Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity
Leyuan Ma, Alexander Hostetler, Duncan M. Morgan, Laura Maiorino, Ina Sulkaj, Charles A. Whittaker, Alexandra Neeser, Ivan S. Pires, Parisa Yousefpour, Justin M. Gregory, Kashif Qureshi, Jonathan Dye, Wuhbet Abraham, Heikyung Suh, Na Li, J. Christopher Love, Darrell J. Irvine
Abstract
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.