Improving Anti-tumor Responses by Degrading Transcription Factors that Impose T cell Exhaustion

Novel Therapeutics & Platforms, Immunotherapies & Personalized Vaccines

Anjana Rao, PhD (LJI)

Erik Ehinger (UC San Diego)

Kristy Perez (UC San Diego)

Emi Sanchez (UC San Diego)

Peng Wu, PhD (Scripps Research)

Patrick Hogan, PhD (LJI)

Although immunotherapy has been successful at treating a substantial proportion of cancer patients, it is limited, especially in solid cancers (90% of all cancers), by a phenomenon termed T cell “exhaustion”. This means that although T cells infiltrate the tumor and are initially effective in destroying cancer cells, they later become “exhausted” and become less effective at killing tumor cells. In our research, we will test a new way of reversibly degrading key proteins which drive the exhaustion program. We will therapeutically hijack the T cells’ own machinery for disposing of unwanted proteins, thus creating exhaustion-resistant T cells that have potent tumor-killing capabilities. Our approach is the first test of whether targeted protein degradation can overcome T cell exhaustion and become a powerful new strategy to fight cancer with immunotherapy.

“In a quest to develop the next generation of cancer immunotherapies, our team discovered novel therapeutic targets that cause tumor-infiltrating T cells to lose their ability to destroy tumours. T cells lacking these proteins have an enhanced ability to fight tumors, but the proteins are transcription factors that are not readily druggable. With Curebound’s generous support, we are testing innovative ways of selectively and reversibly depleting these proteins in tumour-infiltrating immune cells during tumour rejection, but restoring their levels in surviving memory T cells once the cancer is cured.” - Anjana Rao