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

In adoptive cell therapy, longevity of effector T cells is challenged by the immune suppressive microenvironment of tumors, which often lacks co-stimulatory cues. To overcome this limitation, we have designed and tested next-generation T cell receptors (TCRs) harboring co-stimulatory molecules, including CD28, ICOS and OX40 in a murine melanoma model. TCR:ICOS T cells demonstrated remarkable improvement of anti-tumor efficacy resulting in long-term cures and significantly delayed tumor recurrence, which were consistently accompanied by prolonged persistence of TCR-T cells in blood. Regressing tumors displayed an inflammatory phenotype driven by TCR:ICOS T cells that, upon antigen encounter, showed enhanced NFκB signaling, cytokine production and resistance to exhaustion. The use of an ICOS signaling mutant demonstrated that durable anti-tumor effects in vivo and in vitro relied on the PI3K-NFκB pathway. To adapt TCR:ICOS to human T cells, we iteratively tested gene variants and observed that a single amino acid change in the cytosolic tail was necessary for functional expression of this TCR. Moreover, human TCR:ICOS improved the in vitro performance of T cells upon repeated stimulation across multiple clinically relevant antigen specificities. Collectively, we present a novel and uniformly applicable TCR:ICOS format that supports fitter T cell products for adoptive cell therapy.