still hold) 20 put contracts with a strike price of $5 at a cost of $300. It is a small bet to keep me engaged and entertained for a while.

Questions posed to Northwest Biotherapeutics by email

  1. Who are the beneficial owners of Cognate BioServices? From NWBO 10-K filings, it could be understood that Ms. Powers owns 100% of Cognate. Is this correct?
  2. How many employees (full time equivalent) work for Cognate? Where are they located?
  3. How many clients does Cognate have? How many active cell manufacturing projects are being managed by Cognate?
  4. Has NWBO put its contract manufacturing up for competitive bidding? What other contractors (for example Progenitor Cell Therapies or Lonza) have you reviewed? Why do you believe it is necessary to grant "most favored nation" status to Cognate contracts?
  5. Can you give more detail on how your R&D funds were spent in 2013? For example, break out contract manufacturing costs, clinical trial costs, etc. Or how much spent on one trial versus another?
  6. How many products (patients) were manufactured by Cognate for NWBO in 2013? Can you provide more detail about the $25.4 million of fees and costs billed by Cognate in 2013?
  7. Over the past few years, NWBO has repeatedly settled its accounts with Cognate by delivering equity at a significant premium. For example, in 2013, you granted about $16.7 million of stock (based on stock prices of the time) to pay a $11.6 million debt to Cognate. Why is it necessary for NWBO to pay a premium?
  8. Why have you redacted the costs from the NWBO-Cognate contracts in SEC filings? Given the related party interests in the two companies, this did not seem appropriate. Can you comment on the appropriateness?
  9. How many employees does NWBO have?
  10. Especially given the sums at stake between NWBO and Cognate, do you think it is appropriate that Ms. Powers serves as both "Principal Executive Officer" as well as the "Principal Financial and Accounting Officer" of NWBO?
  11. Why did the company change auditors after 2012?
  12. Why do the current auditors express "no opinion" on internal controls at NWBO?

Disclosure: The author holds a very small short position in NWBO and does not intend to initiate any other position within the next 72 hours. The author wrote this article themselves, and it expresses their own opinions. The author is not receiving compensation for it (other than from Seeking Alpha). The author has no business relationship with any company whose stock is mentioned in this article.

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por cyto às 14:19

Sexta-feira, 10.10.14

Cel-Sci Is A Leader In The I-O Class Of Cancer Therapies

Cel-Sci Is A Leader In The I-O Class Of Cancer Therapies

Aug. 12, 2014 10:43 AM ET  |  11 comments  |  About: Cel-Sci Corporation (CVM), Includes: ABLYF, AZN, BMY, CLDX, CLSN, DNDN, FPRX, INCY, INO, MRK, NLNK, NWBO, PPHM, RHHBY by: Sharon di Stefano

Summary

  • Tumor cells that refuse to die have led researchers to develop immuno-oncology drugs, a brand new class, with Big Pharma participation.
  • Cel-Sci Corporation has been ahead of the game for years with Multikine, now in advanced clinical trials for head and neck cancer.
  • Smaller biotechs are entering the race, with varied results.
  • Cel-Sci may face deep-pocketed competition, and must surmount clinical and regulatory hurdles.
  • If successful, a huge global market awaits Cel-Sci's solution to disfiguring surgery.

Tumor cells, tending to persist after treatment, lead to remission and have been a bane to cancer researchers and doctors for decades. Only recently, immuno-oncology, labeled "I-O" first by Bristol-Myers Squibb Co. (NYSE:BMY), has emerged to become a new class of cancer medicines that may someday take a meaningful place alongside chemotherapy, surgery, and radiation. Investors associate cancer immunotherapy with forerunner Dendreon Corporation (NASDAQ:DNDN), whose PROVENGE vaccine shocked health plans with its exorbitant price that only extended life a few months. I-O, in its new form, has sparked a pharmaceutical rivalry reminiscent of the antihypertensive race of the 1990s. Central roles in I-O are occupied by Merck & Co. (NYSE:MRK), Bristol-Myers, AstraZeneca PLC (NYSE:AZN) and Roche Holding AG (OTCQX:RHHBY) in various stages of clinical trials, but with a common scientific theme - the inhibition of programmed cell death proteins, or PD-1 and PD-L1, that block immune responses to allow tumor proliferation.

Cel-Sci Corporation (NYSEMKT:CVM), with its flagship drug Multikine, has been ahead of the pack, investigating the I-O space for many years and currently enrolling a global Phase III trial in head and neck cancer. Multikine is a leukocyte interleukin injection, a cocktail of proteins and cells designed to augment the human immune system in fighting tumor cell infiltration into tissue. In studies as early as 2003, treatment with Multikine in patients with primary tumors of the head and neck proved beneficial by stimulating T-cell migration into cancer "nests", enabling the immune system to elicit an anti-tumor response before tumor recurrence.

