Two teams of researchers working with lead author Dr. Wendell Lim demonstrated the use of synNotch-engineered CD4+ T cells directed towards tissue-specific antigens, triggering the local release of various disease-specific payloads. Reddy et al. utilized this technology to suppress CAR T cell cytotoxicity in on-target/off-tumor tissues and to suppress immune rejection in transplanted organs, while Simic and Watchmaker et al. demonstrated its ability to induce CAR expression only in the brain and to specifically deliver payloads that suppress neuroinflammation.
Also review: Programming tissue-sensing T cells that deliver therapies to the brain
ABSTRACT: Immune homeostasis requires a balance of inflammatory and suppressive activities. To design cells potentially useful for local immune suppression, we engineered conventional CD4(+) T cells with synthetic Notch (synNotch) receptors driving antigen-triggered production of anti-inflammatory payloads. Screening a diverse library of suppression programs, we observed the strongest suppression of cytotoxic T cell attack by the production of both anti-inflammatory factors (interleukin-10, transforming growth factor-_1, programmed death ligand 1) and sinks for proinflammatory cytokines (interleukin-2 receptor subunit CD25). Engineered cells with bespoke regulatory programs protected tissues from immune attack without systemic suppression. Synthetic suppressor T cells protected transplanted beta cell organoids from cytotoxic T cells. They also protected specific tissues from unwanted chimeric antigen receptor (CAR) T cell cross-reaction. Synthetic suppressor T cells are a customizable platform to potentially treat autoimmune diseases, organ rejection, and CAR T cell toxicities with spatial precision.
Author Info: (1) UCSF Cell Design Institute, University of California, San Francisco, San Francisco, CA, USA. Department of Cellular and Molecular Pharmacology, University of California, San Fr
Author Info: (1) UCSF Cell Design Institute, University of California, San Francisco, San Francisco, CA, USA. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. (2) Diabetes Center, University of California, San Francisco, San Francisco, CA, USA. (3) UCSF Cell Design Institute, University of California, San Francisco, San Francisco, CA, USA. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. Diabetes Center, University of California, San Francisco, San Francisco, CA, USA. (4) UCSF Cell Design Institute, University of California, San Francisco, San Francisco, CA, USA. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. (5) UCSF Cell Design Institute, University of California, San Francisco, San Francisco, CA, USA. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. (6) UCSF Cell Design Institute, University of California, San Francisco, San Francisco, CA, USA. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. (7) UCSF Cell Design Institute, University of California, San Francisco, San Francisco, CA, USA. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. (8) UCSF Cell Design Institute, University of California, San Francisco, San Francisco, CA, USA. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. (9) UCSF Cell Design Institute, University of California, San Francisco, San Francisco, CA, USA. Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA. (10) UCSF CoLabs, University of California, San Francisco, San Francisco, CA, USA. (11) UCSF Cell Design Institute, University of California, San Francisco, San Francisco, CA, USA. Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA, USA. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. Department of Medicine, University of California San Francisco, San Francisco, CA, USA. (12) Diabetes Center, University of California, San Francisco, San Francisco, CA, USA. (13) Diabetes Center, University of California, San Francisco, San Francisco, CA, USA. (14) UCSF Cell Design Institute, University of California, San Francisco, San Francisco, CA, USA. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
