These awards are designed to facilitate progress via interactions between the academic and industrial research sectors and are co-funded by MRA and an industrial collaborator whose involvement is essential to the project.
Evaluation of intermittent MEK inhibition in uveal melanoma
CUMC-MSK-MD Anderson-MRA Team Science Academic Industry Partnership Award
Industry Partner: AstraZeneca
• Richard Carvajal, M.D., Columbia University Medical Center
• Paul Chapman, M.D., Memorial Sloan Kettering Cancer Center
• Sapna Patel, M.D., The University of Texas MD Anderson Cancer Center
• Young Investigator: Piro Lito, M.D., Memorial Sloan Kettering Cancer Center
There is no FDA approved therapy for patients with advanced uveal melanoma, and outcomes are exceedingly poor for this patient population. Our group has demonstrated that inhibition of a cellular pathway called the MAPK pathway with a drug called selumetinib is an effective therapy for uveal melanoma, but, despite this treatment, cures are not achieved. Although drugs such as selumetinib have been studied when patients take the treatment every day, research has shown that, in some cases, it may be better to use the treatment on an intermittent schedule. Such a strategy may reduce the side effects, allow higher doses of the drug to be used, more completely block the MAPK pathway, and prevent the development of drug resistance mechanisms within the tumor. In our proposal, we will conduct a clinical trial that will identify the highest safe dose of selumetinib that can be administered to patients with advanced uveal melanoma on an intermittent schedule, evaluate how well this administration schedule of selumetinib works in patients with uveal melanoma, use tumor biopsy samples to evaluate the downstream effects of this treatment, and explore mechanisms of sensitivity and resistance to further optimize therapeutic approaches to treating patients with this disease and continue our efforts to identify a cure for uveal melanoma.
Defining biomarkers of immune activation during anti-PD1+Tvec therapy
Amgen-CUMC-MRA Established Investigator Academic-Industry Partnership Award
Industry Partner: Amgen
Yvonne Saenger, MD, The Trustees of Columbia University in the City of New York
The immune system is known to play a critical role in controlling, and in some cases eliminating, melanoma. We propose to study the efficacy of combining two immunotherapies that have proven efficacy against melanoma to test whether combining agents activating distinct arms of the immune system can provide overall stronger immune response and could potentially cure more patients.. Talimogene laherparepvec (Amgen Inc), is an oncolytic virus that directly infects tumor cells and kills them while also releasing stimulators to draw in and activate immune cells. Anti-PD-1 antibody binds to an inhibitory marker on T cells and prevents T cell exhaustion and immune suppression. The concept is to bring T cells into the tumor using the vaccine and then to activate them using the anti-PD1. We will use a mutant mouse model to mimic the common BRAF mutation seen in melanoma, and use a BRAF inhibitor alongside the immunotherapies. We will define the synergy of combination therapy through survival studies. We will quantify immune cell populations by studying the tissue and blood of the mice. We will investigate cellular mechanisms of combination therapy and immune cell subtypes using flow functional immune assays and immune deficient mouse models. We also propose to define biomarkers predictive of response to treatment using microarray of frozen tumors and comparing mice with different outcomes. The purpose of this study is to provide valuable information for designing clinical protocols combining immunotherapies in patients and to help us understand which immune cell types and signaling pathways will be critical to success using these two agents together.
Improving cancer vaccines with agonistic antibodies to CD40 and CD27
UVA-MRA Established Investigator Academic Industry Partnership Award
Industry Partners: Celldex Therapeutics and Roche
Craig L. Slingluff, M.D., The Rector and Visitors of the University of Virginia
The immune system can reject human cancers, based in part on a balance of activating and inhibitory forces. Therapeutic blockade of inhibitory molecules (checkpoint blockade) causes regression of some human cancers. In counterbalance to the checkpoint molecules are a set of costimulatory molecules, including CD27 and CD40, which can be activated by agonistic antibodies. The present proposal is to test whether administration of agonistic antibodies to CD40 and/or CD27 supports the magnitude and duration of immune responses to a defined cancer vaccine.
