Reprograming T cell immunity to enhance immunotherapy: from protein engineering to bedside

The immune response against tumor cells is crucial to the elimination of cancer, with several types of immune cells, such as T-cells, playing an important role. Cell therapy using genetically engineered T-cells has been shown to cause tumor regression in terminally-ill patients, with noticeable percentages of complete remission in hematological tumors. As such, we will report on a BCMA-specific CAR T-cell therapy we developed, exemplifying the crucial role of protein engineering in elaborating a functionally optimized receptor, now in clinical trials.

Additionally, it has been shown that tumors can overexpress co-inhibitory ligands to greatly impair T-cell function. To remedy this, we will expand on a strategy aimed at enhancing T-cell anti-tumor function by diverting T-cell coinhibitory signals into positive ones using a chimeric costimulatory switch receptor (CSR) composed of checkpoint exodomain fused to the signaling domain of costimulatory molecules such as CD28 or 4-1BB. We will show that these receptors can function along with tumor-specific TCR or CAR in human T-cells. CSR enhancing capability was also demonstrated in an original in vitro model of T-cell of hypofunction induction upon repetitive antigen exposure. Finally, we will show how CSR-engineered human T-cells demonstrate superior anti-tumor function in the context of a xenograft model of established human melanoma tumors. Overall, we are exploring new ways to create and improve the anti-cancer response by patients’ immune cells, which have important implications for the clinical treatment of cancer using immunotherapy approaches.