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

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 substa...

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Published in:JCI insight 2022-09, Vol.7 (17)
Main Authors: Bolivar-Wagers, Sara, Loschi, Michael L, Jin, Sujeong, Thangavelu, Govindarajan, Larson, Jemma H, McDonald-Hyman, Cameron S, Aguilar, Ethan G, Saha, Asim, Koehn, Brent H, Hefazi, Mehrdad, Osborn, Mark J, Jensen, Michael C, Wagner, John E, Pennell, Christopher A, Blazar, Bruce R
Format: Article
Language:English
Subjects:
Animals
Graft vs Host Disease - prevention & control
Hematopoietic Stem Cell Transplantation - adverse effects
Immunology
Mice
Neoplasms
Receptors, Antigen, T-Cell - metabolism
Receptors, Chimeric Antigen
T-Lymphocytes, Regulatory
Transplantation
Transplantation, Homologous
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Summary: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.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.160674