Genetic Engineering of T Cells for Immune Tolerance

Scott, David W.

doi:10.1016/j.omtm.2019.11.022

Cited by 8 publications

(4 citation statements)

References 24 publications

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“…The efficacy of these antigen-specific CD4 iTregs was significantly higher than polyclonal CD4 iTregs. While these results are encouraging, the main limitations of the TCR-engineering strategy are MHC restriction, which limits their coverage to a certain MHC-bearing host (allo-HSCT) or donor (solid organ graft), along with the risk of mispairing the engineered TCR with the endogenous TCR, which can cause undesired reactivity and off-target effects [ 124 , 125 ]. However, the expression of a single antigen-specific TCR in Tregs that is directed toward a donor-host antigen disparity may hinder GVHD prevention in situations in which tissue-specific antigens are not represented in culture systems or there is skewing to an in vitro immunodominant antigen that is subdominant in vivo and potentially diverting Tregs away from their target antigens.…”

Section: Genetic Engineering Strategiesmentioning

confidence: 99%

Regulatory T Cell Therapy of Graft-versus-Host Disease: Advances and Challenges

Hefazi

Bolivar-Wagers

Blazar

2021

IJMS

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Graft-versus-host disease (GVHD) is the leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Immunomodulation using regulatory T cells (Tregs) offers an exciting option to prevent and/or treat GVHD as these cells naturally function to maintain immune homeostasis, can induce tolerance following HSCT, and have a tissue reparative function. Studies to date have established a clinical safety profile for polyclonal Tregs. Functional enhancement through genetic engineering offers the possibility of improved potency, specificity, and persistence. In this review, we provide the most up to date preclinical and clinical data on Treg cell therapy with a particular focus on GVHD. We discuss the different Treg subtypes and highlight the pharmacological and genetic approaches under investigation to enhance the application of Tregs in allo-HSCT. Lastly, we discuss the remaining challenges for optimal clinical translation and provide insights as to future directions of the field.

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Section: Genetic Engineering Strategiesmentioning

confidence: 99%

Regulatory T Cell Therapy of Graft-versus-Host Disease: Advances and Challenges

Hefazi

Bolivar-Wagers

Blazar

2021

IJMS

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“…This regimen induced durable mixed chimerism and tolerance to skin and heart allografts (126, 127), and its clinical applicability is currently being assessed in an ongoing clinical trial (128). In addition to therapies that involve the transfer of ex-vivo expanded Tregs (polyclonal or Ag-specific using TCR-gene transfer and chimeric antigen receptor technology) to increase the Treg pool (129,130), other approaches that aim to directly expand Treg in vivo are being investigated. These approaches are based on the administration of IL-2 (essential cytokine for Treg expansion), in a concentration or form that is biased for a more selective Treg engagement.…”

Section: Future Outlook 41 Belatacept and Tregsmentioning

confidence: 99%

Targeting inflammation and immune activation to improve CTLA4-Ig-based modulation of transplant rejection

et al. 2022

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For the last few decades, Calcineurin inhibitors (CNI)-based therapy has been the pillar of immunosuppression for prevention of organ transplant rejection. However, despite exerting effective control of acute rejection in the first year post-transplant, prolonged CNI use is associated with significant side effects and is not well suited for long term allograft survival. The implementation of Costimulation Blockade (CoB) therapies, based on the interruption of T cell costimulatory signals as strategy to control allo-responses, has proven potential for better management of transplant recipients compared to CNI-based therapies. The use of the biologic cytotoxic T-lymphocyte associated protein 4 (CTLA4)-Ig is the most successful approach to date in this arena. Following evaluation of the BENEFIT trials, Belatacept, a high-affinity version of CTLA4-Ig, has been FDA approved for use in kidney transplant recipients. Despite its benefits, the use of CTLA4-Ig as a monotherapy has proved to be insufficient to induce long-term allograft acceptance in several settings. Multiple studies have demonstrated that events that induce an acute inflammatory response with the consequent release of proinflammatory cytokines, and an abundance of allograft-reactive memory cells in the recipient, can prevent the induction of or break established immunomodulation induced with CoB regimens. This review highlights advances in our understanding of the factors and mechanisms that limit CoB regimens efficacy. We also discuss recent successes in experimentally designing complementary therapies that favor CTLA4-Ig effect, affording a better control of transplant rejection and supporting their clinical applicability.

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“…Among various options to confer target specificity to Tregs, genetic engineering is highly appealing. Transduction of chimeric antigen receptors (CARs) ( 33 ) or synthetic T cell receptors (TCRs) ( 34 ) in Tregs have been demonstrated to be effective in pre-clinical studies in vitro and in vivo and are currently under intensive investigation.…”

Section: Treg Cell-based Therapy In Organ Transplantationmentioning

confidence: 99%

Regulatory Cell Therapy in Organ Transplantation: Achievements and Open Questions

et al. 2021

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The effective development of innovative surgical applications and immunosuppressive agents have improved remarkable advancements in solid organ transplantation. Despite these improvements led to prevent acute rejection and to promote short-term graft survival, the toxicity of long-term immunosuppression regiments has been associated to organ failure or chronic graft rejection. The graft acceptance is determined by the balance between the regulatory and the alloreactive arm of the immune system. Hence, enhance regulatory cells leading to immune tolerance would be the solution to improve long-term allograft survival which, by reducing the overall immunosuppression, will provide transplanted patients with a better quality of life. Regulatory T cells (Tregs), and regulatory myeloid cells (MRCs), including regulatory macrophages and tolerogenic dendritic cells, are promising cell populations for restoring tolerance. Thus, in the last decade efforts have been dedicated to apply regulatory cell-based therapy to improve the successful rate of organ transplantation and to promote allogeneic tolerance. More recently, this approach has been translated into clinical application. The aim of this review is to summarize and discuss results on regulatory cell-based strategies, focusing on Tregs and MRCs, in terms of safety, feasibility, and efficacy in clinical studies of organ transplantation.

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Genetic Engineering of T Cells for Immune Tolerance

Cited by 8 publications

References 24 publications

Regulatory T Cell Therapy of Graft-versus-Host Disease: Advances and Challenges

Regulatory T Cell Therapy of Graft-versus-Host Disease: Advances and Challenges

Targeting inflammation and immune activation to improve CTLA4-Ig-based modulation of transplant rejection

Regulatory Cell Therapy in Organ Transplantation: Achievements and Open Questions

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