Combined CTLA-4 and angiopoietin-2 blockade in advanced melanoma patients
MRA Academic Industry Partnership Award with generous support from the Botica Family
Industry Partner: MedImmune
F. Stephen Hodi, M.D., Dana-Farber Cancer Institute
Improved understanding of mechanisms of immune function has recently provided novel ways to take the brakes off the immune system to treat cancer. One such means has been to block the molecule Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), a signal that can suppress the immune system. Blocking CTLA-4 in patients with metastatic melanoma is now considered standard therapy based on clinical studies that showed improved survival with CTLA-4 blockade, which was the first time a drug for advanced melanoma was proven effective in a phase 3 study. Interestingly, part of the anti-tumor response involves an immune attack of the blood vessels feeding the tumors. We have previously shown that blocking tumor vessel formation by targeting vascular endothelial growth factor (VEGF) in combination with CTLA-4 blockade can have beneficial effects on the immune response in the tumor and is safe in patients. VEGF is a factor known to be involved in the formation of blood vessels that feed tumors and has also been found to suppress the immune system. Another important molecule that contributes to tumor vessel formation is a molecule called angiopoetin-2. We propose to combine for the first time an antibody that blocks CTLA-4 to take the brakes off the immune system with an antibody that blocks angiopoetin-2 to block blood vessel formation in tumors. Importantly, we seek to understand synergies in combining these two drugs that together could target the blood vessels feeding melanoma deposits.
Kinome activation signatures in drug resistant melanoma
MRA Academic Industry Partnership Award with generous support from Anonymous Donor
Industry Partner: GSK
Gary L. Johnson, Ph.D., University of North Carolina at Chapel Hill
A recent clinical trial revealed that the GlaxoSmithKline (GSK) FDA-approved drugs dabrafenib and trametinib are more effective in combination than as single agents in metastatic melanoma that have a mutation known as BRAFV600E/K. Unfortunately, challenges remain as patients treated with these drugs initially exhibit a very favorable response but ultimately succumb to recurrent disease. Retrospective analyses of these clinical samples has shown new mutations arise that contribute to resistance to the combination therapy. Our current knowledge of resistance mechanisms remains incomplete. We now know in response to this promising combination therapy that enzymes known as protein kinases become activated, causing an adaptive response in the tumor cells that leads to therapeutic resistance. In collaboration with GSK, we will utilize a novel technology we have developed to systematically evaluate the response of protein kinases in the melanoma cells to the combination therapy. We will define which kinases contribute to the adaptive response that causes resistance to treatment. A GSK-sponsored clinical trial conducted at the University of North Carolina Cancer Hospital involves melanoma patients receiving dabrafenib/trametinib combination therapy. In this trial pre-treatment biopsies and same-patient tumors are isolated after disease progression following dabrafenib/ trametinib combination therapy. The pre- and post-treatment melanomas will be analyzed to define the adaptive response involving changes in protein kinases. Determining the adaptive response to dabrafenib/trametinib combination therapy will lead to new clinical trials involving the rational design of novel anti-cancer combination therapies to treat melanoma that overcomes and prevents progression to drug-resistant disease.
Double immune suppression blockade to treat melanoma
MRA Academic Industry Partnership Award
Industry Partners: Merck and Plexxikon
Antoni Ribas, M.D., Ph.D., University of California Los Angeles
The success of tumor immunotherapy for the treatment of melanoma is limited by the presence of intratumoral immune suppressive cells. Critical among them are the tumor infiltrating myeloid cells, which dampen T cell responses to cancer. We hypothesized that a small molecule inhibitor of a key myeloid cell receptor called CSF-1R would cripple the immune suppressive myeloid cells and improve the antitumor activity of effector immune cells. We have tested the combination of CSF-1R inhibition and immunotherapy in preclinical models and the results are fully supportive of our hypothesis. These results allowed us to partner with Plexxikon to provide the CSF-1R inhibitor PLX3397 and with Merck to provide the anti-PD-1 antibody MK-3475 and jointly propose a phase 1 dose-escalation study. The phase 1 trial will open to patients with metastatic melanoma with or without progression to prior anti-PD-1 or anti-PD-L1 therapy, and we will undertake studies to test if the combined effects of these two therapies work in humans through the same mechanism as in our preclinical studies.
