Posted May 25, 2018

Dr. Khalid Shah, Brigham and Women's Hospital
Dr. David Fisher, Massachusetts General Hospital
Dr. James Moon, University of Michigan
Dr. Li Wang, Medical College of Wisconsin

Melanoma is a type of skin cancer that forms in melanocytes, the cells that are responsible for skin color. Melanoma cases have been increasing over the last 30 years. It is the fifth most common type of cancer in the United States, representing 5.3% of all new cancer diagnoses every year. The earlier melanoma is detected and diagnosed, the better the odds are of surviving 5 years after being diagnosed. Most cases are diagnosed early, before it has spread to the lymph nodes or other organs; the 5-year survival rate for localized melanoma is 98.4%, but once it has metastasized, the 5-year rate drops to 22.5%.¹ Furthermore, the incidence of melanoma is higher in the U.S. military population compared to the general population, likely due to their deployment history.²

Ten years ago, the diagnoses for advanced cases of melanoma were bleak. There were only two treatment options: chemotherapy, which was ineffective, or an immunotherapy called interleukin-2, which often resulted in dangerous side effects. Fortunately, the last 10 years have seen multiple promising advancements in treatment strategies for melanoma.

The Peer Reviewed Cancer Research Program (PRCRP) has been funding melanoma research since establishment of the program in 2009, with 20% of total funding dedicated to furthering our understanding of this disease, from basic biology to novel therapeutic options. In particular, the PRCRP has been on the forefront of funding diverse treatment strategies for melanoma in the areas of immunotherapy and targeted therapies.

Much attention throughout the research community has been given to a class of antibodies called �checkpoint inhibitors,� which target inhibitory proteins expressed on a set of immune cells called T cells. Two inhibitory proteins, called cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), act as �off switches� for T cells and inhibit their ability to target cancer cells. The checkpoint inhibitors block CTLA-4 and PD-1, allowing T cells to become and stay activated. Antibodies to block CTLA-4 and PD-1 have been approved by the Food and Drug Administration (FDA) for the treatment of melanoma and other cancers. However, not every melanoma patient is a good candidate for these therapies, and some patients who are treated with these antibodies become resistant to the therapy or relapse. Therefore, it is important to have multiple effective strategies for treating metastatic melanoma.

Can we use viruses to kill metastatic melanoma?

Khalid Shah, M.S., Ph.D., Brigham and Women's Hospital
David Fisher, M.D., Ph.D., Massachusetts General Hospital

A very significant fraction of melanoma patients will develop brain metastasis, a condition that is greatly in need of better treatment options. Drs. Khalid Shah and David Fisher, funded with a Fiscal Year 2014 (FY14) Idea Award with Special Focus, used an oncolytic Herpes Simplex Virus (oHSV) to target metastatic melanoma tumors in the brain. To accomplish this work, they first developed mouse models that accurately simulate human melanoma brain metastasis. They then loaded stem cells carrying oHSV, which successfully travelled to the brain, targeted metastatic tumor lesions, and significantly improved the survival of mice bearing melanoma brain metastasis compared to untreated mice. Additionally, combining the oHSV therapy with another immunotherapy further extended the survival of treated mice. This work, which was published in 2017, demonstrated a new clinically applicable therapeutic strategy to target melanoma brain metastasis.³

Can nanoparticles activate the immune system to attack melanoma cells?

James Moon, Ph.D., University of Michigan

Immune checkpoint inhibitors represent only one arm of immunotherapy. Initiation of a strong anti-tumor immune response also requires an increase in the number of immune cells, which can be achieved by a tumor vaccine. Dr. James Moon was funded by an FY15 Career Development Award to develop a new vaccination strategy for treating melanoma using nanoparticles. Vaccine nanoparticles were loaded with melanoma-specific antigens, causing significant activation and expansion of T cells. When combined with checkpoint inhibitors, the vaccine nanoparticles completely eliminated melanoma tumors in mice. This study, which was published in 2017, demonstrated that nanomedicine tailored to patient's cancer cells may be an effective strategy for eliminating tumors.⁴

Are there other immune checkpoints that can be targeted for melanoma immunotherapy?

Li Wang, Ph.D., Medical College of Wisconsin

Not all melanoma patients will express CTLA-4 or PD-1 on their tumor-infiltrating T cells, so they would not be candidates for the checkpoint inhibitor therapies that are currently FDA-approved. Therefore, it is imperative to identify alternative immune checkpoints that can be blocked in order to activate anti-tumor T cells. Dr. Li Wang was funded by an FY13 Career Development Award to study a novel checkpoint called V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) and its role in establishing an immunosuppressive tumor microenvironment. Dr. Wang has discovered mechanisms of regulating the inflammation response in T cells and myeloid cells. The identification of cell populations that express VISTA will inform future studies focused on generating specific VISTA inhibitors that can activate T cells, but not other populations of cells that may overstimulate inflammation.

Publications:

1. SEER Cancer Stat Facts: Melanoma of the Skin. National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/statfacts/html/melan.html.
2. Lea CS, Efird JT, Toland AE, Lewis DR, and Phillips CJ. 2014. Melanoma incidence rates in active duty personnel compared with a population-based registry in the United States, 2000-2007. Mil Med. 179:247-253.
3. Du W, Seah I, Bougazzoul O, et al. 2017. Stem cell-released oncolytic herpes simplex virus has therapeutic efficacy in brain metastatic melanomas. Proc Natl Acad Sci USA. 114(30):E6157-E6165. doi: 10.1073/pnas.1700363114. Epub 2017. Jul 14. PMID: 28710334, PMCID: PMC5544283.
4. Kuai R, Ochyl LJ, Bahjat KS, et al. 2017. Designer vaccine nanodiscs for personalized cancer immunotherapy. Nat Mater. 16(4):489-496. doi: 10.1038/nmat4822. Epub 2016. Dec 26. PMID: 28024156, PMCID: PMC5374005.

Links:

Public and Technical Abstracts: Stem Cell-Loaded Oncolytic Viruses for Metastatic Melanomas

Public and Technical Abstracts: A New Vaccination Strategy for Treatment of Melanoma

Public and Technical Abstracts: Novel Combinatorial Immunotherapy for Melanoma

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