Enhancing the function of TCR and CAR engineered T-cells through the expression of chimeric switch receptors (CSR)

Tumors can employ different mechanisms to evade immune surveillance and function. Overexpression of co-inhibitory ligands that bind to checkpoint molecules on the surface of T-cells can greatly impair the function of latter. PD1 and TIGIT are example to such checkpoint receptors. Upon binding to their ligand (e.g., PDL1, CD155), these receptors can signal a reduction in cytokine production and effector function. Additionally, the absence of positive co-stimulation at the tumor site can further dampen T-cell response. As T-cell genetic engineering has become clinically-relevant in the recent years, we devised herein 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 CD28, 41BB,...

Herein, we show that these receptors can function along with tumor-specific TCR or CAR in human T-cells. CSR-equipped T-cells exhibited enhanced cytokine secretion and upregulation of activation markers upon co-culture with tumor 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 tested the function of these molecules in the context of a xenograft model of established human melanoma tumors and showed that CSR-engineered human T-cells demonstrated superior anti-tumor function. Overall, we propose that immune CSRs can substantially enhance T-cell function and thus contribute to the improvement of engineered T cell-based immunotherapy.