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

2016 ◽  
Vol 44 (2) ◽  
pp. 342-348 ◽  
Author(s):  
Dominic Boardman ◽  
John Maher ◽  
Robert Lechler ◽  
Lesley Smyth ◽  
Giovanna Lombardi
Keyword(s):  
T Cell ◽  
Regulatory T Cell ◽  
Ex Vivo ◽  
Transplant Rejection ◽  
Antigen Receptors ◽  
Antigen Specificity ◽  
Chimeric Antigen Receptors ◽  
T Cell Therapy ◽  
Early Results ◽  
Promising Therapeutic Approach

Adoptive regulatory T-cell (Treg) therapy using autologous Tregs expanded ex vivo is a promising therapeutic approach which is currently being investigated clinically as a means of treating various autoimmune diseases and transplant rejection. Despite this, early results have highlighted the need for potent Tregs to yield a substantial clinical advantage. One way to achieve this is to create antigen-specific Tregs which have been shown in pre-clinical animal models to have an increased potency at suppressing undesired immune responses, compared to polyclonal Tregs. This mini review outlines where Treg therapy currently stands and discusses the approaches which may be taken to generate antigen-specific Tregs, including the potential use of chimeric antigen receptors (CARs), for future clinical trials.

scholarly journals Developing T-cell therapies for lymphoma without receptor engineering

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 622-631 ◽  
Author(s):  
Melanie Grant ◽  
Catherine M. Bollard
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Ex Vivo ◽  
Disease Stage ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Cell Therapeutics ◽  
Clinical Responses

AbstractT-cell therapy has emerged from the bench for the treatment of patients with lymphoma. Responses to T-cell therapeutics are regulated by multiple factors, including the patient’s immune system status and disease stage. Outside of engineering of chimeric antigen receptors and artificial T-cell receptors, T-cell therapy can be mediated by ex vivo expansion of antigen-specific T cells targeting viral and/or nonviral tumor-associated antigens. These approaches are contributing to enhanced clinical responses and overall survival. In this review, we summarize the available T-cell therapeutics beyond receptor engineering for the treatment of patients with lymphoma.

scholarly journals Developing T-cell therapies for lymphoma without receptor engineering

2017 ◽  
Vol 1 (26) ◽  
pp. 2579-2590 ◽  
Author(s):  
Melanie Grant ◽  
Catherine M. Bollard
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Ex Vivo ◽  
Disease Stage ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Cell Therapeutics ◽  
Clinical Responses

Abstract T-cell therapy has emerged from the bench for the treatment of patients with lymphoma. Responses to T-cell therapeutics are regulated by multiple factors, including the patient’s immune system status and disease stage. Outside of engineering of chimeric antigen receptors and artificial T-cell receptors, T-cell therapy can be mediated by ex vivo expansion of antigen-specific T cells targeting viral and/or nonviral tumor-associated antigens. These approaches are contributing to enhanced clinical responses and overall survival. In this review, we summarize the available T-cell therapeutics beyond receptor engineering for the treatment of patients with lymphoma.

scholarly journals Augmented expansion of Treg cells from healthy and autoimmune subjects via adult progenitor cell co-culture

2020 ◽  
Author(s):  
JL Reading ◽  
VD Roobrouck ◽  
CM Hull ◽  
PD Becker ◽  
J Beyens ◽  
...  
Keyword(s):  
T Cell ◽  
Treg Cell ◽  
Regulatory T Cell ◽  
Cellular Therapy ◽  
Ex Vivo ◽  
Fold Increase ◽  
Adoptive Cellular Therapy ◽  
T Cell Therapy

