Penn Medicine and Wistar secure $11.7 million SPORE grant for three melanoma research projects

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.

The grant also includes a career enhancement program focused on training and retaining underrepresented minorities in skin cancer research, and a pilot award program that will expand research into non-melanoma skin cancer.

The SPORE team at Penn and Wistar will carry on a long tradition of developing new treatments for skin cancer with the grant, which follows a previous SPORE grant awarded to the institutions in 2014. With extensive support from the Abramson Cancer Center (ACC) and the Tara Miller Melanoma Research Center, the team developed new expertise and resources, including a tissue specimen core with more than 11,000 banked specimens, that helped secure the new SPORE grant.

Ravi K. Amaravadi, MD, an associate professor of Hematology-Oncology in Penn's Perelman School of Medicine and the co-leader of the Cancer Therapeutics Program in the ACC, and Meenhard Herlyn, DVM, DSc, director of Wistar's Melanoma Research Center and professor in the Molecular & Cellular Oncogenesis Program in Wistar's Cancer Center, will serve as the co-directors of the SPORE.

"Our longstanding team approach to science and new therapies has been recognized by the NCI once again with this new SPORE grant. We can now expand on this collaboration-;which has already led to important developments in melanoma," Amaravadi said. "From new fundamental insights about how skin cancer escapes treatments to new treatment options for patients, these projects-;and the people leading them-;are at the cutting edge of translational medicine, and are entirely focused on improving the health of our patients."

"Despite dramatic improvement brought about by immunotherapy, we still have major challenges for the majority of patients and new approaches are urgently needed," Herlyn said. "Building on major breakthroughs by our team, we are poised to address crucial unanswered questions to improve immunotherapy response and identify new biomarkers to inform patient management and reduce therapy toxicity."

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.

Other Penn faculty involved with the project include Wei Guo, PhD, the Class of 1965 Endowed Term Chair in Biology, Xiaowei Xu, MD, PhD, a professor of Pathology and Dermatology, Phyllis Gimotty, PhD, a professor of Biostatistics and Epidemiology, Giorgos Karakousis, MD, an associate professor of Surgery, Gregory Beatty, MD, PhD, an associate professor of Medicine, Tara Mitchell, MD, an associate professor of Medicine, Lynn Schuchter, MD, chief of Hematology-Oncology and director of the Tara Miller Melanoma Center, and E. John Wherry, Chair of the department of Systems Pharmacology and Translational Therapeutics.

Other Wistar faculty on the team include professor David W. Speicher, Ph.D., associate professor Jessie Villanueva, Ph.D., and assistant professor Andrew Kossenkov, Ph.D., from The Wistar Institute Cancer Center.

The three main SPORE melanoma research projects include:

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.