Adoptive cell therapy using T cell receptors equipped with ICOS yields durable anti-tumor response

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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 tumor model. TCR:ICOS T cells showed enhanced and antigen-specific production of inflammatory cytokines and resistance to exhaustion. Genetic ablation of ICOS-mediated activation of the PI3K-NFκB 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 was necessary for functional surface expression. Notably, the optimized receptor sustained performance of human T cells upon repeated stimulation across multiple antigen specificities. Collectively, we present a novel and uniformly applicable TCR:ICOS format that supports fitter T cell products for adoptive cell therapy. Highlights Newly designed co-stimulatory TCR, with extracellular TCR-V and C domains coupled to CD28 transmembrane domain, and ICOS and CD3ε intracellular domains (in short TCR:ICOS) provides: ➢ durable anti-tumor response and T cell persistence in mouse model ➢ inflammatory T cell phenotype and resistance to T cell exhaustion ➢ effects via PI3K and NFκB activation ➢ translation to human T cells upon single amino acid mutation in TCR:ICOS tail ➢ extension to multiple clinically relevant TCRs while preserving prolonged T cell fitness Abstract Figure

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