Determinants of response to CDK4/6 inhibitors in melanoma
Industry Partner: Pfizer
Andrew E. Aplin, Ph.D., Thomas Jefferson University
Melanoma is the deadliest form of skin cancer with a high lifetime risk. There will be over 60,000 new cases and 8,000 deaths in the U.S. this year. While an increased understanding into the genetics of melanoma has ultimately led to new therapeutic treatments for melanoma, these treatments only provide short-term benefit to patients. Thus, there is a clear need for additional therapies use in combination to prolong the clinical benefit for melanoma patients. In preclinical breast cancer models, our collaborator has shown that highly specific drugs, known as CDK4/6 inhibitors, have substantial activity in terms of blocking cancer cell growth. This proposal will analyze the potential of CDK4/6 inhibitors in melanoma. We foresee 3 potential uses: i) combination with the FDA-approved RAF inhibitors such as Zelboraf; ii) for treatment of recurrent disease; and iii) treatment of a subset of melanomas for which there is no current targeted therapy option. Together, these areas represent large patient populations for involvement in clinical studies. Importantly, we have preclinical models that will enable us to rapidly interrogate the activity of CDK4/6 inhibitors in these subtypes of melanoma and provide the springboard for Phase I/II trials.
Next generation vaccines to augment anti-PD-1 immunotherapy for melanoma
Industry Partner: Aduro Biotech
Charles G Drake, M.D., Ph.D., Johns Hopkins University
Clinical trials in late-stage melanoma patients showed that blocking PD-1 (with anti-PD-1) can cause tumor shrinkage in about 30% of patients. Anti-PD-1 works by binding killer T cells that are trying to eliminate tumor cells, but can’t. Many of those T cells aren’t working because they have PD-1 on their surface, acting like a “brake”. Blocking PD-1 with anti-PD-1 is like taking off the brakes, so that T cells move into the tumor and kill cancer cells. One reason why anti-PD-1 is not more effective is because many patients don’t have anti-melanoma T cells primed and ready. In such patients, we propose to first initiate an anti-tumor immunity using a melanoma-specific vaccine, and to next allow those cells to function by blocking PD-1. The vaccine we plan to use is novel; it is based on a strain of bacteria known as Listeria. We’ve been especially impressed by listeria-based vaccines because, in several challenging animal models, these vaccines can succeed in initiating an immune response where other vaccines fail. Although listeria can cause illness in humans, this strain is very different, it has been toned down so that it is about 10,000 times less likely to cause infection. We will also study another novel way to vaccinate melanoma patients; using molecules known as CDN, which are likely the active ingredient in listeria. Those vaccines would be simpler to make and use. Importantly, both of these vaccines will be studied in combination with PD-1 blockade, with plans for rapid clinical translation.
Exploring the role of CDK4 and CDK6 in melanoma maintenance
Industry Partner: Pfizer
Martin McMahon, Ph.D., The Regents of the University of California, San Francisco
Melanoma is noted for its alarming increase in incidence, especially amongst the young, aggressive clinical behavior and propensity for lethal metastasis, illustrating an urgent need for new treatment strategies for this disease. However, despite the bleak clinical and epidemiological picture, genetic analysis has uncovered key driver oncogenes in melanoma such as mutationally activated BRAF. Importantly, when mutationally activated BRAF is pharmacologically inhibited with vemurafenib, BRAF mutated melanoma patients, even those with widely disseminated, metastatic disease, have enjoyed dramatic tumor regression coupled with significant health improvement. However, since the durability of such responses is limited by the emergence of lethal drug resistant disease, there is a strong emphasis on developing combination therapies to increase the durability of patient response. Another frequent alteration in melanoma is silencing of INK4A, a key regulator of the cell division cycle. INK4A silencing leads to unrestrained activity of two key enzymes, CDK4 and CDK6, which are inhibited by the Pfizer drug PD332991. Here we propose to use genetically engineered mouse (GEM) models of BRAF/INK4A mutated melanoma, which accurately model the human disease, in conjunction with human melanoma cell lines to test the ability of PD332991, either alone or in combination with vemurafenib, to inhibit melanoma growth. Studies proposed here offer the long-term prospect of evidence-based, effective, durable and comparatively less toxic chemotherapy for patients with advanced melanoma based on a molecular understanding of how signal transduction pathways and the machinery of the cell division cycle contribute to the aberrant biology and biochemistry of the melanoma cell.
