Allen et al. engineered a tumor-specific synNotch→interleukin-2 (IL-2) induction circuit that produced IL-2 locally upon tumor recognition, and drove T cell proliferation independent of TCR activation. Combining tumor-reactive CARs with a synthetic autocrine synNotch→IL-2 circuit substantially increased T cell infiltration throughout the tumor core; enhanced activation, proliferation, and cytotoxicity marker expression in CAR T cells; and showed potent and localized tumor control in immune-excluded solid tumor models. The synNotch→IL-2 circuit showed no evidence of systemic cytokine toxicity or exacerbation of CAR T cell toxicity.
Contributed by Shishir Pant
ABSTRACT: Chimeric antigen receptor (CAR) T cells are ineffective against solid tumors with immunosuppressive microenvironments. To overcome suppression, we engineered circuits in which tumor-specific synNotch receptors locally induce production of the cytokine IL-2. These circuits potently enhance CAR T cell infiltration and clearance of immune-excluded tumors, without systemic toxicity. The most effective IL-2 induction circuit acts in an autocrine and T cell receptor (TCR)- or CAR-independent manner, bypassing suppression mechanisms including consumption of IL-2 or inhibition of TCR signaling. These engineered cells establish a foothold in the target tumors, with synthetic Notch-induced IL-2 production enabling initiation of CAR-mediated T cell expansion and cell killing. Thus, it is possible to reconstitute synthetic T cell circuits that activate the outputs ultimately required for an antitumor response, but in a manner that evades key points of tumor suppression.
Author Info: (1) Cell Design Institute; University of California San Francisco, San Francisco, CA 94158, USA. Department of Medicine, University of California San Francisco; San Francisco, CA 9
Author Info: (1) Cell Design Institute; University of California San Francisco, San Francisco, CA 94158, USA. Department of Medicine, University of California San Francisco; San Francisco, CA 94158, USA. (2) Cell Design Institute; University of California San Francisco, San Francisco, CA 94158, USA. Department of Cellular and Molecular Pharmacology, University of California San Francisco; San Francisco, CA 94158, USA. (3) Cell Design Institute; University of California San Francisco, San Francisco, CA 94158, USA. Department of Cellular and Molecular Pharmacology, University of California San Francisco; San Francisco, CA 94158, USA. (4) Cell Design Institute; University of California San Francisco, San Francisco, CA 94158, USA. Biophysics Graduate Program, University of California San Francisco; San Francisco, CA 94158, USA. (5) Cell Design Institute; University of California San Francisco, San Francisco, CA 94158, USA. Department of Cellular and Molecular Pharmacology, University of California San Francisco; San Francisco, CA 94158, USA. (6) Cell Design Institute; University of California San Francisco, San Francisco, CA 94158, USA. Department of Cellular and Molecular Pharmacology, University of California San Francisco; San Francisco, CA 94158, USA. (7) Cell Design Institute; University of California San Francisco, San Francisco, CA 94158, USA. Department of Cellular and Molecular Pharmacology, University of California San Francisco; San Francisco, CA 94158, USA. (8) Cell Design Institute; University of California San Francisco, San Francisco, CA 94158, USA. Department of Cellular and Molecular Pharmacology, University of California San Francisco; San Francisco, CA 94158, USA. (9) Department of Microbiology and Immunology, University of California San Francisco; San Francisco, CA 94158, USA. (10) Cell Design Institute; University of California San Francisco, San Francisco, CA 94158, USA. Department of Cellular and Molecular Pharmacology, University of California San Francisco; San Francisco, CA 94158, USA. (11) Cell Design Institute; University of California San Francisco, San Francisco, CA 94158, USA. Department of Cellular and Molecular Pharmacology, University of California San Francisco; San Francisco, CA 94158, USA. (12) Department of Molecular and Cellular Physiology and Structural Biology, Howard Hughes Medical Institute, Stanford University; Stanford, USA. (13) Cell Design Institute; University of California San Francisco, San Francisco, CA 94158, USA. Department of Biochemistry and Biophysics, University of California San Francisco; San Francisco, CA 94158, USA. (14) Cell Design Institute; 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. Parker Institute for Cancer Immunotherapy, University of California San Francisco; San Francisco, CA 94158, USA. (15) Department of Microbiology and Immunology, University of California San Francisco; San Francisco, CA 94158, USA. Parker Institute for Cancer Immunotherapy, University of California San Francisco; San Francisco, CA 94158, USA. Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco; San Francisco, CA 94158, USA. (16) Cell Design Institute; University of California San Francisco, San Francisco, CA 94158, USA. Department of Cellular and Molecular Pharmacology, University of California San Francisco; San Francisco, CA 94158, USA. Department of Biochemistry and Biophysics, University of California San Francisco; San Francisco, CA 94158, USA. Parker Institute for Cancer Immunotherapy, University of California San Francisco; San Francisco, CA 94158, USA.