AbstractRecent clinical experience has demonstrated that adoptive regulatory T cell therapy is a safe and feasible strategy to suppress immunopathology via induction of host tolerance to allo- and autoantigens. However, clinical trials continue to be compromised due to an inability to manufacture a sufficient Treg cell dose. Multipotent adult progenitor cells (MAPCⓇ) promote regulatory T cell differentiation in vitro, suggesting they may be repurposed to enhance ex vivo expansion of Tregs for adoptive cellular therapy. Here, we use a GMP compatible Treg expansion platform to demonstrate that MAPC cell-co-cultured Tregs (MulTreg) exhibit a log-fold increase in yield across two independent cohorts, reducing time to target dose by an average of 30%. Enhanced expansion is linked with a distinct Treg cell-intrinsic transcriptional program, characterized by diminished levels of core exhaustion (BATF, ID2, PRDM1, LAYN, DUSP1), and quiescence (TOB1, TSC22D3) related genes, coupled to elevated expression of cell-cycle and proliferation loci (MKI67, CDK1, AURKA, AURKB). In addition, MulTreg display a unique gut homing (CCR7lo β7hi) phenotype and importantly, are more readily expanded from patients with autoimmune disease compared to matched Treg lines, suggesting clinical utility in gut and/or Th1-driven pathology associated with autoimmunity or transplantation. Relative to expanded Tregs, MulTreg retain equivalent and robust purity, FoxP3 TSDR demethylation, nominal effector cytokine production and potent suppression of Th1-driven antigen specific and polyclonal responses in vitro and xeno graft vs host disease (xGvHD) in vivo. These data support the use of MAPC cell co-culture in adoptive Treg therapy platforms as a means to rescue expansion failure and reduce the time required to manufacture a stable, potently suppressive product.

scholarly journals A brief review concerning Chimeric Antigen Receptors T cell therapy

2020 ◽  
Vol 11 (18) ◽  
pp. 5424-5431
Author(s):  
Ling-Lin Li ◽  
Hong-Ling Yuan ◽  
Yu-Qiong Yang ◽  
Lin Wang ◽  
Ren-Chao Zou
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
T Cell Therapy

Abstract 3238: Engineering chimeric antigen receptors for adoptive T cell therapy of cancers that express the Tn antigen

2020 ◽  
Author(s):  
Preeti Sharma ◽  
Venkata VVR Marada ◽  
Monika Kizerwetter ◽  
Claire P. Schane ◽  
Yanran He ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Adoptive T Cell Therapy ◽  
Antigen Receptors ◽  
Tn Antigen ◽  
Chimeric Antigen Receptors ◽  
T Cell Therapy

scholarly journals Fully human CD19-specific chimeric antigen receptors for T-cell therapy

Leukemia ◽  
2017 ◽  
Vol 31 (10) ◽  
pp. 2191-2199 ◽  
Author(s):  
D Sommermeyer ◽  
T Hill ◽  
S M Shamah ◽  
A I Salter ◽  
Y Chen ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
T Cell Therapy

scholarly journals Repeated stimulation or tonic-signaling chimeric antigen receptors drive regulatory T cell exhaustion

2020 ◽  
Author(s):  
Caroline Lamarche ◽  
German E. Novakovsky ◽  
Christopher N. Qi ◽  
Evan W. Weber ◽  
Crystal L. Mackall ◽  
...  
Keyword(s):  
T Cell ◽  
Regulatory T Cell ◽  
T Cell Exhaustion ◽  
Antigen Receptors ◽  
Chronic Stimulation ◽  
T Cell Therapy ◽  
Cell Exhaustion ◽  
Graft Versus Host

AbstractRegulatory T cell (Treg) therapy is a promising approach to improve outcomes in transplantation and autoimmunity. In conventional T cell therapy, chronic stimulation can result in poor in vivo function, a phenomenon termed exhaustion. Whether or not Tregs are also susceptible to exhaustion, and if so, if this would limit their therapeutic effect, was unknown. We studied how two methods which induce conventional T cell exhaustion – repetitive stimulation or expression of a tonic-signaling chimeric antigen receptor (CAR) – affect human Tregs. With each repetitive polyclonal stimulation Tregs progressively acquired an exhausted phenotype, and became less suppressive in vitro. Tregs expressing a tonic-signaling CAR rapidly acquired an exhausted phenotype and had major changes in their transcriptome and metabolism. Although tonic-signaling CAR-Tregs remained stable and suppressive in vitro, they lost in vivo function, as tested in a model of xenogeneic graft-versus-host disease. The finding that human Tregs are susceptible to exhaustion has important implications for the design of Treg adoptive immunotherapy strategies.

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