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Human OX40L-CAR-Tregs target activated antigen-presenting cells and control T cell alloreactivity

Researchers at Boston Children's Hospital, Dana-Farber Cancer Institute, and Harvard Medical School have developed an innovative regulatory T cell (Treg)-based therapy to address challenges in allo- and autoimmune diseases. Conventional Treg therapies, which rely on mixed Treg populations, have faced limitations due to inconsistent stability and potency. Rui et al. engineered OX40 ligand-specific chimeric antigen receptor (OX40L–CAR) Tregs, selectively activated by the master Treg transcription factor FoxP3. This targeted approach focuses on OX40L-expressing cells, key players in conditions such as graft-versus-host disease (GVHD), organ transplant rejection, and autoimmune disorders like rheumatoid arthritis and systemic lupus erythematosus.

In vitro experiments demonstrated that OX40L–CAR-Tregs significantly outperformed conventional Tregs. Upon interaction with OX40L-expressing cells, the CAR-Tregs robustly upregulated Treg suppressive proteins without inducing proinflammatory cytokines. They were more effective in suppressing alloreactive T cell proliferation and directly inhibited the activity of monocyte-derived dendritic cells (DCs). A notable mechanism of action was trogocytosis, wherein OX40L–CAR-Tregs removed OX40L from antigen-presenting cells, thereby diminishing their capacity to activate effector T cells. This dual ability to suppress T cells and modulate DC function highlights the enhanced therapeutic potential of these engineered Tregs.

In vivo studies in xenogeneic GVHD mouse models revealed that OX40L–CAR-Tregs effectively controlled disease progression while preserving the essential graft-versus-leukemia effect. This balance is critical, as it ensures therapeutic efficacy without compromising anti-leukemia immunity. The findings suggest that OX40L–CAR-Tregs could be a transformative therapy for managing allo- and autoimmune diseases. The study provides a strong foundation for advancing OX40L–CAR-Tregs into clinical trials to evaluate their safety and efficacy in treating GVHD, transplant rejection, and various autoimmune conditions.

Reference:

Rui X, Alvarez Calderon F, Wobma H, et al. Human OX40L-CAR-T_regs target activated antigen-presenting cells and control T cell alloreactivity. Sci Transl Med. 2024;16(769):eadj9331.

http://doi.org/10.1126/scitranslmed.adj9331