CTLA-4 and anti-PD1 blockade: Correlative assessments for discovery
Leveraged Finance Fights Melanoma-MRA Academic Industry Partnership Award
Industry Partner: Bristol-Myers Squibb
Jedd Wolchok, M.D., Ph.D., Memorial Sloan-Kettering Cancer Center
Drew Pardoll, M.D., Ph.D., Johns Hopkins University
Young Investigator: Janis Taube, M.D., Johns Hopkins University
Mentor: Drew Pardoll, M.D., Ph.D., Johns Hopkins University
Young Investigator: Travis Hollmann, M.D., Ph.D., Memorial Sloan-Kettering Cancer Center
Mentor: Klaus J. Busam, M.D., Memorial Sloan-Kettering Cancer Center
The fundamental basis of cancer immunotherapy is that a patient’s own immune system can be empowered to recognize their cancer cells as foreign and eliminate them. While proof-of-principle for this concept has been observed for many years, only recently has the power to the immune system been demonstrated in significant numbers of patients with advanced cancer. The breakthrough came from discoveries that immune responses are naturally dampened by a set of molecules that “put on the brakes” – these are termed immune checkpoints. While immune checkpoints are normally important in regulating the magnitude of our natural responses to viruses and bacteria, we have discovered that cancers co-opt checkpoints to protect themselves from attack by the patient’s immune system. Antibodies that block two checkpoints, termed CTLA-4 and PD-1, have been shown to unleash anti-tumor immune responses in some melanoma patients, leading to long-term remissions in a proportion of cases. Because these two checkpoints work at very different points in regulating immune responses, the MSKCC and JHU groups have teamed up with Bristol-Myers Squibb, which makes both of these antibodies, to explore their combined use, either together or in sequence. Preliminary clinical results support the enhanced activity of the combination relative to either antibody used alone. This proposal seeks to comprehensively define the immune mechanisms for the potential synergistic effect of these antibodies in a way that will help define which patients will benefit most from this combination strategy and which additional immune checkpoint molecules should be targeted to further improve anti-melanoma activity.
Therapy with anti-PD-1 antibody and Peginterferon alpha-2b for melanoma
Industry Partner: Merck
Hassane M. Zarour, M.D., University of Pittsburgh
Metastatic melanoma remains a disease that is associated with poor prognosis. Antibodies targeting the so-called inhibitory receptors expressed by T lymphocytes have recently demonstrated clinical efficacy. For example, Ipilimumab, which targets the inhibitory receptor CTLA-4 expressed by T cells, appears to promote sustained responses and survival prolongation and has an objective response rate of 10%. Most recently, a novel antibody targeting the inhibitory receptor PD-1 expressed by T cells in the tumor microenvironment has shown evidence of clinical efficacy in a significant faction of patients with advanced melanoma. Here, we propose a novel clinical trial to evaluate whether combinatorial immunotherapy with anti-PD-1 antibody (MK 3475) and Peginterferon (PEG IFN) alpha-2b will further increase the clinical benefits provided by anti-PD-1 antibody alone. This proposal is based on a series of experimental evidence supporting the direct antitumor activity of IFN alpha and the role of anti-PD-1 antibody in combination with IFN alpha in better promoting tumor rejection. This project will benefit from the well-known expertise of our group in IFN-alpha-based therapy of melanoma patients and in basic and translational cancer immunology. Collectively, this clinical trial will represent a unique opportunity to further improve potent therapy of melanoma and to investigate antitumor and immunological effects of the proposed combinatorial immunotherapy.
