Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity
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1-s2.0-S0092867423006426-main.pdf
Description
Published version
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12.16 MB
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Author(s)
Ma, Leyuan
Hostetler, Alexander
Morgan, Duncan M
Maiorino, Laura
Sulkaj, Ina
Whittaker, Charles A
Neeser, Alexandra
Pires, Ivan Susin
Yousefpour, Parisa
Gregory, Justin
Date Issued
July 20, 2023
Journal
Cell
Publisher
Elsevier BV
Citation
Ma, Leyuan, Hostetler, Alexander, Morgan, Duncan M, Maiorino, Laura, Sulkaj, Ina et al. 2023. "Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity." Cell, 186 (15).
Version
Final published version
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.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Materials Science and Engineering
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemical Engineering
Ragon Institute of MGH, MIT and Harvard
Broad Institute of MIT and Harvard
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Creative Commons Attribution
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DOI of Published Version
https://doi.org/10.1016/j.cell.2023.06.002
