A universal boosting strategy for adoptive T cell therapy using a paired vaccine/chimeric antigen receptor

Abstract Vaccines that encode tumour-associated antigens are potent boosting agents for adoptively transferred tumour-specific T cells. Employing vaccines to boost adoptively transferred tumour-reactive T cells relies on a priori knowledge of tumour epitopes, isolation of matched epitope-specific T cells, and personalized vaccines, all of which limit clinical feasibility. Here, we investigated a universal strategy for boosting transferred tumour-specific T cells where boosting is provided through a chimeric antigen receptor (CAR) that is paired with a vaccine encoding the CAR target antigen. To this end, we developed and employed a model wherein murine T cells expressing a TCR specific for antigen on syngeneic tumours were engineered with boosting CARs against a distinct surrogate boosting antigen for studies in immunocompetent hosts. Boosting CAR-engineered tumour-specific T cells with paired vesicular stomatitis virus (VSV) vaccines was associated with robust T cell expansion and delayed tumour progression in the absence of prior lymphodepletion. CAR-T cell expansion and antitumour function was further enhanced by blocking IFNAR1. However, vaccine-boosted CAR-T cells rapidly contracted and antigen-positive tumours re-emerged. In contrast, when the same T cells were boosted with a vaccine encoding antigen that stimulates through the TCR, the adoptively transferred T cells displayed improved persistence, tumour-specific endogenous cells expanded in parallel, and tumour cells carrying the antigen target were completely eradicated. Our findings underscore the need for further research into CAR-mediated vaccine boosting, how this differs mechanistically from TCR-mediated boosting, and the importance of engaging endogenous tumour-reactive T cells during vaccination to achieve long-term tumour control.