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

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

doi:10.1172/jci135754

Cited by 37 publications

(37 citation statements)

References 58 publications

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“…As mentioned above, CAR-T cells have the property of recognizing, binding, and clearing cells carrying target antigens and infusion of donor-derived CAR-T cells after allo-HSCT is less likely to elicit GVHD. Based on these characteristics of CAR-T cells, human CD83-targeted CAR-T cells have been developed for the prevention of GVHD (97). Human CD83 CAR-T cells can eradicate pathogenic CD83+ target cells, substantially increase the ratio of Tregs to alloactivated conventional CD4+ T cells, and have preventive and therapeutic effects on xenogeneic GVHD.…”

Section: Incorporation Of Car Technology Into the Treatment Of Gvhdmentioning

confidence: 99%

How to Combine the Two Landmark Treatment Methods—Allogeneic Hematopoietic Stem Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy Together to Cure High-Risk B Cell Acute Lymphoblastic Leukemia?

Zhang

Huang

2020

Front. Immunol.

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has made tremendous progress in the last few decades and is increasingly being used worldwide. The success of haploidentical HSCT has made it possible to have “a donor for everyone”. Patients who received transplantation in remission may have a favorable outcome, while those who were transplanted in advanced stages of disease have a poor prognosis. Although chimeric antigen receptor T (CAR-T) cell therapy is currently a milestone in the immunotherapy of relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL) and has demonstrated high remission rates in patients previously treated in multiple lines, the relatively high relapse rate remains a barrier to CAR-T cell therapy becoming an excellent cure option. Therefore, combining these two approaches (allo-HSCT and CAR-T cell therapy) is an attractive area of research to further improve the prognosis of R/R B-ALL. In this review, we will discuss the current clinical practices of combining allo-HSCT with CAR-T cell therapy based on available data, including CAR-T cells as a bridge to allo-HSCT for R/R B-ALL and CAR-T cell infusion for post-transplant relapse. We will further explore not only other possible ways to combine the two approaches, including CAR-T cell therapy to clear minimal residual disease peri-transplantation and incorporation of CAR technology to treat graft-versus-host disease, but also the potential of CAR-T cells as a part of allo-HSCT.

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Section: Incorporation Of Car Technology Into the Treatment Of Gvhdmentioning

confidence: 99%

How to Combine the Two Landmark Treatment Methods—Allogeneic Hematopoietic Stem Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy Together to Cure High-Risk B Cell Acute Lymphoblastic Leukemia?

Zhang

Huang

2020

Front. Immunol.

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“…Despite reported differences between CD83 on T cells between mice and humans, neither 3C12C or DCR-5 antibody substantially depletes T cells, including Treg. While human Treg express minimal surface CD83 ( 16 , 49 ), surface CD83 is found on a proportion of activated conventional T cells in humans and mice ( 29 , 49 – 52 ). DCR-5 did not reduce conventional CD4 + or CD8 + T cells when injected into naïve mice.…”

Section: Discussionmentioning

confidence: 99%

Anti-Mouse CD83 Monoclonal Antibody Targeting Mature Dendritic Cells Provides Protection Against Collagen Induced Arthritis

et al. 2022

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Antibodies targeting the activation marker CD83 can achieve immune suppression by targeting antigen-presenting mature dendritic cells (DC). This study investigated the immunosuppressive mechanisms of anti-CD83 antibody treatment in mice and tested its efficacy in a model of autoimmune rheumatoid arthritis. A rat anti-mouse CD83 IgG2a monoclonal antibody, DCR-5, was developed and functionally tested in mixed leukocyte reactions, demonstrating depletion of CD83+ conventional (c)DC, induction of regulatory DC (DCreg), and suppression of allogeneic T cell proliferation. DCR-5 injection into mice caused partial splenic cDC depletion for 2–4 days (mostly CD8+ and CD83+ cDC affected) with a concomitant increase in DCreg and regulatory T cells (Treg). Mice with collagen induced arthritis (CIA) treated with 2 or 6 mg/kg DCR-5 at baseline and every three days thereafter until euthanasia at day 36 exhibited significantly reduced arthritic paw scores and joint pathology compared to isotype control or untreated mice. While both doses reduced anti-collagen antibodies, only 6 mg/kg achieved significance. Treatment with 10 mg/kg DCR-5 was ineffective. Immunohistological staining of spleens at the end of CIA model with CD11c, CD83, and FoxP3 showed greater DC depletion and Treg induction in 6 mg/kg compared to 10 mg/kg DCR-5 treated mice. In conclusion, DCR-5 conferred protection from arthritis by targeting CD83, resulting in selective depletion of mature cDC and subsequent increases in DCreg and Treg. This highlights the potential for anti-CD83 antibodies as a targeted therapy for autoimmune diseases.

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“…Additionally, efforts aimed at developing more effective therapies to prevent and treat GVHD are needed. For example, Shrestha et al 75 developed anti-C83 CAR T cells that effectively prevented/treated GVHD in pre-clinical models and had promising anti-AML activity. Lastly, different groups are also investigating the use of other immune cell types that are less prone to causing GVHD in the allogeneic setting, as platforms for cellular immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Graft‐versus‐host disease risk after chimeric antigen receptor T‐cell therapy: the diametric opposition of T cells

2021

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Chimeric antigen receptor (CAR) T-cell therapy has brought a paradigm shift in the management of haematological malignancies and has opened novel avenues of investigational therapeutic strategies. Given these encouraging responses, it has become imperative to understand the full spectrum of biology and potential toxicities that can arise from these novel agents, as well as those under investigation. With the increasing use of CAR T-cell therapy for relapse following allogeneic haematopoietic cell transplantation (HCT) and the imminence of allogeneic CAR T cells, risks from T cell-based therapy, such as the previously well-recognised graft-versus-host disease (GVHD), have gained prominence and warrant explanation. In the present review, we discuss the risk of GVHD in the: (1) post-HCT setting using recipient or donor-derived CAR T cells, as well as (2) non-HCT setting using autologous, as well as allogeneic T-cell therapies. A better understanding of this risk is important to advance the field and ensure safe development and use of these agents in the clinic.

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

Cited by 37 publications

References 58 publications

How to Combine the Two Landmark Treatment Methods—Allogeneic Hematopoietic Stem Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy Together to Cure High-Risk B Cell Acute Lymphoblastic Leukemia?

How to Combine the Two Landmark Treatment Methods—Allogeneic Hematopoietic Stem Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy Together to Cure High-Risk B Cell Acute Lymphoblastic Leukemia?

Anti-Mouse CD83 Monoclonal Antibody Targeting Mature Dendritic Cells Provides Protection Against Collagen Induced Arthritis

Graft‐versus‐host disease risk after chimeric antigen receptor T‐cell therapy: the diametric opposition of T cells

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