Acute graft-versus-host disease (aGVHD) limits the therapeutic benefit of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and requires immunosuppressive prophylaxis that compromises antitumor and antipathogen immunity. OX40 is a costimulatory receptor upregulated on circulating T cells in aGVHD and plays a central role in driving the expansion of alloreactive T cells. Here, we show that OX40 is also upregulated on T cells infiltrating GVHD target organs in a rhesus macaque model, supporting the hypothesis that targeted ablation of OX40+ T cells will mitigate GVHD pathogenesis. We thus created an OX40-specific cytotoxic receptor that, when expressed on human T cells, enables selective elimination of OX40+ T cells. Because OX40 is primarily upregulated on CD4+ T cells upon activation, engineered OX40-specific T cells mediated potent cytotoxicity against activated CD4+ T cells and suppressed alloreactive T-cell expansion in a mixed lymphocyte reaction model. OX40 targeting did not inhibit antiviral activity of memory T cells specific to Epstein-Barr virus, cytomegalovirus, and adenoviral antigens. Systemic administration of OX40-targeting T cells fully protected mice from fatal xenogeneic GVHD mediated by human peripheral blood mononuclear cells. Furthermore, combining OX40 targeting with a leukemia-specific chimeric antigen receptor in a single T cell product provides simultaneous protection against leukemia and aGVHD in a mouse xenograft model of residual disease posttransplant. These results underscore the central role of OX40+ T cells in mediating aGVHD pathogenesis and support the feasibility of a bifunctional engineered T-cell product derived from the stem cell donor to suppress both disease relapse and aGVHD following allo-HSCT.
|Original language||English (US)|
|State||Accepted/In press - 2023|
Bibliographical noteFunding Information:
This project was supported by the Leukemia and Lymphoma Society Translational Research Award #6566, ASTCT New Investigator Award, CIBMTR/Be the Match Foundation Amy Strelzer Manasevit Research Program, and the National Institute of Health ( F99CA253757 , P50CA126752 , P30 CA125123, 2U19 AI051731, 2R01 HL095791 ).
The authors thank David Quach, Sandhya Sharma, and Naren Mehta in the Cliona Rooney lab for the K562-CS cell line, LCLs, and instructions on VST generation; Cheng-Yen Chang in the Farrah Kheradmand lab and M. Sayeeduddin, Shahida Salar, and Zahida Sayeeduddin in the Baylor College of Medicine Pathology and Histology Core for tissue processing and H&E staining; and Catherine Gillespie for editing the manuscript. This project was supported by the Leukemia and Lymphoma Society Translational Research Award #6566, ASTCT New Investigator Award, CIBMTR/Be the Match Foundation Amy Strelzer Manasevit Research Program, and the National Institute of Health (F99CA253757, P50CA126752, P30 CA125123, 2U19 AI051731, 2R01 HL095791).
© 2022 The American Society of Hematology
PubMed: MeSH publication types
- Journal Article