细胞毒性T细胞
免疫学
干细胞
癌症研究
移植物抗宿主病
造血干细胞移植
T细胞
白细胞介素21
移植
生物
医学
免疫系统
细胞生物学
体外
内科学
生物化学
作者
Feiyan Mo,Norihiro Watanabe,Kayleigh Ingersoll Omdahl,Phillip M Burkhardt,Xiaoyun Ding,Eiko Hayase,Angela Panoskaltsis‐Mortari,Robert R. Jenq,Helen E. Heslop,Leslie S. Kean,Malcolm K. Brenner,Victor Tkachev,Maksim Mamonkin
出处
期刊:Blood
[American Society of Hematology]
日期:2023-03-09
卷期号:141 (10): 1194-1208
被引量:3
标识
DOI:10.1182/blood.2022016052
摘要
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.
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