Clinical Manufacturing of Regulatory T Cell Products For Adoptive Cell Therapy and Strategies to Improve Therapeutic Efficacy

Abstract

Based on successes in preclinical animal transplant models, adoptive cell therapy (ACT) with regulatory T cells (Tregs) is a promising modality to induce allograft tolerance or reduce the use of immunosuppressive drugs to prevent rejection. Extensive work has been done in optimizing the best approach to manufacture Treg cell products for testing in transplant recipients. Collectively, clinical evaluations have demonstrated that large numbers of Tregs can be expanded ex vivo and infused safely. However, these trials have failed to induce robust drug-free tolerance and/or significantly reduce the level of immunosuppression needed to prevent solid organ transplant (SOTx) rejection. Improving Treg therapy effectiveness may require increasing Treg persistence or orchestrating Treg migration to secondary lymphatic tissues or places of inflammation. In this review, we describe current clinical Treg manufacturing methods used for clinical trials. We also highlight current strategies being implemented to improve delivered Treg ACT persistence and migration in preclinical studies.

Treating activated regulatory T cells with pramipexole protects human dopaminergic neurons from 6‐OHDA‐induced degeneration

“…It has been reported that stimulation of Tregs with anti‐CD3/CD28, rapamycin, or retinoic acid increases their proliferation and enhances their regulatory capacity, which could improve their function in the treatment of autoimmune diseases or transplant rejection. 34 This suggests that activation of the suppressive immune response is required to promote a neuroprotective effect of regulatory T cells.…”

Enhancing Regulatory T Cells to Treat Inflammatory and Autoimmune Diseases

“…ATregCT therapy involves the isolation of Tregs from patients, followed by an ex vivo expansion of the cells prior to their autologous transference [69,77]. Tregs used in ATregCT are typically isolated from peripheral mononuclear blood cells (PMBCs) using magnetic or Resident DCs in mucosal tissues participate in the generation and maintenance of FoxP3 + Tregs as well as other subtypes of Tregs through mechanisms that are dependent on IL-27, TGF-β, IL-10, RA, indoleamine-2,3-dioxygenase and vitamin D [65].…”

“…ATregCT therapy involves the isolation of Tregs from patients, followed by an ex vivo expansion of the cells prior to their autologous transference [69,77]. Tregs used in ATregCT are typically isolated from peripheral mononuclear blood cells (PMBCs) using magnetic or fluorescence activated cell sorting with relevant antibody panels [78].…”

“…The most recent advances in cell sorting have enabled the isolation of pure populations of T cells with a CD4 + CD25 + CD127 low CD45RA + phenotype, which seems to be the most appropriate population for ATregCT therapy [76,78]. Subsequently, Tregs are expanded in vitro using different protocols aimed to imprint Tregs with enhanced and enduring immunosuppressive properties [77]. A common protocol consists of culturing Tregs with rapamycin and/or retinoic acid followed by the activation with anti-CD3/CD28 antibodies in the presence of IL-2 and/or TGF-β [79,80].…”