Decision Resources, data provider to the biopharmaceutical industry, predicts the I-O market will grow to almost $9 billion worldwide by 2022, from $1.1 billion in 2012, dominated by only a handful of firms. Small wonder four of the top Big Pharma companies are in what has been described by analysts and journalists as a race to reach FDA approval first.

Merck, AstraZeneca, Bristol-Myers and Roche have all developed drugs in the PD-1 or PD-L1 class to treat lung cancer, with potential indications in melanoma and kidney. The method of action sounds like science fiction - PD proteins allegedly let tumors disguise themselves from the immune system. Inhibiting these proteins from their receptor targets allows biochemical components to recognize the tumor cells as invaders, and kill them as they would any virus or bacteria. Whether the immune response is sustainable against constantly mutating tumor cancer cells has not yet been proven.

Boosting its position in the I-O contest, this past spring, AstraZeneca began a Phase III trial for MEDI4736, acquired with its purchase of MedImmune in 2007, for non-small cell lung carcinoma (NSCLC), the first of its kind. Around the same time, MedImmune joined forces with Incyte Corporation (NASDAQ:INCY) to combine their biochemical potions to erect immune responses to different tumor types.

Bristol-Myers has succeeded in being first to approval: its nivolumab will be available for sale in Japan, and it recently formed a pact with Ono Pharmaceutical Co. (OTC:OPHLF) to market I-O therapies in select Pacific Rim countries upon commercialization of nivolumab and Yervoy, Bristol-Myers' monoclonal antibody for melanoma, gained in the acquisition of Medarex. Working feverishly against big competitors, Bristol-Myers also cut a $350 million deal with Five Prime Therapeutics (NASDAQ:FPRX) for I-O drug discovery.

Merck's I-O pembrolizumab was recently submitted as a rolling biologic license application (BLA) for melanoma, viewed as a coup among its rivals. The drug is fast-tracked at the FDA, and has been given the desired "breakthrough" designation because clinical trials show the possibility of extending life for one year. Merck's intent is to gain approval for pembrolizumab for melanoma patients who have failed Bristol-Myers' Yervoy, a pharmaceutical nose-thumbing to a fellow drug firm developing I-O therapies. Marking its place in the race, Merck began collaborating with foreign-based Ablynx NV (OTC:ABLYF) for joint development of I-O drugs in a deal worth up to $2.3 billion. Pembrolizumab is currently enrolled in 10 clinical trials, a total of 4,000 patients, for cancers of the bladder, stomach, kidney, colon and breast, including some hematological disorders.

Roche, known more for its diagnostic tests and services, bought its way into the I-O field with its 2009 acquisition of Genentech's deep knowledge of making monoclonal antibodies. Toiling behind the curve of its drug company counterparts, Roche's MPDL3280A only recently publicized results of a Phase I study that shrank tumors in 43% of people with refractory metastatic bladder cancer.

The drug is also tested in melanoma and kidney. Roche, like Merck, has been granted the FDA's breakthrough therapy designation.

Cel-Sci has a handful of smaller competitors; some promising, others not. Celldex Therapeutics (NASDAQ:CLDX) has a potential I-O in a late-stage study for brain cancer that is designed to help T-cells better recognize tumors. It caught the attention of Bristol-Myers, who wants to mix Celldex's varlilumab with its nivolumab in a Phase I/II trial on various solid tumor cancers. The technology of NewLink Genetics (NASDAQ:NLNK) looks like voodoo science to me - an immunotherapy platform called HyperAcute is intended to stimulate the immune system via cancer cell lines modified to express a carbohydrate, basically a starch, to attack tumors. Yet, the company is in two Phase III trials for pancreatic cancer. Inovio Pharmaceuticals (NASDAQ:INO) recently announced positive Phase II results with its I-O for cervical neoplasia related to human papillomavirus (HPV), an area Cel-Sci investigates, but treatment is for precancerous lesions, and the company has met with some controversy whether cancer itself can be addressed.

Two additional firms are particularly troubled. Peregrine Pharmaceuticals' (NASDAQ:PPHM) lead drug bavituximab, a monoclonal antibody turned I-O, is in Phase III for NSCLC, but critics question improvements following lackluster and unreliable Phase II data and wonder why more robust statistical information is not provided. The worst in the I-O hopeful category is Northwest Biotherapeutics (NASDAQ:NWBO), in Phase III with DCVax for brain, ovarian and prostate cancer. Widespread controversy not only exists about its choice of clinical endpoints and their acceptance by regulators, but also the dissemination of information, for which it was chastised by renowned cancer center MD Anderson for making unjustified claims related to DCVax.

Yet, these companies carry much higher valuations than Cel-Sci, despite being neck-in-neck along in clinical trial progress, as the table below illustrates. Their separate issues apparently do not figure into investor opinion. However, disparity in value makes for opportunity, especially in this new class of drugs that has captured medical attention.

