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

Milos S. Simic; Payal B. 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 Troyanskaya; Stephen L. Hauser; Michael R. Wilson; Scott S. Zamvil; Hideho Okada; Wendell A. Lim

doi:10.1126/science.adl4237

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

Milos S. Simic, Payal B. 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 Troyanskaya, Stephen L. Hauser, Michael R. WilsonScott S. Zamvil, Hideho Okada, Wendell A. Lim

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English (US)
Pages (from-to)	eadl4237
Journal	Science (New York, N.Y.)
Volume	386
Issue number	6726
DOIs	https://doi.org/10.1126/science.adl4237
State	Published - Dec 6 2024

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10.1126/science.adl4237

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Simic, M. S., Watchmaker, P. B., Gupta, S., Wang, Y., Sagan, S. A., Duecker, J., Shepherd, C., Diebold, D., Pineo-Cavanaugh, P., Haegelin, J., Zhu, R., Ng, B., Yu, W., Tonai, Y., Cardarelli, L., Reddy, N. R., Sidhu, S. S., Troyanskaya, O., Hauser, S. L., ... Lim, W. A. (2024). Programming tissue-sensing T cells that deliver therapies to the brain. Science (New York, N.Y.), 386(6726), eadl4237. https://doi.org/10.1126/science.adl4237

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title = "Programming tissue-sensing T cells that deliver therapies to the brain",

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 = "Simic, {Milos S.} and Watchmaker, {Payal B.} and Sasha Gupta and Yuan Wang and Sagan, {Sharon A.} and Jason Duecker and Chanelle Shepherd and David Diebold and Psalm Pineo-Cavanaugh and Jeffrey Haegelin and Robert Zhu and Ben Ng and Wei Yu and Yurie Tonai and Lia Cardarelli and Reddy, {Nishith R.} and Sidhu, {Sachdev S.} and Olga Troyanskaya and Hauser, {Stephen L.} and Wilson, {Michael R.} and Zamvil, {Scott S.} and Hideho Okada and Lim, {Wendell A.}",

year = "2024",

month = dec,

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doi = "10.1126/science.adl4237",

language = "English (US)",

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Simic, MS, Watchmaker, PB, Gupta, S, Wang, Y, Sagan, SA, Duecker, J, Shepherd, C, Diebold, D, Pineo-Cavanaugh, P, Haegelin, J, Zhu, R, Ng, B, Yu, W, Tonai, Y, Cardarelli, L, Reddy, NR, Sidhu, SS, Troyanskaya, O, Hauser, SL, Wilson, MR, Zamvil, SS, Okada, H & Lim, WA 2024, 'Programming tissue-sensing T cells that deliver therapies to the brain', Science (New York, N.Y.), vol. 386, no. 6726, pp. eadl4237. https://doi.org/10.1126/science.adl4237

TY - JOUR

T1 - Programming tissue-sensing T cells that deliver therapies to the brain

AU - Simic, Milos S.

AU - Watchmaker, Payal B.

AU - Gupta, Sasha

AU - Wang, Yuan

AU - Sagan, Sharon A.

AU - Duecker, Jason

AU - Shepherd, Chanelle

AU - Diebold, David

AU - Pineo-Cavanaugh, Psalm

AU - Haegelin, Jeffrey

AU - Zhu, Robert

AU - Ng, Ben

AU - Yu, Wei

AU - Tonai, Yurie

AU - Cardarelli, Lia

AU - Reddy, Nishith R.

AU - Sidhu, Sachdev S.

AU - Troyanskaya, Olga

AU - Hauser, Stephen L.

AU - Wilson, Michael R.

AU - Zamvil, Scott S.

AU - Okada, Hideho

AU - Lim, Wendell A.

PY - 2024/12/6

Y1 - 2024/12/6

N2 - 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.

AB - 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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ER -

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

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