Penn Medicine and The Wistar Institute have been awarded a prestigious $11.7 million Specialized Programs of Research Excellence, or SPORE, grant from the National Cancer Institute. The five-year award will fund three new melanoma research projects that translate fundamental laboratory discoveries made in the Perelman School of Medicine at the University of Pennsylvania and The Wistar Institute into new therapeutics to treat skins cancers.
Melanoma is the deadliest form of skin cancer and the fifth deadliest form of cancer, overall. According to NCI statistics, more than 100,000 new cases of melanoma will occur in 2021 in the U.S. alone. The incidence of melanoma and other skin cancers, such as Merkel cell carcinoma and squamous cell carcinoma, are rising both nationally and regionally. If caught early, skin cancer is considered treatable; however, when these cancers metastasize, they are especially deadly.
Project 1: Exosomal PD-L1 in immunotherapy resistance
Co-Project Leaders: Guo, Xu, Mitchell, and Wherry
Currently, there is no approved assay that can help determine which melanoma patients will respond to immunotherapy. This project builds on a fundamental discovery that small segments of lipid-encapsulated vesicles released from cells called exosomes that carry PD-L1 on their surface are floating circulating in the blood of melanoma patients. Exosomal PD-L1 is an immunosuppressive factor, and can be measured in the blood noninvasively with assay developed by Guo and Xu. Working with collaborators at the John Wayne Cancer Institute, MD Anderson Cancer Center and New York University, the team will conduct rigorous clinical utility studies designed to demonstrate this blood-based measurement as a highly sensitive and specific predictive biomarker for response to immunotherapy in melanoma.
Project 2: Targeting autophagy to improve immunotherapy in melanoma
Co-Project Leaders: Amaravadi and Speicher
There are limited options for patients whose tumors have progressed on immunotherapy in melanoma. Based on extensive preclinical data and a new molecular target in the autophagy pathway, the team has developed a clinical trial of combined immunotherapy and autophagy inhibition. Targeting autophagy during immunotherapy can reprogram cells within the tumor to enhance the efficacy of T cell killing of melanoma cells. This clinical trial will include a novel PET imaging tracer that can track T cells as they enter the tumors in patients. The project also works with several biotech companies developing new autophagy inhibitors for cancer.
Project 3: Neoadjuvant immunotherapy for early-stage melanoma
Co-Project Leaders: Beatty, Karakousis, and Herlyn
Currently, patients with stage III melanoma are treated with immunotherapy after surgical resection. Some stage II melanoma patients have a higher risk of metastasis than stage III patients, but there is no approved therapy to reduce this risk. Based on previous work showing that one cycle of immunotherapy given before surgery can produce major benefits in stage III melanoma patients, the team has launched a clinical trial of neoadjuvant immunotherapy in stage IIB/C melanoma patients. Besides in-depth characterization of the immune response, the project’s preclinical studies, which include several innovative mouse models to study immunotherapy in stage II melanoma, will lead to new strategies for enhancing the immune stimulatory capacity of dendritic cells in the tumor microenvironment.
Source – Penn Medicine