Programming tissue-sensing T cells that deliver therapies to the brain

• 成果类型: Article
• 署名作者: Simic, Milos S.; Watchmaker, Payal B.; Gupta, Sasha; Wang, Yuan; Sagan, Sharon A.; Duecker, Jason; Shepherd, Chanelle; Diebold, David; Pineo-Cavanaugh, Psalm; Haegelin, Jeffrey; Zhu, Robert; Ng, Ben; Yu, Wei; Tonai, Yurie; Cardarelli, Lia; Reddy, Nishith R.; Sidhu, Sachdev S.; Troyanskaya, Olga; Hauser, Stephen L.; Wilson, Michael R.; Zamvil, Scott S.; Okada, Hideho; Lim, Wendell A.
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Princeton University; Princeton University; University of Waterloo; Simons Foundation; Flatiron Institute; University of California System; University of California San Francisco; University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8311
• DOI: 10.1126/science.adl4237
• 发表日期: 2024-12-06
• 关键词: experimental autoimmune encephalomyelitis; multiple-sclerosis; cancer regression; expression; interleukin-10; ocrelizumab

摘要

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.