{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T14:30:10Z","timestamp":1788877810770,"version":"build-2803163510"},"reference-count":88,"publisher":"American Society of Hematology","issue":"10","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,3,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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.<\/jats:p>","DOI":"10.1182\/blood.2022016052","type":"journal-article","created":{"date-parts":[[2022,8,31]],"date-time":"2022-08-31T19:03:39Z","timestamp":1661972619000},"page":"1194-1208","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":24,"title":["Engineering T cells to suppress acute GVHD and\u00a0leukemia relapse after allogeneic hematopoietic stem cell transplantation"],"prefix":"10.1182","volume":"141","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8167-2025","authenticated-orcid":false,"given":"Feiyan","family":"Mo","sequence":"first","affiliation":[{"name":"1Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children\u2019s Hospital and Houston Methodist Hospital, Houston, TX"},{"name":"2Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7678-0141","authenticated-orcid":false,"given":"Norihiro","family":"Watanabe","sequence":"additional","affiliation":[{"name":"1Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children\u2019s Hospital and Houston Methodist Hospital, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0255-5547","authenticated-orcid":false,"given":"Kayleigh I.","family":"Omdahl","sequence":"additional","affiliation":[{"name":"3Division of Pediatric Hematology\/Oncology, Boston Children\u2019s Hospital, Boston, MA"},{"name":"5Department of Pediatrics, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6290-6532","authenticated-orcid":false,"given":"Phillip M.","family":"Burkhardt","sequence":"additional","affiliation":[{"name":"1Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children\u2019s Hospital and Houston Methodist Hospital, Houston, TX"},{"name":"6Graduate Program in Immunology and Microbiology, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9786-6630","authenticated-orcid":false,"given":"Xiaoyun","family":"Ding","sequence":"additional","affiliation":[{"name":"7Department of Neuroscience, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiko","family":"Hayase","sequence":"additional","affiliation":[{"name":"8Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Panoskaltsis-Mortari","sequence":"additional","affiliation":[{"name":"9Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert R.","family":"Jenq","sequence":"additional","affiliation":[{"name":"8Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7049-7698","authenticated-orcid":false,"given":"Helen E.","family":"Heslop","sequence":"additional","affiliation":[{"name":"1Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children\u2019s Hospital and Houston Methodist Hospital, Houston, TX"},{"name":"2Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie S.","family":"Kean","sequence":"additional","affiliation":[{"name":"3Division of Pediatric Hematology\/Oncology, Boston Children\u2019s Hospital, Boston, MA"},{"name":"4Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA"},{"name":"5Department of Pediatrics, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malcolm K.","family":"Brenner","sequence":"additional","affiliation":[{"name":"1Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children\u2019s Hospital and Houston Methodist Hospital, Houston, TX"},{"name":"2Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX"},{"name":"6Graduate Program in Immunology and Microbiology, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6011-0576","authenticated-orcid":false,"given":"Victor","family":"Tkachev","sequence":"additional","affiliation":[{"name":"3Division of Pediatric Hematology\/Oncology, Boston Children\u2019s Hospital, Boston, MA"},{"name":"4Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA"},{"name":"5Department of Pediatrics, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7178-8163","authenticated-orcid":false,"given":"Maksim","family":"Mamonkin","sequence":"additional","affiliation":[{"name":"1Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children\u2019s Hospital and Houston Methodist Hospital, Houston, TX"},{"name":"2Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX"},{"name":"6Graduate Program in Immunology and 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