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: Engineering synthetic suppressor T cells that execute locally targeted immunoprotective programs
ABSTRACT: To engineer cells that can specifically target the central nervous system (CNS), we identified extracellular CNS-specific antigens, including components of the CNS extracellular matrix and surface molecules expressed on neurons or glial cells. Synthetic Notch receptors engineered to detect these antigens were used to program T cells to induce the expression of diverse payloads only in the brain. CNS-targeted T cells that induced chimeric antigen receptor expression efficiently cleared primary and secondary brain tumors without harming cross-reactive cells outside of the brain. Conversely, CNS-targeted cells that locally delivered the immunosuppressive cytokine interleukin-10 ameliorated symptoms in a mouse model of neuroinflammation. Tissue-sensing cells represent a strategy for addressing diverse disorders in an anatomically targeted manner.
Author Info: (1) UCSF Cell Design Institute and Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA. (2) Department of Neurological S
Author Info: (1) UCSF Cell Design Institute and Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA. (2) Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA. (3) Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, USA. (4) Department of Computer Science, Princeton University, Princeton, NJ, USA. Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA. (5) Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, USA. (6) UCSF Cell Design Institute and Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA. (7) UCSF Cell Design Institute and Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA. (8) Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA. (9) Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA. (10) Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA. (11) UCSF Cell Design Institute and Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA. (12) UCSF Cell Design Institute and Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA. (13) UCSF Cell Design Institute and Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA. (14) UCSF Cell Design Institute and Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA. (15) School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada. (16) UCSF Cell Design Institute and Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA. (17) School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada. (18) Department of Computer Science, Princeton University, Princeton, NJ, USA. Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA. Center for Computational Biology, Flatiron Institute, New York, NY, USA. (19) Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, USA. (20) Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, USA. (21) Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, USA. Program in Immunology, University of California San Francisco, San Francisco, CA, USA. (22) Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Helen Diller Cancer Center, University of California San Francisco, San Francisco, CA, USA. (23) UCSF Cell Design Institute and Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