Company

Ticker

Market Cap

Disease Indication and Trial Phase

Celldex Therapeutics

CLDX

$1.35 billion

Glioblastoma - Phase 3

NewLink Genetics

NLNK

$691.3 million

Pancreatic Cancer - Phase 3

Inovio Pharmaceuticals

INO

$539.6 million

Cervical Dysplasia HPV - Phase 2

Peregrine Pharmaceuticals

PPHM

$301.1 million

Non-small Cell Lung Cancer - Phase 3

Northwest Biotherapeutics

NWBO

$385.5 million

Brain Cancer - Phase 3

Cel-Sci Corp.

CVM

$72.57 million

Head and Neck Cancer - Phase 3

Smaller biotechs that have traditionally adopted other medical modalities to treat cancer have been drawn by I-O's promise. Recently, Celsion Corporation (NASDAQ:CLSN) acquired privately held EGEN, Inc., developer of an immunotherapeutic using a small circle of DNA called a plasmid that, combined with interleukin (IL)-12 and a chemotherapeutic agent wrapped inside a nano-sized material, can be directed to tumors to induce remission.

Big Pharma's approach wants to combine I-Os with other cancer remedies or treat patients that have failed prior therapy, but Cel-Sci seeks to use Multikine first, before any compromise of the immune system takes hold, to create a greater anti-tumor response. The company has undertaken the huge task of enrolling the largest Phase III for an I-O, in head and neck cancer (a disease with very poor prognosis), with the goal of petitioning the FDA and other agencies to approve Multikine as a first-line treatment. Besides its potential benefit as the first medicine given before surgery, radiation or chemotherapy, Multikine has been developed to be an "off-the-shelf" drug, much easier to manufacture large-scale. Making monoclonal antibodies (the basis for I-Os) is tedious business, and batch-to-batch consistency is an ever-present challenge.

There are side effects to consider. Drugs that stimulate the immune system run the risk of damaging healthy tissue or triggering autoimmunity. Bristol-Myers' Yervoy may well extend a melanoma patient's life by four months, but colitis can result. Merck's leading I-O caused fatigue in 30% of subjects, rash and itching in another 21%. Patients developed inflammation of the lungs. Roche's drug fared better, although 12.6% of patients had more serious Grade 3 or 4 side effects, including fatigue, shortness of breath and vomiting. By contrast, Multikine's trials have shown no severe adverse effects, with events limited to pain and swelling at the injection site, headache and nausea.

Cel-Sci's change in contract research organizations (CRO) is resulting in faster enrollment: the company announced last month's total patient enrollment of 232 people, more than one-quarter towards its goal of 880 by the end of next year. Critics complain that Cel-Sci cannot meet its target, but do not take into consideration acceleration of enrollment made possible by the number of countries and organizations for which trials have been and continue to be approved, with multiple sites available in each. In the past three months alone, Turkey, Austria, Sri Lanka, France and the UK have come on board, totaling 17 countries in all. This is truly a global trial - sites also include those in Canada, India, Israel, Poland, Hungary, Russia, Taiwan, Ukraine, Serbia, Croatia and Bosnia and Herzegovina.

In the US, Cel-Sci gained approval from Detroit's Henry Ford Health System, one of the nation's largest group practices, with over 1,200 doctors in 40 specialties. This followed 21st Century Oncology of Greenville, North Carolina, with 166 treatment centers in 16 states and six Latin American countries. My question is why would management, by keeping a running count of enrollees, hold itself up to public embarrassment and investor scorn if it did not fully expect to reach its desired enrollee numbers?

No doubt, Cel-Sci has a long road ahead, and a pivotal trial of this magnitude may quickly burn through its remaining cash, forcing it to seek dilutive financing. Its own clinical and regulatory risks notwithstanding, Cel-Sci faces upcoming competition from AstraZeneca, Merck and Bristol-Myers, who plan studies in head and neck cancer, big firms with deep pockets. The I-O arena is also drawing critics: oncologists have gone on-record urging caution concerning the results being churned out by Big Pharma, citing small sample sizes, lack of control groups, efficacy in only a minority of cancer patients and bad side effects. Particularly when using two I-Os in combination for best results, a trend seen recently.

Regardless of risks, Cel-Sci is well-positioned to enter the I-O race. Head and neck cancer, including disease of the larynx, thyroid, salivary glands and nasal passages, account for up to 5% of all cancers in the US and cause 12,000 deaths per year, for a total market of slightly over $3 billion. Because of its prominent, visible position on the body, better agents are needed to reduce the size of tumors and limit the amount of disfiguring surgery. Cel-Sci is ahead of Big Pharma in filling this medical need, and given its undervalued status compared to competitors large and small, presents a golden opportunity to take advantage of the budding I-O industry.

