Human CD83-targeted chimeric antigen receptor T cells prevent and treat graft-versus-host disease
Bishwas Shrestha, … , Brian C. Betts, Marco L. Davila
Bishwas Shrestha, … , Brian C. Betts, Marco L. Davila
Published May 21, 2020
Citation Information: J Clin Invest. 2020;130(9):4652-4662. https://doi.org/10.1172/JCI135754.
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Research Article Oncology

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

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.

Authors

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

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Figure 2

CD83 is differentially expressed on human activated conventional CD4+ T cells compared with regulatory T cells.

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CD83 is differentially expressed on human activated conventional CD4+ T ...
Human T cells were stimulated by allogeneic moDCs (DC/T cell ratio, 1:30) or CD3/CD28 beads (bead/T cell ratio, 1:30). CD83 expression on activated Tconvs (CD4+, CD127+, CD25+) or Tregs (CD4+, CD127–, CD25+, Foxp3+) was measured at baseline, 4 hours, 8 hours, 24 hours, and 48 hours after stimulation. Graphs show the amount of CD83+ Tconvs or Tregs (mean ± SEM) after (A) allogeneic DC or (B) CD3/CD28 bead stimulation (n = 5 independent experiments). (C) Graph shows the frequency (mean ± SEM) of CD83+ Th1 (CD4+, T-bet+), Th2 (CD4+, GATA3+), or Th17 (CD4+, RORγt+) cells after 8 hours of DC-allostimulation (n = 8 independent experiments). Human CD83 CAR or mock T cells were cultured with DC-allostimulated PBMCs at a ratio of 1:10 over 48 hours. (D) Graph shows the frequency of CD83+, CD3+, and CD3– target cells when cultured with CD83 CAR or mock-transduced T cells (n = 7 independent experiments). (E) Contour plots show the expression of CD83 among EGFP+ CAR T cells over time. One representative experiment of 2 is shown. (F) Human CD4+ or CD8+ T cells were activated with CD3/CD28 beads for 8 hours, then removed from the beads and cocultured with autologous CD83 CAR T cells or mock-transduced T cells for 24 hours (CAR T–to–T cell ratio, 5:1). Graph shows the triplicate mean ± SEM of live CD4+ or CD8+ T cells at the end of culture. One representative experiment of 2 is shown. ANOVA (A–D and F). *P < 0.05, **P = 0.001–0.01; ***P = 0.0001–0.001; ****P < 0.0001.