Adoptive Cell Therapy with Tregs to Improve Transplant Outcomes: the Promise and the Stumbling Blocks

Abstract

The contribution of regulatory T cells (Treg) to the induction and maintenance of tolerance is well-recognized in rodents and may contribute to long-term human organ allograft survival. The therapeutic efficacy of adoptively-transferred Treg in promoting tolerance to organ allografts is well-recognized in mouse models. Early phase 1/2 clinical studies of Treg therapy have been conducted in patients with type-1 (autoimmune) diabetes and refractory Crohn's disease, and for inhibition of graft-versus-host disease following bone marrow transplantation with proven safety. The feasibility of adoptive Treg therapy in the clinic is subject to various parameters, including optimal cell source, isolation procedure, expansion, target dose, time of infusion, as well as generation of a GMP-cell product. Several phase 1/2 Treg dose-escalation studies are underway in organ transplantation. Recent evidence suggests that additional factors are critical to ensure Treg safety and efficacy in allograft recipients, including Treg characterization, stability, longevity, trafficking, concomitant immunosuppression, and donor antigen specificity. Accordingly, Treg therapy in the context of organ transplantation may prove more challenging in comparison to other prospective clinical settings of Treg immunotherapy, such as type-1 diabetes.

Ex Vivo Expanded Human Non-Cytotoxic CD8+CD45RClow/− Tregs Efficiently Delay Skin Graft Rejection and GVHD in Humanized Mice

“…The establishment of cellular therapy with regulatory cells has recently emerged as a promising future therapy in autoimmunity as well as bone marrow and solid organ transplantation ( 2 – 4 ). Phase I studies in GVHD and solid organ transplantation have started with regulatory cells from different types (different CD4 + Tregs, macrophages, and DCs) without apparent toxicity ( 5 – 7 ), but to date, there are no clinical trials using CD8 + Tregs despite abundant literature in animals models ( 8 – 10 ). One limitation for translation of CD8 + Tregs in humans might be the lack of recognized marker such as Foxp3, a critical gene in the function of canonical CD4 + CD25 high CD127 low/− Tregs ( 11 , 12 ).…”

Regulatory cells in the skin: Pathophysiologic role and potential targets for anti-inflammatory therapies

“…Looking beyond psoriasis, therapeutic application of Treg cells has proved effective in animal models of other skin diseases, such as pemphigoid disease (a B cell-driven blistering autoimmune disease), and is studied in translational settings across several medical specialties, including gastroenterology and transplantation. [94][95][96] Namely, in transplantation additional regulatory cell populations, such as regulatory macrophages, dendritic cells, and MDSCs, are also being studied for the promotion of tolerance to organ allografts. [97][98][99] Taken together, the concept of targeting regulatory cells to treat chronic inflammatory diseases becomes increasingly attractive in the light of recent data from different groups.…”

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

“…All clinical trials to date unfortunately have not reduced the levels of immunosuppressive drugs needed to prevent SOTx rejection. 5 , 21 , 28 , 33 Thus, we also provide examples of ways investigators are working to improve Treg ACT and move the needle toward the field’s goal of maintenance of normal graft function without the use of immunosuppression, also known as drug-free tolerance or operational tolerance (OT).…”

“… 24 Efforts to improve long-term outcomes and 10-year survival remain unsuccessful due to the failure of multi-drug immunosuppression to address chronic rejection despite their toxic side effects. 21 , 35 Other therapeutic strategies such as co-stimulation-blockade (CoSB) or monoclonal antibody (Ab) therapy to target cytokines and other co-stimulatory molecules have only had limited success at reducing the use of immunosuppressive drugs. 21 Therefore, utilizing Tregs or other regulatory immune cells as a potential immune cell therapy may be a promising alternative to reduce the use of immunosuppressive drugs and even induce allograft tolerance based on data obtained from various preclinical murine and NHP studies.…”

“…Thus, Treg isolation and ex vivo expansion is required to reach the numbers of Treg predicted in animal studies to be therapeutic after adoptive transfer. 21 , 41 , 42 As introduced above, the Tregs for clinical trials have been most commonly isolated from PBMC or UCB. 24 , 26 , 27 , 43–45 A recent novel strategy used pediatric thymuses which are routinely discarded during pediatric heart transplantation as a Treg source.…”