Editor's Note: This article covers one or more stocks trading at less than $1 per share and/or with less than a $100 million market cap. Please be aware of the risks associated with these stocks.

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por cyto às 14:13

Sexta-feira, 10.10.14

Why Immunotherapies Have Made DelMar's Lead Drug A Necessity In Brain Cancer

Why Immunotherapies Have Made DelMar's Lead Drug A Necessity In Brain Cancer

Jul. 15, 2014 2:40 PM ET  |  36 comments  |  About: DelMar Pharmaceuticals, Inc. (DMPI), Includes: CLDX, IMUC, NWBO by: Rajiv Puri

Summary

  • A large void in the Glioblastoma Multiforme treatment paradigm leaves patients with poor prognosis.
  • DelMar is tremendously undervalued on a NPV/DCF basis and relative to peers Northwest Biotherapeutics, Agenus, Celldex, and ImmunoCellular.
  • My estimates put fair value at $3.5/share, or 3X upside; analysts have assigned price targets as high as $8/share.
  • DelMar's VAL-083 addresses a large GBM population (>50%) unresponsive to standard of care, Temodar, and could be the answer to failures rampant in cancer vaccines (aka immunotherapies).
  • VAL-083 has approval in China for the treatment of Lung Cancer and CML. This serves as positive precedence for regulatory approval by the FDA and EMA.

In Glioblastoma Multiforme (GBM), the deadliest form of brain cancer, companies like Northwest Biotherapeutics (NASDAQ:NWBO), ImmunoCellular Therapeutics (NYSEMKT:IMUC) and Celldex Therapeutics (NASDAQ:CLDX) have stolen the spotlight, prematurely. As I explain later, these companies present a less than compelling case for producing strong risk-adjusted returns. They have also necessitated DelMar Pharmaceuticals' (OTCQB:DMPI) lead product, VAL-083, which is initially vying for a low-hanging $250M+ opportunity in 3rd line therapy that its peers have ignored. With ~45M shares outstanding on a fully diluted basis, DelMar is valued at just $40M. By any conservative measure, shares are worth at least $3.5, or 3X recent prices (valuation discussed below). If DelMar were valued in line with its peers, shares would trade at $5+. Maxim analyst Jason Kolbert assigned DMPI a 12-month target price of $8/share. But to understand the opportunity, we first need to understand GBM and where the current standard of care lies.

The Trending Combinational Therapy Model in GBM

With poor prognosis for patients and minimal improvement in the standard of care, Glioblastoma Multiforme is a highly focused area of cancer research. Like other areas of cancer research, novel targeted immunotherapies have been headlining developments. Similarly, these immunotherapies are primarily being implemented as the targeting agent in combinational therapies for reasons I have previously written about, here and here.

The driving force behind this paradigm shift is the presence of an enzyme which renders the chemotherapeutic agent Temodar, currently the first-line standard, useless in roughly 50% of patients. With the second-line treatment (Avastin, discussed later) having no evidence of improving chances of overall survival, patients are left without options. For analysis of the current state of GBM refer to the next section.

As an investor looking at the evolving treatment model, it is easy to forget that the chemotherapeutic agent, or more generally non targeting agent, plays a vital role in the overall success of the treatment. Some might argue even more importance, being that the one can exist as a stand-alone therapy. That being said, developments on that front (part B in figure 1) may prove useful in improving the current stand-alone model and further amplify the success of next-generation combinational treatments. For an investor, these developments may be a better bet given the uncertainty and volatile track record associated with immunotherapies.

With all the hype surrounding immunotherapies, DelMar Pharmaceuticals, which is involved in introducing a known (approved and selling in China) chemotherapeutic agent in GBM, has fallen under the radar. DelMar is undervalued and presents an asymmetrical risk/reward investment considering it is entering at least a $250M market (10x current market cap) of patients who have failed the standard of care and are left without options. The total addressable market remains upwards of $1B.

Background Information On The State Of GBM

According to the Cancer Research Institute, Glioblastoma Multiforme is one of the most aggressive types of brain cancer, with most patients failing to reach the one year survival mark and few living to see three years following diagnosis. For newly diagnosed GBM patients treated under the current standard of care, median progression free survival is 6.9 months and median overall survival is 14.6 months. Only 25% of newly diagnosed patients survive for 24 months and less than 10% survive more than 5 years. With approximately 16,000 newly diagnosed patients and 10,000 deaths from the disease in the US alone, there is a dire need to improve the standard of care.

The current standard of care consists of Temodar as the chemotherapeutic agent in chemoradiative therapy as a first line treatment. Temodar received approval in 2005 for the treatment of newly diagnosed GBM on the basis that it improved overall survival by 2.5 months. In 2009, the FDA approved Avastin as a second line treatment for patients with disease progression following treatment with temodar. Avastin's approval was based off an improvement in progression free survival.