Novel IL-15/IL-15 Receptor-IgFc Complex in Advanced Melanoma Patients
Industry Partner: Altor BioScience Corporation
Mac Cheever, MD, Fred Hutchinson Cancer Research Center
Interleukins, proteins that mediate communication in the immune system, can be used to treat cancer. IL-2 is one such interleukin, which is active against melanoma in a small fraction of patients, but IL-2 is very toxic and difficult to administer. Another interleukin, IL-15, shows promise, both in animal studies and in early work in humans. Because of its properties and differences from IL-2, IL-15 is considered one of the most promising immunotherapeutic agents, especially in patients with melanoma. IL-15 works by activating certain T cells, which enhance the immune system's response to the cancer. Due to differences in its structure and how it is used by the immune system, unmodified IL-15 may have properties that make it difficult to use in people with cancer. However, ALT-803, a compound that modifies the protein structure of IL-15, has been shown in animals to work at lower doses for longer periods than unmodified types of IL-15. Our study is a first-in-humans use of ALT-803 for treating patients with incurable melanoma. We will study the safety and efficacy of ALT-803 to understand how it is handled by the body, whether it is active against melanoma, and how best to combine it with other cancer therapies to make them more effective. We will also perform a series of research laboratory tests to learn more about the effects of ALT-803 on various components of the immune system that might impact how it works against melanoma and enhances other forms of therapy.
Enhancing melanoma specific T cell function by CD27 stimulation
Industry Partner: Celldex Therapeutics
Timothy Bullock, Ph.D., The University of Virginia
Until recently, patients with advanced melanoma had few effective treatment options. The exquisite sensitivity and specificity of the immune system offers hope for both acute and long-term control of melanoma. Particularly intriguing are recent studies with antibodies that block molecules that put the brakes on the immune response. The tumor control that results from these interventions indicates that not only does the immune system recognize the growing tumor, but when appropriate activated, has the tools to combat tumor outgrowth. An alternative, or complimentary, approach to blocking inhibitory molecules that reduce immune responses is to activate stimulatory molecules on immune cells that are responsible for driving their proliferation, survival and enhancing their functional capabilities. One such molecule is CD27, which is expressed on several subsets of immune cells found in the blood. Importantly, we have previously shown in preclinical mouse models of melanoma that stimulation of CD27 can activate immune cells within melanoma, which in turn supports the control of tumor outgrowth. We now propose to study whether an antibody that stimulates CD27 on human immune cells has the same effect; can it stimulate the activity of immune cells within melanoma metastases or melanoma patient's blood? These studies will be performed in collaboration with Celldex, the maker of the antibody, partially in the context of a phase I clinical trial to test the safety of the antibody.
Comprehensive diagnostic imaging system for melanoma detection
Industry Partner: Canfield Scientific, Inc.
Allan Halpern, M.D., Memorial Sloan-Kettering Cancer Center
Promotion of early detection in high risk individuals has the greatest likelihood of decreasing melanoma mortality in the short term. The use of total body photographs to help identify new and changing lesions and sequential digital dermoscopy for the assessment of individual concerning lesions, can improve the detection of thin melanomas while preventing unnecessary biopsies. Nonetheless, these imaging techniques are not routinely employed by dermatologists in the U.S. A major obstacle to the use of these technologies is the logistic difficulty of implementing them in routine practice. In this project, we propose to develop a comprehensive imaging solution that will facilitate the use of total body photographs and sequential digital dermoscopy by reducing the time and expertise associated with their use. Specifically, we propose to develop a semi-automated system to instantaneously capture a total body 3-dimensional image of a patient's skin at a reasonable cost and with minimal expertise. We further propose to develop a software solution that will enable physicians to easily acquire and track close up and dermoscopic images of patients' individual moles for monitoring over time. For this project, we have established a partnership between the country's leading provider of dermatology photography services (Canfield Scientific, Inc.) and one of the country's leading melanoma programs (Memorial Sloan-Kettering Cancer Center) to leverage recent technologic advances to develop the proposed imaging solution.
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