Human CD83-targeted chimeric antigen receptor T cells prevent and treat graft-versus-host disease

Bishwas Shrestha, Kelly Walton, Jordan Reff, Elizabeth M. Sagatys, Nhan Tu, Justin Boucher, Gongbo Li, Tayyebb Ghafoor, Martin Felices, Jeffrey S. Miller, Joseph Pidala, Bruce R. Blazar, Claudio Anasetti, Brian C. Betts, Marco L. Davila

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)4652-4662
Number of pages11
JournalJournal of Clinical Investigation
Volume130
Issue number9
DOIs
StatePublished - Sep 1 2020

Bibliographical note

Funding Information:
Our study received assistance from the Flow Cytometry Core Facility at the H. Lee Moffitt Cancer Center & Research Institute (P30-CA076292) and the Flow Cytometry Resource at the University of Minnesota, both of which are NCI-designated Comprehensive Cancer Centers. The authors would like to acknowledge the animal care staff in the Department of Comparative Medicine at the University of South Florida for providing technical assistance. This work was supported by funds from the Moffitt Cancer Center (to MLD); NIH grants K08 HL116547 (to BCB), R01 HL133823 (to BCB), R01 HL11879, R01 HL56067, and R37 AI34495 (to BRB); and Leukemia & Lymphoma Society Translational Research Grant 6462-15 (to BRB).

Publisher Copyright:
Copyright: © 2020, American Society for Clinical Investigation.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

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