Programming tissue-sensing T cells that deliver therapies to the brain
Milos Simic, Payal Watchmaker, Sasha Gupta, Yuan Wang, Sharon A. Sagan, Jason Duecker, Chanelle Shepherd, David Diebold, Psalm Pineo-Cavanaugh, Jeffrey Haegelin, Robert Zhu, Ben Ng, Wei Yu, Yurie Tonai, Lia Cardarelli, Nishith R. Reddy, Sachdev S. Sidhu, Olga G. Troyanskaya, Stephen L. Hauser, Michael R. Wilson, Scott S. Zamvil, Hideho Okada, Wendell A. Lim
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.