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

Milos Simic(University of California, San Francisco), Payal Watchmaker(University of California, San Francisco), Sasha Gupta(University of California, San Francisco), Yuan Wang(Princeton University), Sharon A. Sagan(University of California, San Francisco), Jason Duecker(University of California, San Francisco), Chanelle Shepherd(University of California, San Francisco), David Diebold(University of California, San Francisco), Psalm Pineo-Cavanaugh(University of California, San Francisco), Jeffrey Haegelin(University of California, San Francisco), Robert Zhu(University of California, San Francisco), Ben Ng(University of California, San Francisco), Wei Yu(University of California, San Francisco), Yurie Tonai(University of California, San Francisco), Lia Cardarelli(University of Waterloo), Nishith R. Reddy(University of California, San Francisco), Sachdev S. Sidhu(University of Waterloo), Olga G. Troyanskaya(Princeton University), Stephen L. Hauser(University of California, San Francisco), Michael R. Wilson(University of California, San Francisco), Scott S. Zamvil(University of California, San Francisco), Hideho Okada(University of California, San Francisco), Wendell A. Lim(University of California, San Francisco)
Science
December 5, 2024
10.1126/science.adl4237
Cited by 73Open Access
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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.

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