Adoptive cell therapy using T cell receptors equipped with ICOS yields 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 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-NF{kappa}B 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. HighlightsNewly designed co-stimulatory TCR, with extracellular TCR-V and C domains coupled to CD28 transmembrane domain, and ICOS and CD3{varepsilon} intracellular domains (in short TCR:ICOS) provides:[tpltrtarr] durable anti-tumor response and T cell persistence in mouse model [tpltrtarr]inflammatory T cell phenotype and resistance to T cell exhaustion [tpltrtarr]effects via PI3K and NF{kappa}B activation [tpltrtarr]translation to human T cells upon single amino acid mutation in TCR:ICOS tail [tpltrtarr]extension to multiple clinically relevant TCRs while preserving prolonged T cell fitness O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/682056v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1ff752borg.highwire.dtl.DTLVardef@6579d9org.highwire.dtl.DTLVardef@22bdc4org.highwire.dtl.DTLVardef@d8c445_HPS_FORMAT_FIGEXP M_FIG C_FIG