The inability of the standard of care to effectively treat the GBM patient population can be attributed to the effect of the presence of an enzyme called MGMT. Also known as the DNA repair enzyme, MGMT corrects any damage done to the genetic information of the cancer cells by the chemotherapeutic agent. This effectively renders the treatment useless. Roughly 50% of GBM tumors highly express this enzyme, leaving a large void in the standard of care for this large subgroup of patients. As a result, many novel immunotherapeutic developments have received large visibility from investors.

Drawbacks Of Investing In the Current Targeting Therapies in GBM

As it pertains to GBM, immunotherapeutic vaccines are thought to be the answer to the Temodar's MGMT resistance issue. In theory, when combined, the drugs should have a synergistic effect; however, it seems unlikely that the net effect will sustain if the chemotherapy is ineffective. A clear example of this is ImmunoCellular Therapeutics' comparison between the unmethylated and methylated MGMT subgroup of patients expressing the HLA-A2 antigen from their Phase II trial studying their dendritic vaccine, ICT-107. For those wondering, unmethylated refers to a higher expression of the MGMT enzyme and methylated the lower expression.

HLA-A2 Patients

PFS in Control Group

PFS in Active Group

Unmethylated MGMT

6 months

15.8 months

Methylated MGMT

8.5 months

24.1 months

The chart above highlights the difference between the two groups. There was a 2.5 month difference between the control groups and a 8.3 month difference between the treated groups. This huge discrepancy suggests that the vaccine is marginally helping deal with Temodar's resistance to MGMT. The underlying issue is still there. As a disclaimer, the subgroups mentioned were not powered to show statistical significance. For IMUC investors, this last statement is taken directly from their latest press release and should raise some red flags considering the company has rationalized moving forward with a Phase III trial. Especially since the Phase II trial mentioned above did not meet its primary endpoint of overall survival (OS).

Northwest Biotherapeutics should be approaching the conclusion of their Phase III study of GBM vaccine DC-Vax-L, with the primary endpoint being extended PFS in newly diagnosed patients. This seems strange since approval as a first-line treatment would usually demand improvement in OS which was the primary endpoint of IMUC's trial. At face value, it would seem the company is leading the pack in GBM, with its Phase III trial scheduled to conclude in September 2014, as per the clinical trial page; however, the controversy surrounding the company provokes uncertainty. NWBO has its fair share of skeptics challenging the drug's efficacy following the failure of IMUC's similar dendritic cell immunotherapy, ICT-107. Granted, there are differences between the two vaccines; however, they are both dependent on the presence of an effective chemotherapeutic agent. In my opinion, the necessary coupling with effective Temodar treatment will prevent the two vaccines from becoming a benchmark under the evolving standard. The company has also been scrutinized for its "inappropriate" reporting of data, which has proven disconcerting to investors to say the least.

Anecdotal evidence of the associated risk of investing in vaccine type cancer immunotherapies can be derived from the story of Dendreon's (NASDAQ:DNDN) Provenge. Behind the approval of Provenge, the first and only cancer vaccine (but not immunotherapy), the company's stock rose to an all-time high of $54. This was short-lived due to the competitive landscape that formed in the field of prostate cancer subsequent to Provenge's approval. Both Johnson & Johnson's (NYSE:JNJ) Zytiga and Medivation's (NASDAQ:MDVN) Xtandi offered better results at a cheaper cost making both more favorable to Provenge. Currently, Dendreon has a market cap of $350M and trades at $2.30/share. As it relates to GBM, the anecdote is meant to remind investors of companies such as NWBO that even if the drug is approved (in my opinion, not likely), a position in the marketplace is not guaranteed.

On an optimistic note, Agenus Inc. (NASDAQ:AGEN) announced encouraging final results from a Phase II study on its autologous cancer vaccine Prophage. The drug is being developed for patients with newly diagnosed Glioblastoma Multiforme. Like the other two GBM vaccines, the treatment is designed to be in combination with the current standard of care. Since the drug is being developed for newly diagnosed GBM patients, it will be implemented as a first-line treatment. This means that the company will have to register for a lengthy Phase III trial prior to FDA approval.

Next in line, after NWBO's DCVax-L, to gain regulatory approval is Celldex Therapeutics' Rindopepimut. The company is expecting to conclude its Phase III ACT IV trial of its GBM drug candidate Rindopepimut in November of 2016 as outlined in its clinical trial page. ACT IV is modelled after a successful ACT III Phase II trial that produced an OS of 21.8 months and 26% 3-year survival vs. the 15.1 months OS and 18% 3-year survival obtained from an independent control dataset. The drug is also involved in a Phase II trial assessing Rindopepimut as a second line treatment in combination with Avastin. The trial is set to conclude in June of 2015. Using the Avastin approval in 2004 as a baseline, the drug could get approval from a Phase II study and potentially be on the market as early as late 2015. Like DCVax-L, the drug is designed to be in combination with the standard of care. However, unlike DCVax-L, Rindopepimut is specifically targeted at patients expressing EGFRvIII, representing at most a 30% subgroup of all GBM tumors. With that being said, the targeted drug market for GBM will not see any change from Celldex's Rindopepimut until early 2016 following the conclusion of ACT IV. This means that when (or, more appropriately IF) immunotherapies finally penetrate the standard of care, they won't apply to the majority 70% of patients.

