Murine CAR19 Tregs suppress acute graft-versus-host disease and maintain graft-versus-tumor responses

Sara Bolivar-Wagers, Michael L. Loschi, Sujeong Jin, Govindarajan Thangavelu, Jemma H. Larson, Cameron S. McDonald-Hyman, Ethan A. Aguilar, Asim Saha, Brent H. Koehn, Mehrdad Hefazi, Mark J. Osborn, Michael C. Jensen, John E. Wagner, Christopher A. Pennell, Bruce R. Blazar

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) efficacy is complicated by graft-versus-host disease (GVHD), a leading cause of morbidity and mortality. Regulatory T cells (Tregs) have shown efficacy in preventing GVHD. However, high Treg doses are often required, necessitating substantial ex vivo or in vivo expansion that may diminish suppressor function. To enhance in vivo suppressor function, murine Tregs were transduced to express an anti–human CD19 chimeric antigen receptor (hCAR19) and infused into lethally irradiated, hCD19-transgenic recipients for allo-HSCT. Compared with recipients receiving control transduced Tregs, those receiving hCAR19 Tregs had a marked decrease in acute GVHD lethality. Recipient hCD19 B cells and murine hCD19 TBL12-luciferase (TBL12luc) lymphoma cells were both cleared by allogeneic hCAR19 Tregs, which was indicative of graft-versus-tumor (GVT) maintenance and potentiation. Mechanistically, hCAR19 Tregs killed syngeneic hCD19+ but not hCD19– murine TBL12luc cells in vitro in a perforin-dependent, granzyme B–independent manner. Importantly, cyclophosphamide-treated, hCD19-transgenic mice given hCAR19 cytotoxic T lymphocytes without allo-HSCT experienced rapid lethality due to systemic toxicity that has been associated with proinflammatory cytokine release; in contrast, hCAR19 Treg suppressor function enabled avoidance of this severe complication. In conclusion, hCAR19 Tregs are a potentially novel and effective strategy to suppress GVHD without loss of GVT responses.

Original languageEnglish (US)
Article numbere160674
JournalJCI Insight
Volume7
Issue number17
DOIs
StatePublished - Sep 8 2022

Bibliographical note

Funding Information:
remuneration as an advisor to Magenta Therapeutics and BlueRock Therapeutics; has received research funding from BlueRock Therapeutics, Rheos Medicines, and Carisma Therapeutics, Inc.; and is a cofounder of Tmunity Therapeutics.

Funding Information:
This work was funded by the National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; and National Cancer Institute under grant numbers NIH R01 56067, R37 AI34495, R01 HL11879, R01 HL155114, P01 CA 065493, T32 AI007313, F30 HL156312, and T32 HL007062. We would like to give special thanks to Peter Hinderlie for his help with the IncuCyte experiments.

Publisher Copyright:
© 2022, Bolivar-Wagers et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

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