Regulatory T cells for minimising immune suppression in kidney transplantation: phase I/IIa clinical trial

Abstract

ObjectiveTo assess whether reshaping of the immune balance by infusion of autologous natural regulatory T cells (nTregs) in patients after kidney transplantation is safe, feasible, and enables the tapering of lifelong high dose immunosuppression, with its limited efficacy, adverse effects, and high direct and indirect costs, along with addressing several key challenges of nTreg treatment, such as easy and robust manufacturing, danger of over immunosuppression, interaction with standard care drugs, and functional stability in an inflammatory environment in a useful proof-of-concept disease model.DesignInvestigator initiated, monocentre, nTreg dose escalation, phase I/IIa clinical trial (ONEnTreg13).SettingCharité-University Hospital, Berlin, Germany, within the ONE study consortium (funded by the European Union).ParticipantsRecipients of living donor kidney transplant (ONEnTreg13, n=11) and corresponding reference group trial (ONErgt11-CHA, n=9).InterventionsCD4+ CD25+ FoxP3+ nTreg products were given seven days after kidney transplantation as one intravenous dose of 0.5, 1.0, or 2.5-3.0×106 cells/kg body weight, with subsequent stepwise tapering of triple immunosuppression to low dose tacrolimus monotherapy until week 48.Main outcome measuresThe primary clinical and safety endpoints were assessed by a composite endpoint at week 60 with further three year follow-up. The assessment included incidence of biopsy confirmed acute rejection, assessment of nTreg infusion related adverse effects, and signs of over immunosuppression. Secondary endpoints addressed allograft functions. Accompanying research included a comprehensive exploratory biomarker portfolio.ResultsFor all patients, nTreg products with sufficient yield, purity, and functionality could be generated from 40-50 mL of peripheral blood taken two weeks before kidney transplantation. None of the three nTreg dose escalation groups had dose limiting toxicity. The nTreg and reference groups had 100% three year allograft survival and similar clinical and safety profiles. Stable monotherapy immunosuppression was achieved in eight of 11 (73%) patients receiving nTregs, while the reference group remained on standard dual or triple drug immunosuppression (P=0.002). Mechanistically, the activation of conventional T cells was reduced and nTregs shifted in vivo from a polyclonal to an oligoclonal T cell receptor repertoire.ConclusionsThe application of autologous nTregs was safe and feasible even in patients who had a kidney transplant and were immunosuppressed. These results warrant further evaluation of Treg efficacy and serve as the basis for the development of next generation nTreg approaches in transplantation and any immunopathologies.Trial registrationNCT02371434 (ONEnTreg13) and EudraCT:2011-004301-24 (ONErgt11).

Artemisinin Attenuates Transplant Rejection by Inhibiting Multiple Lymphocytes and Prolongs Cardiac Allograft Survival

“…Intriguingly, ART treatment also dramatically enhanced the expansion of Treg cells, which play a central role in transplant tolerance. This is consistent with other assays and our previously published data showing that Treg cell therapy could significantly alleviate renal allograft injury and induce immune tolerance in animal and clinical trials (27,28). Our data thus showed that ART could effectively inhibit TCMR and induce Treg cell expansion.…”

Cellular therapies in organ transplantation

“…Published data from Treg cell therapy trials in transplantation provide some cause for cautious optimism, with evidence for safety and perhaps a reduced requirement for induction immunosuppression in renal transplantation [58] or even maintenance immunosuppression in liver transplantation [59]. A recent study in 11 kidney transplant patients demonstrated that stable monotherapy immunosuppression was achieved in 8 patients receiving autologous Treg [60]. While these trials are still in early phases, the benefits of reducing immunosuppression are becoming apparent in terms of lower viral infection rates and normalization of immune composition [58].…”

“…The study of Roemhild et al . [60] reported a transient increase in Treg levels with a return to control levels 12 weeks after administration of Tregs. For other cell types, survival times are not clear, and the use of autologous cells in clinical studies hampers long‐term tracking.…”

Emerging Therapeutic Strategies to Restore Regulatory T Cell Control of Islet Autoimmunity in Type 1 Diabetes

“…One approach would be to adoptively transfer ex vivo expanded Tregs back into the patient. In fact clinical trials in kidney transplantation showing improved clinical outcomes in some patients suggest that transfer of autologous Tregs can be promising across multiple immune-dysfunctional conditions (53)(54)(55). In addition, modifying the Tregs ex vivo before transplanting them back into the patient may increase efficacy and avoid potential systemic immunosuppression.…”