Co-stimulatory Switch Receptors – deriving benefit from immunosuppression to enhance T-cell function

Adoptive cell transfer of tumor specific lymphocytes, whether naturally occurring in patients or genetically engineered can lead to impressive objective response in terminally patients. 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 (T cell immunoreceptor with Ig and ITIM domains) are such a co-inhibitory receptors expressed by T and/or NK cells which, upon binding to their ligand on tumor cells can diminish 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 either the PD1 or TIGIT exodomain fused to the signaling domain of CD28.

After selecting an optimized TIGIT-28 CSR, we co-transduced it along with tumor-specific TCR or CAR into human T-cells. TIGIT-28-equipped T-cells exhibited enhanced cytokine secretion and upregulation of activation markers upon co-culture with tumor cells. TIGIT-28 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 this molecule in the context of a xenograft model of established human melanoma tumors and showed that TIGIT-28-engineered human T-cells demonstrated superior anti-tumor function. Overall, we propose that TIGIT-based CSR can substantially enhance T-cell function and thus contribute to the improvement of engineered T cell-based immunotherapy.