From an investor's perspective, prospects on the immunotherapeutic front, in particular cancer vaccines, seem volatile given their uncertainty and the possibility of inadequacy. This is not to write off all immunotherapies, treatments under this umbrella have shown promise. In particular, checkpoint inhibitors have and continue to impress.

On the contrary, enhancing the current treatment paradigm or future combinational treatments through exploring the benefit of other known chemotherapeutic agents presents a more compelling investment opportunity with an asymmetrical risk/reward. Companies such as the one I am about to discuss have been overshadowed due to the hype surrounding immunotherapies.

VAL-083: The Answer To Temodar's Resistance?

As an investment opportunity, DelMar's chemotherapeutic drug VAL-083 has flown under the radar due to the hype of higher profile immunotherapies.

VAL-083 is an alkylating agent similar to its present market counterpart Temodar. The drug works by binding to DNA and interfering with the normal processes within the cancer cell. The cell is rendered dysfunctional and dies from improper protein production. Unlike Temodar, VAL-083 has demonstrated functionality in the presence of the enzyme MGMT. This is ultimately because Temodar damages with DNA at the O-6 guanine position and VAL-083 targets at the N-7 guanine position. This inherent attribute could threaten Temodar's reign in GBM. This short video better elaborates on the science.

What makes the company a particularly attractive investment is the approach it is taking to gain approval. The drug is being tested as a possible treatment for patients who have failed both first and second line therapy. The company would like to establish the drug as a "third line" treatment which, according to their 10-K, roughly represents 50% of all patients under the current standard of care, amounting to a $250M market in GBM alone (Refer to Valuation Section). Using Avastin's FDA approval as a comparative metric, the drug would likely have to show a good safety profile and demonstrate progression free survival.

To Reiterate: The company is seeking to treat a patient population with no current treatments available or likely to be available in the foreseeable future. This population is roughly half of all GBM patients.

Also streamlining its approval process and de-risking shareholder value is the data the company brings from over 40 clinical trials sponsored by the National Cancer Institute, NCI. The company is looking to approve a drug that has been tested on over 1000 patients and presents a safety profile that is well tolerated. To further solidify its case, the company can leverage the drug's international approval in China for CML and NSCLC.

An important fact about VAL-083 is that it is a drug that has been studied since the 70s under the name DAG (Dianhydrogalactitol). So why were developments dropped then and renewed now? According to the company's 10-K, this was ironically due to the attention targeted therapies were receiving which is consistent with the history of immunotherapies. The resurgence of the drug is fueled by a better understanding of cancer mechanisms and, as CEO Jeffrey Bacha explains, the increased availability for screening patients that are more prone to response from the drug.

VAL-083 is currently being studied in a Phase I/II, open label, single-arm study to determine the safety and maximal tolerated dose (NYSE:MTD) of VAL-083. Highlights of their clinical trial interim data from their presentation at ASCO include:

1) One of two patients in cohort 6 exhibited stable disease after one cycle of treatment. Outcome of analysis of cohorts 6 and 7 are ongoing.

2) No drug related serious adverse events have been detected, and maximum tolerated dose has not been reached at doses up to 30mg/m^2. Enrolment and evaluation of cohort 7 (40mg/m^2) is ongoing.

3) Pharmacokinetics are linear and consistent with previous published data, suggesting that concentrations of VAL-083 being obtained are effective against glioma cell lines in vitro.

If the MTD is not determined following treatment of the 7th cohort, DelMar will likely request regulatory approval for studying the drug in doses larger than 40mg/m^2. This will likely delay, with good reason, the readout of final data. Following the conclusion of the trial, DelMar will likely obtain guidance from the FDA before proceeding with a final Phase II/III trial. Assuming the trial can produce positive data, the drug would be in a position to penetrate the US GBM market in 2017.

DelMar's Valuation Reveals An Upside of 300% to $3.45/Share

Below is a table of assumptions that I used in my valuation. Most important among these is that sales are solely contingent on VAL-083 use in refractory GBM. This analysis neglected the future cashflows from possible label expansion into first and second line therapy, as this may be looking too far ahead for the cautious investor. Inclusion of this would cause the company's valuation to further increase. With 16,000 newly diagnosed patients in GBM every year, this represents $800M market opportunity under the same assumptions mentioned below.

