Choe et al. combined synthetic Notch (SynNotch) receptors that recognize specific priming antigens, such as EGFRvIII or a CNS-specific non-tumor antigen (MOG), with a tandem CAR that simultaneously targets EphA2 OR IL-13Rɑ2 to form SynNotch-CAR T cells, which induce CAR expression upon recognition of priming antigen. EGFRvIII-triggered synNotch-CAR T cells showed tumor region-restricted priming and killing, an improved stem-like phenotype, enhanced persistence, reduced exhaustion, and durable antitumor activity against U87 xenograft and GBM6 PDX tumors. MOG-triggered synNotch-CAR T cells effectively killed GBM6 tumors.
Contributed by Shishir Pant
ABSTRACT: Treatment of solid cancers with chimeric antigen receptor (CAR) T cells is plagued by the lack of ideal target antigens that are both absolutely tumor specific and homogeneously expressed. We show that multi-antigen prime-and-kill recognition circuits provide flexibility and precision to overcome these challenges in the context of glioblastoma. A synNotch receptor that recognizes a specific priming antigen, such as the heterogeneous but tumor-specific glioblastoma neoantigen epidermal growth factor receptor splice variant III (EGFRvIII) or the central nervous system (CNS) tissue-specific antigen myelin oligodendrocyte glycoprotein (MOG), can be used to locally induce expression of a CAR. This enables thorough but controlled tumor cell killing by targeting antigens that are homogeneous but not absolutely tumor specific. Moreover, synNotch-regulated CAR expression averts tonic signaling and exhaustion, maintaining a higher fraction of the T cells in a nave/stem cell memory state. In immunodeficient mice bearing intracerebral patient-derived xenografts (PDXs) with heterogeneous expression of EGFRvIII, a single intravenous infusion of EGFRvIII synNotch-CAR T cells demonstrated higher antitumor efficacy and T cell durability than conventional constitutively expressed CAR T cells, without off-tumor killing. T cells transduced with a synNotch-CAR circuit primed by the CNS-specific antigen MOG also exhibited precise and potent control of intracerebral PDX without evidence of priming outside of the brain. In summary, by using circuits that integrate recognition of multiple imperfect but complementary antigens, we improve the specificity, completeness, and persistence of T cells directed against glioblastoma, providing a general recognition strategy applicable to other solid tumors.
Author Info: (1) Cell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. (2) Department of Neurologic
Author Info: (1) Cell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. (2) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA. (3) Cell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. (4) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA. (5) Cell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. (6) Cell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. (7) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA. (8) Cell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. (9) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA. (10) Department of Veterans' Affairs Medical Center, University of California, San Francisco, San Francisco, CA 94158, USA. (11) Cell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. (12) Cell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. (13) Cell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. (14) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA. (15) Department of Computer Science, Princeton University, Princeton, NJ 08540, USA. Center for Computational Biology, Flatiron Institute, New York, NY 10010, USA. (16) Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada. (17) Department of Computer Science, Princeton University, Princeton, NJ 08540, USA. Center for Computational Biology, Flatiron Institute, New York, NY 10010, USA. (18) Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada. (19) Cell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. kole.roybal@ucsf.edu hideho.okada@ucsf.edu wendell.lim@ucsf.edu. Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA 94158, USA. Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA. Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Helen Diller Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. (20) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA. kole.roybal@ucsf.edu hideho.okada@ucsf.edu wendell.lim@ucsf.edu. Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA 94158, USA. Helen Diller Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. (21) Cell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. kole.roybal@ucsf.edu hideho.okada@ucsf.edu wendell.lim@ucsf.edu. Helen Diller Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
