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 7

CD83 is a cellular target for human AML.

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CD83 is a cellular target for human AML. Histograms show CD83 expression...
Histograms show CD83 expression among proliferating (A) K562 and (B) Thp-1 cells with MFI noted in the lower right-hand corner (FMO, unfilled). Human CD83 CAR or mock-transduced T cells were cocultured with fresh K562 or Thp-1 cells at an E/T ratio of 10:1. (C and D) Target cell killing was monitored using the xCELLigence RTCA system. A representative experiment for each is shown (triplicate mean ± SEM). NSG-SGM3 mice were injected with MOLM-13 EGFP/luciferase+ 1 × 106 cells. Bioluminescence (BLI) was performed (IVIS Systems) on day +9 and then the mice were treated with 2.5 × 106 CD83 CAR T or mock-transduced T cells. Mice were then imaged weekly. (E) Graph shows fold change (mean ± SEM) for average radiance (p/sec/cm2/Sr) at 1 week after injection of CD83 CAR or mock-transduced T cells. (F) Representative image shows weekly BLI intensities among each mouse per group over 4 weeks (n = 2 independent experiments, with 7–8 mice per experimental arm). (G) Graph shows the expression (mean ± SEM) of CD83 compared with CD33 or CD123 among freshly acquired human CD34+ AML blasts. (H) Representative histogram shows CD83 expression among human CD34+ AML blasts (FMO, unfilled) (n = 15 patient samples). ANOVA (C, D, E, and G). *P < 0.05, **P = 0.001–0.01, ***P = 0.0001–0.001, and ****P < 0.0001.