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Funded Research

Integrative Analysis of Prognostic Factors to Neoadjuvant Nivolumab/CMP-001 in Stage III B/C/D Melanoma

Integrative Analysis of Prognostic Factors to Neoadjuvant Nivolumab/CMP-001 in Stage III B/C/D Melanoma

Integrative Analysis of Prognostic Factors to Neoadjuvant Nivolumab/CMP-001 in Stage III B/C/D Melanoma

Diwakar Davar, MD

Co-PI Meghan Mooradian, MD; Julie Stein, MD
Mentor Hassan Zarour, MD; Ryan Sullivan, MD; Janis Taube, MD, MSc
Award Type Team Awards
Institution University of Pittsburgh
Donor Support MRF Breakthrough Consortium-Bristol Myers Squibb Young Investigator Research Team Award to Advance the Field of Translational Immuno-Oncology

Description:

Patients with lymph-node positive melanoma have a high risk of recurrence despite curative surgery. While adjuvant therapy given after surgery improves RFS and OS, ~25% of patients particularly those with bulky lymph-node disease, progress prior to commencing adjuvant therapy.

Neoadjuvant immunotherapy with anti-PD-1 produces pathologic responses in 25-30% of patients and is well tolerated. While combinations of anti-PD-1 with anti-CTLA-4 produce even greater pathological response rates, this combination is associated with considerable side effects in >50% of treated patients. Combinations that improve upon the benefit seen with anti-PD-1 with minimal additional side effects are desirable.

Based upon the successes of anti-PD-1/CMP-001 in advanced melanoma, we launched a clinical trial studying CMP/nivo in high-risk resectable melanoma with promising results. In 20 treated patients, we have shown that the neoadjuvant CMP/nivo produces pathologic responses in approximately 70% of patients. The combination is well tolerated with low incidence of adverse events. Patients who experience major pathologic response have prolonged RFS. In this context, we propose a tri-institutional collaboration to analyze immunophenotypic, histopathologic and ctDNA biomarkers of response to this therapeutic modality.

Novel Target for Melanoma Therapeutic Development

Novel Target for Melanoma Therapeutic Development

Novel Target for Melanoma Therapeutic Development

Linda Malkas, PhD

Mentor Long Gu, PhD
Award Type Established Investigator Award
Institution Beckman Research Institute of the City of Hope

Description:

Melanoma is one of the fastest growing malignancies and accounts for 5.5% of all new cancer cases in the United States. Treatment options and prognosis of melanoma patients depend on the risk stratification. Survival is excellent in low risk groups and localized diseases often require simple surgery only. In fact, a very thin melanoma may be removed entirely during the biopsy and require no further treatment. In contrast, metastatic melanoma is very difficult to treat. The current standard of care uses aggressive multi-regimen treatment, which could cause severe side effects. The 5-year survival rate for patients with metastatic melanoma is less than 25%. There is a significant unmet medical need for new therapies to improve the treatment outcomes of this aggressive cancer phenotype. Proliferating cell nuclear antigen (PCNA) is a protein that helps regulate DNA synthesis and repair. It is an attractive molecular target to develop a drug to treat melanoma, because melanoma cancer cells depend on PCNA for growth and survival. While studying this protein, we discovered a cancer-associated isoform of PCNA (caPCNA) that is present in a broad range of cancer cells and tumor tissues (including melanoma), but not present in otherwise healthy cells. We tested a series of drugs designed by computer modeling and medicinal chemistry to target caPCNA and identified AOH1996, a potent inhibitor that selectively melanoma cells but causes no significant toxicity to a broad range of normal cells. The pharmacologic and therapeutic properties of AOH1996 are extremely favorable in animal studies. When orally given to mice, AOH1996 suppresses the growth of a broad range tumor types without causing any observable side effects, including weight loss.

Based on our communication with the US Food and Drug Administration (FDA), we are confident that we will readily meet the FDA’s regulatory requirement for a new investigational drug (IND) filing. The information derived from this proposal will inform the design and implementation of the expected clinical trials. Specifically, our proposal will determine the effective dose range for clinical trials. It will also validate biomarker(s) in tumor cells that will enable us to select melanoma patients who are likely to respond to AOH1996 treatment. Based on its favorable therapeutic properties seen so far in our animal studies, AOH1996 is likely to lead to a novel class of drug and significantly improve treatment options and outcomes of patients with metastatic melanoma.

