Preclinical assessment of antigen-specific chimeric antigen receptor regulatory T cells for use in solid organ transplantation.

Abstract

A primary goal in transplantation medicine is the induction of a tolerogenic environment for prevention of transplant rejection without the need for long-term pharmacological immunosuppression. Generation of alloantigen-specific regulatory T cells (Tregs) by transduction with chimeric antigen receptors (CARs) is a promising strategy to achieve this goal. This publication reports the preclinical characterization of Tregs (TR101) transduced with a human leukocyte antigen (HLA)-A*02 CAR lentiviral vector (TX200) designated to induce immunosuppression of allograft-specific effector T cells in HLA-A*02-negative recipients of HLA-A*02-positive transplants. In vitro results demonstrated specificity, immunosuppressive function, and safety of TX200-TR101. In NOD scid gamma (NSG) mice, TX200-TR101 prevented graft-versus-host disease (GvHD) in a xenogeneic GvHD model and TX200-TR101 Tregs localized to human HLA-A*02-positive skin transplants in a transplant model. TX200-TR101 persisted over the entire duration of a 3-month study in humanized HLA-A*02 NSG mice and remained stable, without switching to a proinflammatory phenotype. Concomitant tacrolimus did not impair TX200-TR101 Treg survival or their ability to inhibit peripheral blood mononuclear cell (PBMC) engraftment. These data demonstrate that TX200-TR101 is specific, stable, efficacious, and safe in preclinical models, and provide the basis for a first-in-human study.

• Authors: Emma Proics, Marion David, Majid Mojibian, Madeline Speck, Nadia Lounnas-Mourey, Adeline Govehovitch, Wissam Baghdadi, Justine Desnouveaux, Hervé Bastian, Laura Freschi, Geoffrey Privat, Cédric Pouzet, Mauro Grossi, Pierre Heimendinger, Tobias Abel, David Fenard, Megan K Levings, François Meyer, Céline Dumont
• Journal: Gene therapy (Gene Ther) Vol. 30 Issue 3-4 Pg. 309-322 (04 2023) ISSN: 1476-5462 [Electronic] England
• PMID: 35931871 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Receptors, Chimeric Antigen
• HLA-A Antigens

Topics

• Mice
• Animals
• Humans
• Receptors, Chimeric Antigen
• T-Lymphocytes, Regulatory
• Leukocytes, Mononuclear (transplantation)
• Graft vs Host Disease
• Organ Transplantation
• HLA-A Antigens