Table 1. Valuation Assumptions

The company obtains FDA approval and begins marketing the drug as a "third line" treatment in 2017.

The 10,000 patients that die annually from GBM are the targeted patient population. For conservatism, I assumed that only 50% of this population can afford the treatment either through insurance coverage or otherwise.

The cost of one round of treatment is $50,000. The total addressable market is therefore $250M. Sales experience a 30% growth rate in the 7 years (2017-2024) of market exclusivity following approval.

Sales are discounted backwards at a rate of 15% and additionally a 60% margin of safety is applied to net present value.

All Outstanding warrants are exercised.

 

Options

3,240,000

Estimated Out Shares following exercise of warrants

41,360,245

Fully Diluted Shares

44,600,245

Source: Prospectus as of April 29, 2014

Below is a Sensitivity Table, illustrating the change in market valuation as a function of the market penetration.

Mkt Penetration(%)

5

10

15

20

25

Mkt Cap ($)

51.4

102.8

154.1

205

257

**Market Cap is in millions.

Assuming a 15% market penetration, the company should be valued at $154.1M. This reveals an approximate 300% upside from the current price of a share to $3.45.

In my opinion, this valuation represents a significant upside given its conservatism.

Understanding The Risks Associated With DelMar

The main risk associated with the company's success is its ability finance its operations for the foreseeable future. The company most recently raised $2.4 million in net proceed upon the closing of a lead order, which management believes will fund operations till December 2015. The company has also filed a tender offer on June 9, 2014 to outstanding warrant holders, decreasing the exercise price from $0.80 to $0.65. Potential exercise of these warrants could bring in a total of $6M and fund the registration trial of VAL-083. This financing is not truly dilutive, as all current warrants were introduced from previous rounds of financing. There still remains the risk that the company may need to raise funds via purely dilutive financing.

The second major risk is that company's success is solely contingent on the approval and commercialization of VAL-083. Although the company has approval in China for CML and Lung Cancer, it requires the approval of the FDA, which may be more stringent than other regulatory bodies. There are no other drugs in the company's pipeline, although the company has presented pre-clinical data of VAL-083 in treatment of non-small-cell-lung-cancer (NSCLC). This means that the drug's failure in GBM does not imply the end of VAL-083 in all cancer indications.

The third major risk is competition. The immunotherapy companies mentioned above can all be considered competition. With that being said, DelMar does have one major advantage that would allow them to gain approval on a much shorter time scale. DelMar is trying to treat patients who have failed the current standard of care making them a "third line" treatment. This is in contrast to the companies mentioned above who are either going for first or second line treatment, and likely to be scrutinized more heavily prior to regulatory approval. On the chemotherapeutic front, the company also has a competitor in CyTRX Corporation. Just like its counterparts in immunotherapy, the company will likely face a relatively long road to approval as it begins its Phase II trial determining efficacy and safety in patients who have failed first line treatment with Temodar.

Near Term De-Risking Catalysts and Concluding Remarks

The company performance should see upside from approaching catalysts, most notably from the conclusion of its current clinical trial, meetings with regulatory authorities and registration of its Phase II/III trial, among others. For a more extensive list of catalysts, refer to this. Each of these milestones will likely serve as de-risking events in the company's maturation and drug's approval process.

As a concluding remark, I would like to remind investors of the benefits that prospective combinational treatments bring. The use of multiple drugs not only improves results for patients, but also creates multiple investment opportunities within the same indication. This creates an interesting dichotomy between therapies, such as chemotherapy and immunotherapy, where the two are symbiotic competitors. This decouples the risk for agents that are more integral to the overall efficacy, such as Temodar, under the current treatments and hopefully VAL-083 in future treatments.

Editor's Note: This article covers one or more stocks trading at less than $1 per share and/or with less than a $100 million market cap. Please be aware of the risks associated with these stocks.

Autoria e outros dados (tags, etc)

por cyto às 14:06

Sexta-feira, 10.10.14

Long Or Short: Cancer Cures

Long Or Short: Cancer Cures

Jun. 26, 2014 10:12 AM ET  |  14 comments  |  Includes: DNDN, NWBO by: Ryan Pawell

Disclosure: The author is long NWBO. The author wrote this article themselves, and it expresses their own opinions. The author is not receiving compensation for it (other than from Seeking Alpha). The author has no business relationship with any company whose stock is mentioned in this article. (More...)

Summary

  • Autologous immune cells for curative cancer therapies.
  • Dendritic cells initially proven to be safe and effective.
  • Dominant market player will need autologous immune cells that are safe, effective and affordable.

Recently, Forbes ran an article titled "Is This How We'll Cure Cancer?" and discussed the potential benefits of chimeric antigen receptor T lymphocytes (CARTs) or white blood cells that are engineered to hunt down and attack cancer.

