T cell receptors equipped with ICOS provide T cells with durable anti-tumor response

Abstract

Treatment with adoptively transferred T cells is challenged by limited longevity of therapeutic cells within tumors. To enhance the durability of anti-tumor T cell products, we have created T cell receptors (TCRs) with built-in co-stimulatory molecules. We observed that TCRs coupled to ICOS mediated exceptionally long-term responses, including delay of tumor recurrence and cures in a mouse melanoma model. TCR:ICOS T cells showed enhanced and antigen-specific production of inflammatory cytokines, enrichment for a stem-like state and resistance to exhaustion. TCR:ICOS-mediated activation of PI3K and NFκB, yet restrained activation of AKT. Genetic ablation of the ICOS-PI3K pathway neutralized the long-term anti-tumor effects. To translate TCR:ICOS to human T cells, we identified a single amino acid change in the cytosolic tail which enabled functional surface expression without proneness to TCR mispairing nor competition for CD3. Notably, the optimized receptor sustained functional performance of human T cells upon repeated stimulation across multiple tumor antigens. Collectively, we present a novel and uniformly applicable TCR:ICOS format that supports fitter T cell products for adoptive cell therapy. Newly designed TCR, with extracellular TCR-V and C domains, CD28 transmembrane domain, and ICOS and CD3ε intracellular domains (in short TCR:ICOS) shows: highly durable anti-tumor response and T cell persistence in mouse model inflammatory T cell phenotype, stem-like state and resistance to T cell exhaustion effects via activation of PI3K and NFκB, yet restraining activation of AKT translation to human T cells upon single amino acid mutation in tail no TCR mispairing nor competition for endogenous CD3 extension to multiple TCRs while preserving T cell fitness