A Universal Boosting Strategy for Adoptive T-cell Therapy Using a Paired Vaccine/Chimeric Antigen Receptor

Vaccines that encode tumor-associated antigens are potent boosting agents for adoptively transferred tumor-specific T cells. Employing vaccines to boost adoptively transferred tumor-reactive T cells relies on a priori knowledge of tumor epitopes, isolation of matched epitope-specific T cells, and personalized vaccines, all of which limit clinical feasibility. In this study, we investigated a universal strategy for boosting transferred tumor-specific T cells for which 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 in which murine T cells expressing a T-cell receptor (TCR) specific for antigen on syngeneic tumors were engineered with boosting CARs against a distinct surrogate boosting antigen for studies in immunocompetent hosts. Boosting CAR-engineered tumor-specific T cells with paired vesicular stomatitis virus vaccines was associated with robust T-cell expansion and delayed tumor progression in the absence of prior lymphodepletion. CAR T-cell expansion and antitumor function were further enhanced by blocking IFNAR1. However, vaccine-boosted CAR T cells rapidly contracted and antigen-positive tumors 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, tumor-specific endogenous cells expanded in parallel, and tumor 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 tumor-reactive T cells during vaccination to achieve long-term tumor control.