Vaccine-Boosted CAR T-cell Therapy Elicits Antigen Spreading

Chimeric antigen receptor (CAR) T cells eliminate tumors expressing a specific cancer-associated antigen, and, while CAR T-cell therapy provides clinical benefit for hematologic malignancies, efficacy in solid tumors is limited by antigen loss and heterogeneity. Antigen spreading (AS) describes when an initial immune response directed against a specific antigen elicits a secondary response that comprises recognition of antigens distinct from the original target, and, although AS has been observed during immunotherapy, it remains unclear whether AS can be induced by CAR T cells. Previously, Ma and colleagues developed a vaccine strategy to enhance CAR T-cell efficacy in solid tumors by stimulating CAR T cells with CAR ligands localized to surfaces of macrophages and dendritic cells (DC) within lymph nodes, prompting examination of whether AS may contribute to the antitumor response induced by this regimen. In syngeneic murine models of EGFR-mutant glioblastoma and TRP1-expressing melanoma, administration of antigen-specific CAR T cells, followed by vaccination with CAR ligands plus an adjuvant, promoted endogenous CD4⁺ and CD8⁺ T-cell immune responses against nontargeted antigens and increased transcriptional signatures of cytotoxicity and T-cell activation, providing evidence of AS, which did not occur with CAR T-cell transfer alone. Endogenous T-cell involvement through AS was required for long-term effects on tumor growth and survival and facilitated the regression of tumors containing up to 20% cells that did not express the targeted antigen. Vaccine boosting was shown to shift CAR T-cell metabolism toward oxidative metabolism, thereby elevating IFNγ secretion, which in turn increased DC recruitment and tumor antigen presentation. Sustained elevation of CAR T cell–derived IFNγ was dependent on DC-derived IL12, and a modified regimen of vaccine-boosted CAR T cells engineered to overexpress IFNγ upon CAR activation further improved tumor regression and survival. In summary, this study describes a vaccine-boosted CAR T-cell therapy that promotes an effective adaptive and innate immune response to tumors with antigen heterogeneity.

Ma L, Hostetler A, Morgan DM, Maiorino L, Sulkaj I, Whittaker CA, et al. Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity. Cell 2023 Jul 5 [Epub ahead of print].

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