Converting Regulatory into Proinflammatory Anti-Tumor Effector T Cells

Converting Regulatory into Proinflammatory Anti-Tumor Effector T Cells

Converting Regulatory into Proinflammatory Anti-Tumor Effector T Cells

Thorsten Mempel, MD, PhD

Award Type Established Investigator Award
Institution Massachusetts General Hospital

Description:

The majority of cancer patients do not yet benefit from immunotherapy, including from immune checkpoint therapies that invigorate the patients’ own immune systems to fight their tumors. In many cases the underlying reason is that tumors are not recognized strongly enough by the patients’ immune systems and consequently, are only poorly infiltrated by anti-tumor effector T cells that could otherwise reject the tumor. In addition, so-called regulatory T cells (Treg) actively limit the anti-tumor activity of those effector T cells that manage to enter the tumor tissue. One approach to address this situation has been to deplete Treg. However, effective depletion of these cells may cause autoimmune disease, because Treg also prevent our immune system from turning against our healthy tissues.

We have discovered a method to selectively reprogram immunosuppressive Treg in tumor tissue, but not those in healthy tissues, and convert them from immuno-suppressive pro-tumor into inflammation-causing anti-tumor effector cells. Thereby, we are able to sensitize otherwise treatment-resistant mouse tumors to immune checkpoint therapy and cause their rejection. This finding suggests a potential new strategy to successfully treat many of those cancer patients who currently do not respond to immunotherapy. However, in order to develop this method for human therapy we will need to understand 1) why only Treg in tumor tissue are reprogrammed, 2) through what mechanism Treg are induced to produce inflammatory cytokines, and 3) if human Treg can be reprogrammed the same way as mouse Tregs. We propose to address these questions in this project.

Defining the Mechanisms of Resistance to Anti-CTLA4 Antibodies in the TME

Defining the Mechanisms of Resistance to Anti-CTLA4 Antibodies in the TME

Defining the Mechanisms of Resistance to Anti-CTLA4 Antibodies in the TME

Jeffrey Ravetch, MD, PhD

Award Type Established Investigator Award
Institution The Rockefeller University

Description:

Over the past decade, harnessing the power of a patient’s own immune system for the treatment of cancer has been a major medical breakthrough. By using drugs to block inhibitory signals on immune cells, these medicines help “release the brakes” allowing them to kill cancer cells. One of these drugs is an antibody directed against a protein called CTLA-4. So transformative to the care of patients with melanoma and other cancers, the investigators who initially described such pathways were recently awarded the Nobel Prize. While these therapies have been lifesaving for many, they still fail to benefit the majority of patients receiving them. The reason for this lack of activity in some remains poorly understood. We recently uncovered a mechanism of how this may happen, in that cancers develop another “checkpoint” preventing the activity of anti-CTLA-4 antibodies at the tumor site. This checkpoint, called FcyRIIB, becomes increased in tumors and limits the ability of anti-CTLA-4 antibodies to deplete an important cell type contributing to the suppression of anti-cancer immunity. These studies will investigate this pathway in pre-clinical models and patient specimens, with the goal of using this knowledge to translate improved anti-CTLA-4 antibodies into the clinic.

Elucidating Metabolic Changes that Occur in Melanoma Brain Metastases

Elucidating Metabolic Changes that Occur in Melanoma Brain Metastases

Elucidating Metabolic Changes that Occur in Melanoma Brain Metastases

Zachary Schug, PhD

Mentor Meenhard Herlyn, DVM, DSc
Award Type Career Development Award
Institution The Wistar Institute

Description:

Melanoma is the third most common malignancy to metastasize to the brain. It is estimated that at least 50% of patients with stage IV melanoma will develop brain metastases during the course of disease. There is now abundant evidence that some of the most common treatment options for non-resectable melanoma brain metastases, such as radiotherapy and targeted therapies, fail to confer complete responses in patients and offer little to no benefit for survival. A common reason for the failure of radiotherapy and anticancer drugs in patients with melanoma brain metastases is due to presence of therapy resistant cancer cells within the tumor. One of the driving forces that creates these resistant cell populations in the tumor is the constant state of stress that melanoma cells are exposed to in the tumor microenvironment. Melanoma cells must adapt to cope and survive these harsh and unhospitable conditions in the tumor. The consequence of this is the emergence of melanoma cells that are more aggressive and more resistant to treatment.

In our proposal, we describe a metabolic pathway that supports cancer cell survival during these episodes of stress in the tumor. Indeed, the enzymes we propose to target are involved in supporting melanoma tumor growth and promoting the transition to a more aggressive and resistant state during stress. We propose that targeting these enzymes will help prevent metastasis to the brain and help to treat patients with existing melanoma brain metastases. Since melanoma brain metastases are currently associated with dismal survival rates, our studies have the potential to address a significant unmet clinical need. We expect the proposed studies to advance the translation of our findings to the clinic and help reduce melanoma brain metastasis disparities.