IFNγ Is Critical for CAR T Cell–Mediated Myeloid Activation and Induction of Endogenous Immunity

Abstract

Chimeric antigen receptor (CAR) T cells mediate potent antigen-specific antitumor activity; however, their indirect effects on the endogenous immune system are not well characterized. Remarkably, we demonstrate that CAR T-cell treatment of mouse syngeneic glioblastoma (GBM) activates intratumoral myeloid cells and induces endogenous T-cell memory responses coupled with feed-forward propagation of CAR T-cell responses. IFNγ production by CAR T cells and IFNγ responsiveness of host immune cells are critical for tumor immune landscape remodeling to promote a more activated and less suppressive tumor microenvironment. The clinical relevance of these observations is supported by studies showing that human IL13Rα2–CAR T cells activate patient-derived endogenous T cells and monocytes/macrophages through IFNγ signaling and induce the generation of tumor-specific T-cell responses in a responding patient with GBM. These studies establish that CAR T-cell therapy has the potential to shape the tumor microenvironment, creating a context permissible for eliciting endogenous antitumor immunity.

Additional Information

© 2021 American Association for Cancer Research. Received November 16, 2020. Revision received February 24, 2021. Accepted April 5, 2021. Published first April 9, 2021. This work was supported in part by Mustang Bio., Inc., R01-CA236500 (to D. Alizadeh, R.A. Wong, C.E. Brown), CA234923 (to D. Wang), California Institute for Regenerative Medicine CLIN2-10248 (to D. Alizadeh, R.A. Wong, C.E. Brown), Ben and Catherine Ivy Foundation (to D. Alizadeh, R.A. Wong, M. Maker, C.E. Brown), Ligue Nationale contre le Cancer and SIRIC-BRIO (to N. Larmonier), and Cancer Center Support Grant P30 CA33572. S. Gholamin is a Parker Institute scholar. Patents associated with IL13Rα2-CAR T have been licensed by Mustang Bio., Inc., for which S.J. Forman and C.E. Brown receive royalty payments. The authors would like to thank Leo D. Wang MD, PhD, for critical paper review and feedback, and the technical assistance of Jinhui Wang, Ryan Urak, Supraja Saravanakumar, Charles Warden, and Aniee Sarkissian. Authors' Contributions: D. Alizadeh: Conceptualization, data curation, formal analysis, supervision, methodology, writing–original draft, writing–review and editing. R.A. Wong: Data curation, formal analysis, methodology, writing–review and editing. S. Gholamin: Data curation, methodology, writing–review and editing. M. Maker: Data curation, methodology, writing–review and editing. M. Aftabizadeh: Data curation, methodology. X. Yang: Methodology. J.R. Pecoraro: Methodology. J.D. Jeppson: Methodology, writing–review and editing. D. Wang: Methodology, writing–review and editing. B. Aguilar: Resources, methodology. R. Starr: Resources, data curation, methodology. C.B. Larmonier: Data curation, methodology, writing–review and editing. N. Larmonier: Software, formal analysis, writing–review and editing. M. Chen: Data curation, software, formal analysis. X. Wu: Data curation, software, writing–review and editing. A. Ribas: Writing–review and editing. B. Badie: Writing–review and editing. S.J. Forman: Conceptualization, funding acquisition, writing–original draft, writing–review and editing. C.E. Brown: Conceptualization, data curation, funding acquisition, writing–original draft, writing–review and editing. Authors' Disclosures: D. Wang reports grants from NCI during the conduct of the study. N. Larmonier reports grants from Ligue Nationale Contre le Cancer and grants from SIRIC-BRIO during the conduct of the study. A. Ribas reports personal fees from Amgen, Chugai, Genentech, Merck, Novartis, Roche, Sanofi, and Vedanta; personal fees from Advaxis, Apricity, Arcus, Compugen, CytomX, Five Prime, Highlight, ImaginAb, Isoplexis, Kite-Gilead, Lutris, Merus, PACT, RAPT, Rgenix and Tango Therapeutics; and grants from Agilent and Bristol-Myers Squibb outside the submitted work. B. Badie reports grants from NIH and other support from Mustang Therapeutics during the conduct of the study and other support from Mustang Therapeutics outside the submitted work; in addition, B. Badie has a patent for CAR T-cell delivery pending and with royalties paid from Mustang Therapeutics. C.E. Brown reports other support from Mustang Bio, grants from NCI, and grants from CIRM during the conduct of the study; personal fees and other support from Chimeric Therapeutics and personal fees and other support from Mustang Bio outside the submitted work; in addition, C.E. Brown has a patent pending. No disclosures were reported by the other authors.

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Accepted Version - 2159-8290.CD-20-1661.full.pdf

Supplemental Material - 255535_2_supp_7025532_qqvy2y.docx

Supplemental Material - 255535_2_supp_7025537_qqvn2n.docx

Supplemental Material - 255535_2_supp_7026210_qqw2tt.pdf

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