| Autor: |
Proics, Emma, David, Marion, Mojibian, Majid, Speck, Madeline, Lounnas-Mourey, Nadia, Govehovitch, Adeline, Baghdadi, Wissam, Desnouveaux, Justine, Bastian, Hervé, Freschi, Laura, Privat, Geoffrey, Pouzet, Cédric, Grossi, Mauro, Heimendinger, Pierre, Abel, Tobias, Fenard, David, Levings, Megan K., Meyer, François, Dumont, Céline |
| Zdroj: |
Gene Therapy; April 2023, Vol. 30 Issue: 3-4 p309-322, 14p |
| Abstrakt: |
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 scidgamma (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. |
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