Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity

Chimeric antigen receptor (CAR) T cell therapy effectively treats human cancer, but the loss of the antigen recognized by the CAR poses a major obstacle. We found that in vivo vaccine boosting of CAR T cells triggers the engagement of the endogenous immune system to circumvent antigen-negative tumor escape. Vaccine-boosted CAR T promoted dendritic cell (DC) recruitment to tumors, increased tumor antigen uptake by DCs, and elicited the priming of endogenous anti-tumor T cells. This process was accompanied by shifts in CAR T metabolism toward oxidative phosphorylation (OXPHOS) and was critically dependent on CAR-T-derived IFN-γ. Antigen spreading (AS) induced by vaccine-boosted CAR T enabled a proportion of complete responses even when the initial tumor was 50% CAR antigen negative, and heterogeneous tumor control was further enhanced by the genetic amplification of CAR T IFN-γ expression. Thus, CAR-T-cell-derived IFN-γ plays a critical role in promoting AS, and vaccine boosting provides a clinically translatable strategy to drive such responses against solid tumors. [Display omitted] •Vaccine boosting enhances CAR T cell metabolism and polyfunctionality•Vaccine-boosted CAR T therapy elicits robust and potent antigen spreading•Antigen spreading supports CAR T therapy to treat antigenically heterogeneous tumors•CAR-T-derived IFN-γ and DC-derived IL-12 are critical for sustaining antigen spreading Vaccine boosting modifies CAR T cell metabolism and promotes crosstalk between CAR T cells and endogenous immunity to elicit and sustain antigen spreading, thereby effectively treating tumors with antigen heterogeneity.