Antigen-specificity using chimeric antigen receptors: the future of regulatory T-cell therapy?

Boardman, Dominic A.; Maher, John; Lechler, Robert I.; Smyth, Lesley A.; Lombardi, Giovanna

doi:10.1042/bst20150247

Cited by 44 publications

(26 citation statements)

References 49 publications

(81 reference statements)

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“…89 Genetic modification of polyclonal Tregs with CAR to promote antigen-specificity has demonstrated that CAR Tregs mediate enhanced suppression of inflammation compared with polyclonal Tregs in mouse models of TNP-induced colitis, 96 experimental autoimmune encephalitis, 97 anti-factor VIII autoantibody formation, 98 and skin graft rejection. 99 CARs may also redirect the function of human natural Tregs. 100 HLA-A2-specific CAR Treg were recently shown to inhibit xenogeneic GVHD mediated by HLA-A2 1 peripheral blood mononuclear cells in immunedeficient mice infused with Treg:HLA-A2 1 peripheral blood mononuclear cell ratios of 1:1 to 1:2.…”

Section: Car Tregsmentioning

confidence: 98%

Posttransplant chimeric antigen receptor therapy

Smith

Zakrzewski

James

et al. 2018

Blood

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Therapeutic T-cell engineering is emerging as a powerful approach to treat refractory hematological malignancies. Its most successful embodiment to date is based on the use of second-generation chimeric antigen receptors (CARs) targeting CD19, a cell surface molecule found in most B-cell leukemias and lymphomas. Remarkable complete remissions have been obtained with autologous T cells expressing CD19 CARs in patients with relapsed, chemo-refractory B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. Allogeneic CAR T cells may also be harnessed to treat relapse after allogeneic hematopoietic stem cell transplantation. However, the use of donor T cells poses unique challenges owing to potential alloreactivity. We review different approaches to mitigate the risk of causing or aggravating graft-versus-host disease (GVHD), including CAR therapies based on donor leukocyte infusion, virus-specific T cells, T-cell receptor-deficient T cells, lymphoid progenitor cells, and regulatory T cells. Advances in CAR design, T-cell selection and gene editing are poised to enable the safe use of allogeneic CAR T cells without incurring GVHD.

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Section: Car Tregsmentioning

confidence: 98%

Posttransplant chimeric antigen receptor therapy

Smith

Zakrzewski

James

et al. 2018

Blood

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“…Regulatory T cells (Tregs) also play a critical role in regulating the immune system by inhibiting the function of immune cells to keep immunologic self-tolerance and immune homeostasis, and an AID will occur when the specific transcription factor Forkhead box protein P3 (Foxp3) of Tregs is mutated or the CD4+CD25+ T cells are eliminated [50]. Therefore, applying Treg therapy in AIDs after being engineered to CAR-Tregs having antigen specificity may be a new choice [16,21,51,52]. CAR-Tregs can induce antigen-specific cytolysis of the targeted cell in a granzyme B-dependent way, suppressing antigen-specific effector T cells' (Teffs) response, and releasing immunosuppressive cytokines, like transforming growth factor β1 (TGF-β1) and IL-10 [53].…”

Section: Car-t Cell-derived Immunotherapy In Aidsmentioning

confidence: 99%

Immunotherapy Deriving from CAR-T Cell Treatment in Autoimmune Diseases

Chen

Sun

Liu

et al. 2019

Journal of Immunology Research

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Chimeric antigen receptor T (CAR-T) cells are T cells engineered to express specific synthetic antigen receptors that can recognize antigens expressed by tumor cells, which after the binding of these antigens to the receptors are eliminated, and have been adopted to treat several kinds of malignancies. Autoimmune diseases (AIDs), a class of chronic disease conditions, can be broadly separated into autoantibody-mediated and T cell-mediated diseases. Treatments for AIDs are focused on restoring immune tolerance. However, current treatments have little effect on immune tolerance inverse; even the molecular target biologics like anti-TNFα inhibitors can only mildly restore immune balance. By using the idea of CAR-T cell treatment in tumors, CAR-T cell-derived immunotherapies, chimeric autoantibody receptor T (CAAR-T) cells, and CAR regulatory T (CAR-T) cells bring new hope of treatment choice for AIDs.

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“…204 In addition to expansion by donor cell stimulation, alloantigen-specific Treg can also be generated through transfection of viral vectors encoding chimeric antigen receptors (CARs). 205 CARs are synthetic fusion proteins consisting of a single-chain variable fragment (scFv, a binding moiety of monoclonal antibody), an extracellular hinge, a transmembrane region, and an intracellular signaling domain. Transfected CARs in nTregs are capable of redirecting the specificity of nTregs toward the desired antigens without altering their regulatory phenotype or epigenetic stability.…”

Section: Regulatory Immune Cell Infusionsmentioning

confidence: 99%

Impact of infection on transplantation tolerance

Luo

2019

Immunological Reviews

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Allograft tolerance is the ultimate goal of organ transplantation. Current strategies for tolerance induction mainly focus on inhibiting alloreactive T cells while promoting regulatory immune cells. Pathogenic infections may have direct impact on both effector and regulatory cell populations, therefore can alter host susceptibility to transplantation tolerance induction as well as impair the quality and stability of tolerance once induced. In this review, we will discuss existing data demonstrating the effect of infections on transplantation tolerance, with particular emphasis on the role of the stage of infection (acute, chronic, or latent) and the stage of tolerance (induction or maintenance) in this infection‐tolerance interaction. While the deleterious effect of acute infection on tolerance is mainly driven by proinflammatory cytokines induced shortly after the infection, chronic infection may generate exhausted T cells that could in fact facilitate transplantation tolerance. In addition to pathogenic infections, commensal intestinal microbiota also has numerous significant immunomodulatory effects that can shape the host alloimmunity following transplantation. A comprehensive understanding of these mechanisms is crucial for the development of therapeutic strategies for robustly inducing and stably maintaining transplantation tolerance while preserving host anti‐pathogen immunity in clinically relevant scenarios.

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Antigen-specificity using chimeric antigen receptors: the future of regulatory T-cell therapy?

Cited by 44 publications

References 49 publications

Posttransplant chimeric antigen receptor therapy

Posttransplant chimeric antigen receptor therapy

Immunotherapy Deriving from CAR-T Cell Treatment in Autoimmune Diseases

Impact of infection on transplantation tolerance

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