Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity
Menée à l'aide de lignées cellulaires et de modèles murins, cette étude met en évidence l'intérêt thérapeutique d'un vaccin à base de molécules amphiphiles capables de se fixer à la surface des cellules dendritiques et d'améliorer l'efficacité des lymphocytes CAR-T lorsque les tumeurs présentent une hétérogénéité antigénique
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-?. 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-? expression. Thus, CAR-T-cell-derived IFN-? plays a critical role in promoting AS, and vaccine boosting provides a clinically translatable strategy to drive such responses against solid tumors.
Cell 2023