Purpose: Acute and chronic GVHD remain major causes of transplant-related morbidity and mortality (TRM) after allogeneic hematopoietic cell transplantation (alloHCT). We have shown CD83 chimeric antigen receptor (CAR) T cells prevent GVHD and kill myeloid leukemia cell lines. In this pilot study, we investigate CD83 expression on GVHD effector cells, correlate these discoveries with clinical outcomes, and evaluate critical therapeutic implications for transplant recipients. Experimental Design: CD83 expression was evaluated among circulating CD4+ T cells, B-cell subsets, T follicular helper (Tfh) cells, and monocytes from patients with/without acute or chronic GVHD (n = 48 for each group), respectively. CD83 expression was correlated with survival, TRM, and relapse after alloHCT. Differential effects of GVHD therapies on CD83 expression was determined. Results: CD83 overexpression on CD4+ T cells correlates with reduced survival and increased TRM. Increased CD83+ B cells and Tfh cells, but not monocytes, are associated with poor posttransplant survival. CD83 CAR T eliminate autoreactive CD83+ B cells isolated from patients with chronic GVHD, without B-cell aplasia as observed with CD19 CAR T. We demonstrate robust CD83 antigen density on human acute myeloid leukemia (AML), and confirm potent antileukemic activity of CD83 CAR T in vivo, without observed myeloablation. Conclusions: CD83 is a promising diagnostic marker of GVHD and warrants further investigation as a therapeutic target of both GVHD and AML relapse after alloHCT.
Bibliographical noteFunding Information:
Our study received assistance from the Flow Cytometry Core Facility at the H. Lee Moffitt Cancer Center & Research Institute and the Flow Cytometry Resource at the University of Minnesota, both of which are NCI-designated Comprehensive Cancer Centers. This work was supported by funds from Masonic Cancer Center (BCB), Moffitt Cancer Center (MLD), CCSG grants at Moffitt and the Masonic Cancer Centers, and grant support including NHLBI R01 HL56067, R01 HL 11879, R01 HL 155114, and NIAID R37 AI 34495 (BRB).
S.G. Holtan reports other support from Incyte and VITRAC Therapeutics outside the submitted work; in addition, S.G. Holtan serves as a clinical trial adjudicator for CSL Behring. A.A. Eaton reports grants from NCI during the conduct of the study, as well as grants from NIH outside the submitted work. J. Maakaron reports other support from Gilead, ADC Therapeutics, CRISPR, and Precision BioSciences outside the submitted work. D.J. Weisdorf reports grants from Fate Therapeutics and Incyte outside the submitted work. M. Felices reports personal fees from GT Biopharma outside the submitted work. J.S. Miller consults for and holds stock in Fate Therapeutics, GT BioPharma, and Vycellix, as well as reports research funds from Fate Therapeutics and GT Biopharma; these interests have been reviewed and managed by the University of Minnesota in accordance with its conflict of interest policy. J.S. Miller serves on the Scientific Advisory Board of ONK Therapeutics, Wugan, and Sanofi; none of these relationships are related to the content of this manuscript. M.L. Davila reports grants from CRISPR during the conduct of the study. M.L. Davila also reports personal fees and other support from Bellicum and Adicet; personal fees from Capstan and CARGO; grants from Kite/Gilead and Novartis; and other support from Adaptive Biotechnologies outside the submitted work. In addition, M.L. Davila has a patent for CAR design pending to Atara and a patent for CD83 CAR pending to CRISPR. B.C. Betts reports personal fees and other support from CRISPR Therapeutics during the conduct of the study, as well as other support from VITRAC Therapeutics, Incyte, and CTI BioPharma outside the submitted work; in addition, B.C. Betts has a patent for WO2019165156 licensed to CRISPR Therapeutics. No disclosures were reported by the other authors.
© 2023 The Authors.
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't