Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression

Olivia Sirpilla; R. Leo Sakemura; Mehrdad Hefazi; Truc N. Huynh; Ismail Can; James H. Girsch; Erin E. Tapper; Michelle J. Cox; Kendall J. Schick; Claudia Manriquez-Roman; Kun Yun; Carli M. Stewart; Ekene J. Ogbodo; Brooke L. Kimball; Long K. Mai; Omar L. Gutierrez-Ruiz; Makena L. Rodriguez; Martina Gluscevic; Daniel P. Larson; Alex M. Abel; Wesley A. Wierson; Gloria Olivier; Elizabeth L. Siegler; Saad S. Kenderian

doi:10.1038/s41551-024-01195-6

Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression

Olivia Sirpilla, R. Leo Sakemura, Mehrdad Hefazi, Truc N. Huynh, Ismail Can, James H. Girsch, Erin E. Tapper, Michelle J. Cox, Kendall J. Schick, Claudia Manriquez-Roman, Kun Yun, Carli M. Stewart, Ekene J. Ogbodo, Brooke L. Kimball, Long K. Mai, Omar L. Gutierrez-Ruiz, Makena L. Rodriguez, Martina Gluscevic, Daniel P. Larson, Alex M. AbelWesley A. Wierson, Gloria Olivier, Elizabeth L. Siegler, Saad S. Kenderian

Hematology

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

Abstract

Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice. CAR-MSCs led to superior T-cell suppression and localization to E-cadherin⁺ colonic cells, ameliorating the animals’ symptoms and survival rates. On antigen-specific stimulation, CAR-MSCs upregulated the expression of immunosuppressive genes and receptors for T-cell inhibition as well as the production of immunosuppressive cytokines while maintaining their stem cell phenotype and safety profile in the animal models. CAR-MSCs may represent a widely applicable therapeutic technology for enhancing immunosuppression.

Original language	English (US)
Journal	Nature Biomedical Engineering
DOIs	https://doi.org/10.1038/s41551-024-01195-6
State	Accepted/In press - 2024

ASJC Scopus subject areas

Biotechnology
Bioengineering
Medicine (miscellaneous)
Biomedical Engineering
Computer Science Applications

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10.1038/s41551-024-01195-6

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Sirpilla, O., Sakemura, R. L., Hefazi, M., Huynh, T. N., Can, I., Girsch, J. H., Tapper, E. E., Cox, M. J., Schick, K. J., Manriquez-Roman, C., Yun, K., Stewart, C. M., Ogbodo, E. J., Kimball, B. L., Mai, L. K., Gutierrez-Ruiz, O. L., Rodriguez, M. L., Gluscevic, M., Larson, D. P., ... Kenderian, S. S. (Accepted/In press). Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression. Nature Biomedical Engineering. https://doi.org/10.1038/s41551-024-01195-6

Sirpilla, O, Sakemura, RL, Hefazi, M, Huynh, TN, Can, I, Girsch, JH, Tapper, EE, Cox, MJ, Schick, KJ, Manriquez-Roman, C, Yun, K, Stewart, CM, Ogbodo, EJ, Kimball, BL, Mai, LK, Gutierrez-Ruiz, OL, Rodriguez, ML, Gluscevic, M, Larson, DP, Abel, AM, Wierson, WA, Olivier, G, Siegler, EL & Kenderian, SS 2024, 'Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression', Nature Biomedical Engineering. https://doi.org/10.1038/s41551-024-01195-6

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title = "Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression",

abstract = "Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice. CAR-MSCs led to superior T-cell suppression and localization to E-cadherin+ colonic cells, ameliorating the animals{\textquoteright} symptoms and survival rates. On antigen-specific stimulation, CAR-MSCs upregulated the expression of immunosuppressive genes and receptors for T-cell inhibition as well as the production of immunosuppressive cytokines while maintaining their stem cell phenotype and safety profile in the animal models. CAR-MSCs may represent a widely applicable therapeutic technology for enhancing immunosuppression.",

author = "Olivia Sirpilla and Sakemura, {R. Leo} and Mehrdad Hefazi and Huynh, {Truc N.} and Ismail Can and Girsch, {James H.} and Tapper, {Erin E.} and Cox, {Michelle J.} and Schick, {Kendall J.} and Claudia Manriquez-Roman and Kun Yun and Stewart, {Carli M.} and Ogbodo, {Ekene J.} and Kimball, {Brooke L.} and Mai, {Long K.} and Gutierrez-Ruiz, {Omar L.} and Rodriguez, {Makena L.} and Martina Gluscevic and Larson, {Daniel P.} and Abel, {Alex M.} and Wierson, {Wesley A.} and Gloria Olivier and Siegler, {Elizabeth L.} and Kenderian, {Saad S.}",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature Limited 2024.",

year = "2024",

doi = "10.1038/s41551-024-01195-6",

language = "English (US)",

journal = "Nature Biomedical Engineering",

issn = "2157-846X",

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T1 - Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression

AU - Sirpilla, Olivia

AU - Sakemura, R. Leo

AU - Hefazi, Mehrdad

AU - Huynh, Truc N.

AU - Can, Ismail

AU - Girsch, James H.

AU - Tapper, Erin E.

AU - Cox, Michelle J.

AU - Schick, Kendall J.

AU - Manriquez-Roman, Claudia

AU - Yun, Kun

AU - Stewart, Carli M.

AU - Ogbodo, Ekene J.

AU - Kimball, Brooke L.

AU - Mai, Long K.

AU - Gutierrez-Ruiz, Omar L.

AU - Rodriguez, Makena L.

AU - Gluscevic, Martina

AU - Larson, Daniel P.

AU - Abel, Alex M.

AU - Wierson, Wesley A.

AU - Olivier, Gloria

AU - Siegler, Elizabeth L.

AU - Kenderian, Saad S.

PY - 2024

Y1 - 2024

N2 - Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice. CAR-MSCs led to superior T-cell suppression and localization to E-cadherin+ colonic cells, ameliorating the animals’ symptoms and survival rates. On antigen-specific stimulation, CAR-MSCs upregulated the expression of immunosuppressive genes and receptors for T-cell inhibition as well as the production of immunosuppressive cytokines while maintaining their stem cell phenotype and safety profile in the animal models. CAR-MSCs may represent a widely applicable therapeutic technology for enhancing immunosuppression.

AB - Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice. CAR-MSCs led to superior T-cell suppression and localization to E-cadherin+ colonic cells, ameliorating the animals’ symptoms and survival rates. On antigen-specific stimulation, CAR-MSCs upregulated the expression of immunosuppressive genes and receptors for T-cell inhibition as well as the production of immunosuppressive cytokines while maintaining their stem cell phenotype and safety profile in the animal models. CAR-MSCs may represent a widely applicable therapeutic technology for enhancing immunosuppression.

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Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression

Abstract

ASJC Scopus subject areas

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