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- Title
Human CD83-targeted chimeric antigen receptor T cells prevent and treat graft-versus-host disease.
- Authors
Shrestha, Bishwas; Walton, Kelly; Reff, Jordan; Sagatys, Elizabeth M.; Nhan Tu; Boucher, Justin; Gongbo Li; Ghafoor, Tayyebb; Felices, Martin; Miller, Jeffrey S.; Pidala, Joseph; Blazar, Bruce R.; Anasetti, Claudio; Betts, Brian C.; Davila, Marco L.; Tu, Nhan; Boucher, Justin C; Li, Gongbo; Ghafoor, Tayyeb; Miller, Jeffrey
- Abstract
Graft-versus-host disease (GVHD) remains an important cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). For decades, GVHD prophylaxis has included calcineurin inhibitors, despite their incomplete efficacy and impairment of graft-versus-leukemia (GVL). Distinct from pharmacologic immune suppression, we have developed what we believe is a novel, human CD83-targeted chimeric antigen receptor (CAR) T cell for GVHD prevention. CD83 is expressed on allo-activated conventional CD4+ T cells (Tconvs) and proinflammatory dendritic cells (DCs), which are both implicated in GVHD pathogenesis. Human CD83 CAR T cells eradicate pathogenic CD83+ target cells, substantially increase the ratio of regulatory T cells (Tregs) to allo-activated Tconvs, and provide durable prevention of xenogeneic GVHD. CD83 CAR T cells are also capable of treating xenogeneic GVHD. We show that human acute myeloid leukemia (AML) expresses CD83 and that myeloid leukemia cell lines are readily killed by CD83 CAR T cells. Human CD83 CAR T cells are a promising cell-based approach to preventing 2 critical complications of allo-HCT - GVHD and relapse. Thus, the use of human CD83 CAR T cells for GVHD prevention and treatment, as well as for targeting CD83+ AML, warrants clinical investigation.
- Subjects
CHIMERIC antigen receptors; SUPPRESSOR cells; GRAFT versus host disease; T cells; ACUTE myeloid leukemia; PRELEUKEMIA; ACUTE myeloid leukemia treatment; GRAFT versus host disease prevention; PROTEINS; RESEARCH; IMMUNOGLOBULINS; IMMUNIZATION; HOMOGRAFTS; ANIMAL experimentation; RESEARCH methodology; EVALUATION research; MEDICAL cooperation; MEMBRANE glycoproteins; COMPARATIVE studies; RESEARCH funding; HEMATOPOIETIC stem cell transplantation; CELL lines; ANTIGENS; MICE
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 9, p4652
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI135754