The AACR-KidneyCAN Kidney Cancer Innovation and Discovery Grant is a new grant mechanism that seeks to stimulate creative approaches to translate basic research into new treatment options for kidney cancer.

2024 Grantees

Research

Human endogenous retroviral (HERV) antigens are considered leading candidates to account for a higher immune checkpoint inhibitor response rate for clear cell renal cell carcinoma (ccRCC) than predicted by its low mutation and neoantigen density. Four candidate hERV-encoded HLA-A2 epitopes recognized by spontaneously arising CD8+ T cells have been identified in breast cancer patients. T-cell responses arising in ccRCC patients targeting these broadly shared HLA-A2-associated hERV antigens have not been investigated and would be of great interest. Dr. Warren and his team plan to identify and quantify T-cell reactivity for hERV-encoded, HLA-A2 associated T-cell epitopes spontaneously arising in HLA-A2+ RCC patients and assess the anti-tumor potency of these T cells. Validation of spontaneous T-cell immunity targeting hERV can be translatable to future vaccine or engineered T cell-based therapies.

Biography

Dr. Warren received his bachelor’s, medical, and doctoral degrees from Harvard University. He is now an oncologist and cancer immunologist with a focus on cellular and molecular dissection of antitumor immune responses and also the program head for Global Oncology at the Fred Hutchinson Cancer Center. His lab has long been interested in harnessing the exquisite specificity and potency of T cells to recognize and eliminate cancer. Another major focus of his lab’s effort has been on the immunobiology of kidney cancer and the development of T-cell therapy for advanced kidney cancer.

Acknowledgment of Support

“Kidney cancer is known for its sensitivity to immune therapy and developing antigen-specific therapy for kidney cancer is a major focus of our laboratory. The AACR-KidneyCAN Kidney Cancer Innovation and Discovery Grant will support the development of immune therapy for kidney cancer that targets the protein products of human endogenous retroviruses.”

Research

Most clear cell renal carcinoma (ccRCC) cases are associated with the inactivation of VHL protein, which leads to the stabilization and accumulation of HIF-2α protein. The HIF-2α inhibitor belzultifan was recently developed and approved by the FDA to treat advanced RCC patients. However, both intrinsic and adaptive resistance to this drug were reported in preclinical studies using kidney cancer cell lines or xenograft models. By generating a HIF-2α inhibitor adaptive resistant ccRCC cell line model, Dr. Zhang plans to identify potential targetable pathways that may contribute to HIF-2α inhibitor resistance. Through further mechanistic studies, he aims to identify potential therapeutic options that can reverse drug resistance to HIF-2α inhibitor in ccRCC.

Biography

Dr. Zhang obtained his undergraduate degree from Wuhan University in China, and his doctoral degree from University of Pittsburgh School of Medicine. He worked as a postdoctoral fellow and an instructor at the Dana Farber Cancer Institute. He became an assistant professor at UNC Chapel Hill in 2013 and was promoted to associate professor in 2019. He is an associate professor with tenure in the Department of Pathology at UT Southwestern Medical Center.  

Acknowledgment of Support

“Belzultifan, a HIF-2a inhibitor was approved by the FDA to treat advanced RCC. However, both intrinsic and adaptive resistance was reported, posing critical clinical challenges. This award will help generate vital preliminary data, uncovering the mechanisms underlying drug resistance and developing alternative treatments for HIF-2a inhibitor-resistant patients in kidney cancer.”