Treg adoptive therapy: is more better?

Parmar, Simrit; Shpall, Elizabeth J.

doi:10.1182/blood-2015-12-682492

Cited by 9 publications

(8 citation statements)

References 10 publications

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“…Further strategies to improve Treg purity and cell dose are through the generation of allo-antigen specific Tregs. Brunstein and colleagues [28,29] were able to generate UCB Treg doses as high as 100 × 10 6 /kg by modifying the ex vivo expansion procedure to include a K562 antigen presenting cells expressing CD64 and CD86 instead of immunogenic CD3 and CD28 beads. A total of 11 patients were treated in this trial.…”

Section: Ntreg Expansionmentioning

confidence: 99%

Advances in the Use of Regulatory T-Cells for the Prevention and Therapy of Graft-vs.-Host Disease

Ramlal

2017

Biomedicines

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Regulatory T (Tregs) cells play a crucial role in immunoregulation and promotion of immunological tolerance. Adoptive transfer of these cells has therefore been of interest in the field of bone marrow and solid organ transplantation, autoimmune diseases and allergy medicine. In bone marrow transplantation, Tregs play a pivotal role in the prevention of graft-verus-host disease (GvHD). This has generated interest in using adoptive Treg cellular therapy in the prevention and treatment of GvHD. There have been several barriers to the feasibility of Treg cellular therapy in the setting of hematopoietic stem cell transplantation (HSCT) which include low Treg concentration in peripheral blood, requiring expansion of the Treg population; instability of the expanded product with loss of FoxP3 expression; and issues related to the purity of the expanded product. Despite these challenges, investigators have been able to successfully expand these cells both in vivo and in vitro and have demonstrated that they can be safely infused in humans for the prevention and treatment of GvHD with no increase in relapse risk or infections risk.

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Section: Ntreg Expansionmentioning

confidence: 99%

Advances in the Use of Regulatory T-Cells for the Prevention and Therapy of Graft-vs.-Host Disease

Ramlal

2017

Biomedicines

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“…A further complication to estimating the required dose for clinical use is the issue of trafficking and specificity; where do the Tregs need to be to exert their function and what proportion of the Treg pool are responding? These factors are known to impact on allometric scaling calculations (retention in tissues, active proliferation in lymph nodes) ( 85 ) and may also impact on the current clinical trials using Tregs ( 86 ). Recent trials have shown that increased total Treg dose did not lead to increased Treg presence in the periphery ( 45 , 63 ).…”

Section: Producing Tregs For Clinical Usementioning

confidence: 99%

Clinical Grade Regulatory CD4+ T Cells (Tregs): Moving Toward Cellular-Based Immunomodulatory Therapies

et al. 2018

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Regulatory T cells (Tregs) are CD4+ T cells that are key players of immune tolerance. They are powerful suppressor cells, able to impact the function of numerous immune cells, including key effectors of inflammation such as effector T cells. For this reason, Tregs are an ideal candidate for the development of cell therapy approaches to modulate immune responses. Treg therapy has shown promising results so far, providing key knowledge on the conditions in which these cells can provide protection and demonstrating that they could be an alternative to current pharmacological immunosuppressive therapies. However, a more comprehensive understanding of their characteristics, isolation, activation, and expansion is needed to be able design cost effective therapies. Here, we review the practicalities of making Tregs a viable cell therapy, in particular, discussing the challenges faced in isolating and manufacturing Tregs and defining what are the most appropriate applications for this new therapy.

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“…It is crucial, however, to emphasize the importance of good manufacturing practice-compliant cell therapy procedures, especially for the generation of polyclonal Tregs, which require dosing at larger cell numbers to reach therapeutic efficacy ( 180 ). A current challenge with using Tregs in the clinic is the need for the isolation and expansion of a pure population of functional and stable cells in sufficient numbers.…”

Section: Challenges and Future Directionsmentioning

confidence: 99%

Gene Therapy With Regulatory T Cells: A Beneficial Alliance

et al. 2018

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Gene therapy aims to replace a defective or a deficient protein at therapeutic or curative levels. Improved vector designs have enhanced safety, efficacy, and delivery, with potential for lasting treatment. However, innate and adaptive immune responses to the viral vector and transgene product remain obstacles to the establishment of therapeutic efficacy. It is widely accepted that endogenous regulatory T cells (Tregs) are critical for tolerance induction to the transgene product and in some cases the viral vector. There are two basic strategies to harness the suppressive ability of Tregs: in vivo induction of adaptive Tregs specific to the introduced gene product and concurrent administration of autologous, ex vivo expanded Tregs. The latter may be polyclonal or engineered to direct specificity to the therapeutic antigen. Recent clinical trials have advanced adoptive immunotherapy with Tregs for the treatment of autoimmune disease and in patients receiving cell transplants. Here, we highlight the potential benefit of combining gene therapy with Treg adoptive transfer to achieve a sustained transgene expression. Furthermore, techniques to engineer antigen-specific Treg cell populations, either through reprogramming conventional CD4+ T cells or transferring T cell receptors with known specificity into polyclonal Tregs, are promising in preclinical studies. Thus, based upon these observations and the successful use of chimeric (IgG-based) antigen receptors (CARs) in antigen-specific effector T cells, different types of CAR-Tregs could be added to the repertoire of inhibitory modalities to suppress immune responses to therapeutic cargos of gene therapy vectors. The diverse approaches to harness the ability of Tregs to suppress unwanted immune responses to gene therapy and their perspectives are reviewed in this article.

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Treg adoptive therapy: is more better?

Cited by 9 publications

References 10 publications

Advances in the Use of Regulatory T-Cells for the Prevention and Therapy of Graft-vs.-Host Disease

Advances in the Use of Regulatory T-Cells for the Prevention and Therapy of Graft-vs.-Host Disease

Clinical Grade Regulatory CD4+ T Cells (Tregs): Moving Toward Cellular-Based Immunomodulatory Therapies

Gene Therapy With Regulatory T Cells: A Beneficial Alliance

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