Development of TCR-T Cell Therapeutics for Targeting Metastatic Uveal Melanoma

Yuri Sykulev, MD, PhD, is leading a team with a focus on developing effective T cell therapeutics for treatment of metastatic uveal melanoma (UM). T cell therapies have shown promising responses in multiple refractory solid tumors including skin melanoma. Thus far, the most promising T cell therapy to treat skin melanoma is infusion of tumor infiltrating lymphocytes (TIL), which recognize tumor-specific neo-antigens abundant in skin melanoma. The barrier to successful treatment of UM with TIL is much lower frequency of tumor-reactive T cells within the metastases and strength of their anti-tumor response. To overcome the barriers for production of highly effective UM-specific T cell therapeutics, researchers propose to utilize TCR genes that recognize driver mutations of UM (GNAQ/GNA11 mutations). The researchers design to incorporate these TCR genes to otherwise non-specific T cells to manufacture UM-specific TCR-T cells to produce “off-shelf” products. The research team will investigate various strategies to generate these melanoma-specific TCR-T cells and will compare the ability of these cells to control the growth of human UM cells in vitro and in mouse models. The goal of this multi-phased project is to begin the development of effective T cell therapeutics, which would change the treatment for future uveal melanoma patients.

Team Members

Development of Novel Therapeutics for Uveal Melanoma

Gyorgy Hajnoczky, MD, PhD, is leading a team with a focus on mitochondrial diagnostics and therapy to look into the development of novel therapeutics for uveal melanoma. This research team brings together expertise in uveal melanoma liver metastases (Mizue Terai, PhD, Assistant Professor, Thomas Jefferson University), the inherited defect (Philip B. Wedegaertner, PhD, Professor, Thomas Jefferson University), and therapeutic cell death activation (Gyorgy Hajnoczky, MD, PhD, Professor, Thomas Jefferson University) to test this hypothesis and understand the disease process and therapy of uveal melanoma. Piyush Mishra, PhD, a senior fellow, is the primary driving force in moving this uveal melanoma project further.

The group discovered that primary liver cancer and normal liver have distinctive cell death signatures, and developed an approach based on this difference to kill hepatocarcinoma without harming normal liver. Because uveal melanoma mortality is primarily due to its liver metastases, they speculated whether the liver metastases are also different from normal liver in their cell death signature and can be selectively targeted with the therapy that is effective for primary liver cancer. This project has the opportunity to develop new therapeutics for this disease, which would have an immeasurable impact on metastatic uveal melanoma patients.

Team Members