These engineered white blood cells are exciting - clinical trials demonstrate these cells "[make] blood cancers seem to disappear and then stay vanished".

Companies large and small are placing bets on this potential cancer cure and the value of these deals range from millions to billions of dollars. Juno Therapeutics recently raised an unprecedented nine-figure Series A and claims "CARTS… eradicate treatment-resistant cancers in patients with a large tumor burden"

CARTS are enjoying a healthy amount of attention and funding, however, the use of engineered immune cells for cancer therapeutics is far from the bleeding edge. Dendreon (NASDAQ:DNDN), a company spun out of Stanford Medical School in 1992, demonstrated engineered dendritic cells (DC) are both safe and effective for treating metastatic prostate cancer, receiving FDA approval in 2010. Some believe DNDN is a flop as their current model is struggling to turn a profit.

Most of these exciting therapies use autologous cells or cells from your own body and require a centralized manufacturing plant with an eight-figure price tag. For autologous cell therapies, the centralized manufacturing requires one's own cells to be extracted at a local hospital or blood bank then shipped to the manufacturing plant for engineering, and shipped back for infusion. Logistics is a major bottleneck for this centralized manufacturing model.

Ask any biologist, working with live cells is not easy and live cells require constant feeding in a controlled environment if you cannot freeze them. Live cells require a precisely controlled sterile environment with respect to temperature, pH, osmotic pressure, O2, CO2 - it ain't easy to keep cells alive in a lab, let alone during transportation. Additionally, live cells must be surrounded by the appropriate hormones and nutrients, which are consumed quite quickly.

For DNDN, logistics looks to be their most daunting challenge. DNDN maintains a logistics command center for coordinating each personalized therapeutic across the United States and the complexity of this system significantly adds to the cost of goods sold.

The key technical advantage for CARTs is cryopreservation or freezing, CARTs can be frozen down and shipped in vials immersed in liquid nitrogen increasing the shelf-life of the cells. DNDN's DCs could not be frozen and may require complex environmental controls described above if short shipping times are not available - transporting biologics in a timely manner is quite expensive. For this reason, CARTs look to be a safe, effective and economically viable choice.

Another dendritic cell initiative is Northwest Biotherapuetics (NASDAQ:NWBO). NWBO maintains a healthy clinical pipeline with therapeutics for brain cancer, metastatic ovarian cancer, colon cancer metastases and prostate cancer. An NWBO patient received their therapy nearly a decade ago and is still kicking, whereas the average patient in a DNDN clinical trial lived 4.1 months longer when compared a placebo patient.

NWBO looks to be taking a more holistic approach with their therapeutic. The NWBO cells are engineered to identify a range of biomarkers, if the cancer adapts it can still be recognized by the DCs. For some reason, NWBO does not disclose this on their "DCVax ® Technology" webpage nor is this key technical advantage disclosed on their Wikipedia page, but NWBO can freeze their dendritic cells.

From a biological perspective, dendritic cells are the ideal choice. These cells could be likened to a parent cell that can teach its kids to attack cancer in the body where the kids are T-cells.

On balance, these promising cancer cures come in two platforms (1) engineered T-cells and (2) engineered dendritic cells. Both look to be fairly effective in eradicating previously untreatable cancers. However, NWBO's use of the ideal biological platform and their ability to freeze these cells positions them to dominate the market in the long term.

I believe the winner of this race will be autologous engineered dendritic cell therapies manufactured in a safe, effective and affordable manner.

DNDN demonstrated Provenge, a DC-based therapy, is safe and effective for the treatment of metastatic or advanced prostate cancer. According to Yahoo! Finance, DNDN's operations resulted in negative net income of about $300 - $400 million for 2011 - 2013. This is about 22 years after launch and some attribute these losses to live cell logistics.

NWBO has been around for quite some time too, with the IPO occurring in late 2001. And, according to Yahoo! Finance, NWBO enjoyed negative net income of $30 - $70 million for 2011 - 2013. NWBO's therapeutic looks to be safe and effective just like DNDN's and Steven Giardion did a great job addressing recent negative publicity. NWBO worked out a way to freeze DCVax - a key competitive advantage over DNDN. A physician just needs to warm up a few drops of DCVax and inject the patient intradermally.

Going long on DNDN might mean you think it can turn itself around, going short on NWBO might mean you do not think its therapeutic will be safe and effective. Going long on NWBO after regulatory approval means you might think NWBO's therapeutics are going to be safe, effective and economically viable.

A final note, both DNDN and NWBO employ complex laboratory processes in their manufacturing facilities. If economic viability is simply not in the cards with current processes, both DNDN and NWBO will need to look to alternative technologies to reduce the cost of goods sold. That technology exists. It is just a matter of implementation.

Autoria e outros dados (tags, etc)

por cyto às 13:39

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