Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials

Sawitzki, Birgit; Harden, Paul; Reinke, Petra; Moreau, Aurélie; Hutchinson, James A.; Game, David; Tang, Qizhi; Guinan, Eva C.; Battaglia, Manuela; Burlingham, William J.; Roberts, Ian S.; Streitz, Mathias; Josien, Régis; Böger, Carsten A.; Scottà, Cristiano; Markmann, James F.; Hester, Joanna; Jürchott, Karsten; Braudeau, Cécile; James, Ben; Contreras-Ruiz, Laura; Net, Jeroen B. van der; Bergler, Tobias; Caldara, Rossana; Petchey, William; Edinger, Matthias; Dupas, Nathalie; Kapinsky, Michael; Mutzbauer, Ingrid; Otto, Natalie; Öllinger, Robert; Hernandez-Fuentes, Maria P.; Issa, Fadi; Ahrens, Norbert; Meyenberg, Christoph; Karitzky, Sandra; Kunzendorf, Ulrich; Knechtle, Stuart J.; Grinyó, Josep M.; Morris, Peter J.; Brent, L.; Bushell, Andrew; Turka, Laurence A.; Bluestone, Jeffrey A.; Lechler, Robert I.; Schlitt, Hans J.; Cuturi, María Cristina; Schlickeiser, Stephan; Friend, Peter J.; Miloud, Tewfik; Scheffold, Alexander; Secchi, Antonio; Crisalli, Kerry; Kang, ⋅Sang-Mo; Hilton, Rachel; Banas, Bernhard; Blancho, Gilles; Volk, Hans‐Dieter; Lombardi, Giovanna; Wood, Kathryn J.; Geissler, Edward K.

doi:10.1016/s0140-6736(20)30167-7

Cited by 322 publications

(356 citation statements)

References 32 publications

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“…T cell receptor repertoire analysis of our nTreg GMP products by next generation sequencing confirmed their polyclonal pattern, as described previously. 22 Clinical monitoring and exploratory biomarker analysis More than 100 parameters for determining safety, efficacy, and mechanism of action were monitored in the nTreg and reference groups over the study period of 60 weeks, with follow-up of up to three years, consisting of the consensus biomarker portfolio within the ONE study consortium 19 and additional site specific markers. Monitoring included assessing biopsy confirmed acute rejection, clinical analysis and biochemical indices for renal function, and immune monitoring for measures of safety, immune activation or tolerance, and pharmacokinetics or dynamics, as outlined in supplementary table S7.…”

Section: Gmp Manufacturing and Characterisation Of Ntregsmentioning

confidence: 99%

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

Roemhild

Otto

Moll

et al. 2020

BMJ

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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).

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Section: Gmp Manufacturing and Characterisation Of Ntregsmentioning

confidence: 99%

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

Roemhild

Otto

Moll

et al. 2020

BMJ

Self Cite

130

132

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“…An early approach involved infusing donor antigen-specific Treg and allowed seven out of ten patients to successfully wean from immunosuppression by 18 months post-transplantation ( 151 ). Recently data from the ONE study have been published, demonstrating that Treg cell therapy in donor kidney transplant recipients is safe, although missing the efficacy endpoint ( 152 ). Other transplant centers have ongoing clinical trials mainly focusing on manufacturing alloantigen-specific Treg ( Table 1 ).…”

Section: Future Therapeutic Strategies To Induce Long Term Tolerancementioning

confidence: 99%

The Immunological Basis of Liver Allograft Rejection

et al. 2020

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Liver allograft rejection remains a significant cause of morbidity and graft failure in liver transplant recipients. Rejection is caused by the recognition of non-self donor alloantigens by recipient T-cells. Antigen recognition results in proliferation and activation of T-cells in lymphoid tissue before migration to the allograft. Activated T-cells have a variety of effector mechanisms including direct T-cell mediated damage to bile ducts, endothelium and hepatocytes and indirect effects through cytokine production and recruitment of tissue-destructive inflammatory cells. These effects explain the histological appearances of typical acute T-cell mediated rejection. In addition, donor specific antibodies, most typically against HLA antigens, may give rise to antibody-mediated rejection causing damage to the allograft primarily through endothelial injury. However, as an immune-privileged site there are several mechanisms in the liver capable of overcoming rejection and promoting tolerance to the graft, particularly in the context of recruitment of regulatory T-cells and promotors of an immunosuppressive environment. Indeed, around 20% of transplant recipients can be successfully weaned from immunosuppression. Hence, the host immunological response to the liver allograft is best regarded as a balance between rejection-promoting and tolerance-promoting factors. Understanding this balance provides insight into potential mechanisms for novel anti-rejection therapies.

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“…Treg therapy has reached the organ transplant arena as well (UMIN-000015789 and NCT02088931) (15,16). We have demonstrated the safety of adoptively transferred Tregs in two phase I clinical trials in liver (ThRIL, NCT02166177) and kidney (ONE study, NCT02129881) transplant patients (17,18).…”

Section: Adoptive Treg Therapy: From Polyclonal To Antigen Specificmentioning

confidence: 99%

The Future of Regulatory T Cell Therapy: Promises and Challenges of Implementing CAR Technology

et al. 2020

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Cell therapy with polyclonal regulatory T cells (Tregs) has been translated into the clinic and is currently being tested in transplant recipients and patients suffering from autoimmune diseases. Moreover, building on animal models, it has been widely reported that antigen-specific Tregs are functionally superior to polyclonal Tregs. Among various options to confer target specificity to Tregs, genetic engineering is a particularly timely one as has been demonstrated in the treatment of hematological malignancies where it is in routine clinical use. Genetic engineering can be exploited to express chimeric antigen receptors (CAR) in Tregs, and this has been successfully demonstrated to be robust in preclinical studies across various animal disease models. However, there are several caveats and a number of strategies should be considered to further improve on targeting, efficacy and to understand the in vivo distribution and fate of CAR-Tregs. Here, we review the differing approaches to confer antigen specificity to Tregs with emphasis on CAR-Tregs. This includes an overview and discussion of the various approaches to improve CAR-Treg specificity and therapeutic efficacy as well as addressing potential safety concerns. We also discuss different imaging approaches to understand the in vivo biodistribution of administered Tregs. Preclinical research as well as suitability of methodologies for clinical translation are discussed.

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Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials

Cited by 322 publications

References 32 publications

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

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

The Immunological Basis of Liver Allograft Rejection

The Future of Regulatory T Cell Therapy: Promises and Challenges of Implementing CAR Technology

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