Toward an Optimized Process for Clinical Manufacturing of CAR-Treg Cell Therapy

Fritsche, Enrico; Volk, Hans‐Dieter; Reinke, Petra; Abou‐El‐Enein, Mohamed

doi:10.1016/j.tibtech.2019.12.009

Cited by 76 publications

(52 citation statements)

References 104 publications

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“…We were able to show that GMP compliant production of nTreg products from patients with end stage renal disease who had several comorbidities is feasible, robust, and possible at reasonable costs (€17 500/product (£15 800; $20 500))-a prerequisite for trustworthy data from clinical adoptive cell treatment trials. [34][35][36] In line with the main trial objective, we also showed that infusion of autologous nTregs at the end of the first week after kidney transplantation was well tolerated. No evidence was found of cell infusion related short term or long term adverse effects, and we observed no signs of over immunosuppression.…”

Section: Discussionsupporting

confidence: 70%

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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127

132

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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: Discussionsupporting

confidence: 70%

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

Roemhild

Otto

Moll

et al. 2020

BMJ

Self Cite

127

132

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“…258 Here, the authors confirmed that GvHD was less pronounced in mice that had received CXCR3-engineered Tregs than in mice that received nontransfected Tregs and that these genetically engineered Tregs mainly targeted and localized in the liver. 258 Furthermore, chimeric antigen receptor (CAR)-Tregs 259,260 provide an attractive option to optimize Treg stability and prevent exhaustion by the introduction of costimulatory molecules, such as CD28 or CD137/ 4-1BB. 260,261 The first CAR-Tregs contained an HLA-A2-specific CAR (A2-CAR) that was used to generate alloantigen-specific human Tregs.…”

Section: Tregs In Autoimmune Liver Diseasesmentioning

confidence: 99%

“…258 Furthermore, chimeric antigen receptor (CAR)-Tregs 259,260 provide an attractive option to optimize Treg stability and prevent exhaustion by the introduction of costimulatory molecules, such as CD28 or CD137/ 4-1BB. 260,261 The first CAR-Tregs contained an HLA-A2-specific CAR (A2-CAR) that was used to generate alloantigen-specific human Tregs. 259 Leving´s group demonstrated that in a mouse model of GvHD, engineered CAR-Tregs provided more effective immunosuppression than transferred polyclonal Tregs.…”

Section: Tregs In Autoimmune Liver Diseasesmentioning

confidence: 99%

Antigen presentation, autoantibody production, and therapeutic targets in autoimmune liver disease

et al. 2020

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The liver is an important immunological organ that controls systemic tolerance. The liver harbors professional and unconventional antigen-presenting cells that are crucial for tolerance induction and maintenance. Orchestrating the immune response in homeostasis depends on a healthy and well-toned immunological liver microenvironment, which is maintained by the crosstalk of liver-resident antigen-presenting cells and intrahepatic and liver-infiltrating leukocytes. In response to pathogens or autoantigens, tolerance is disrupted by unknown mechanisms. Intrahepatic parenchymal and nonparenchymal cells exhibit unique antigen-presenting properties. The presentation of microbial and endogenous lipid-, metabolite- and peptide-derived antigens from the gut via conventional and nonconventional mechanisms can educate intrahepatic immune cells and elicit effector responses or tolerance. Perturbation of this balance results in autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. Although the exact etiologies of these autoimmune liver diseases are unknown, it is thought that the disruption of tolerance towards self-antigens and microbial metabolites and lipids, as well as alterations in bile acid composition, may result in changes in effector cell activation and polarization and may reduce or impair protective anti-inflammatory regulatory T and B cell responses. Additionally, the canonical and noncanonical transmission of antigens and antigen:MHC complexes via trogocytosis or extracellular vesicles between different (non) immune cells in the liver may play a role in the induction of hepatic inflammation and tolerance. Here, we summarize emerging aspects of antigen presentation, autoantibody production, and the application of novel therapeutic approaches in the characterization and treatment of autoimmune liver diseases.

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“…Nach abgeschlossener Selektion erfolgt eine Aktivierung der Tregs, die häufig mit CD3- und CD28-Antikörper-Beads sowie über IL-2-Gabe durchgeführt wird [ 33 ]. Als Alternative wird die Aktivierung über letal bestrahlte, rekombinant antigenpräsentierende Zellen beschrieben.…”

Section: Herstellung Und Qualitätskontrolle Regulatorischer T-zellenunclassified

“…Letzteres gilt zwar auch für die Verwendung der Antikörper-Beads, insgesamt ist das mit ihrer Verwendung assoziierte Risikopotenzial für den Patienten allerdings als geringer einzuschätzen. Durch eine zusätzliche Gabe von Rapamycin lässt sich die selektive Depletion von T‑Effektorzellen erreichen und damit eine Instabilität der Tregs durch Expansion der T‑Effektorzellen verhindern [ 33 ].…”

Section: Herstellung Und Qualitätskontrolle Regulatorischer T-zellenunclassified

Genetisch modifizierte regulatorische T-Zellen: Therapiekonzepte und ihr regulatorischer Rahmen

Sebe

Anliker

et al. 2020

Bundesgesundheitsbl

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Zusammenfassung Adoptive T‑Zelltherapien sind neuartige Konzepte zur Behandlung verschiedener Krankheiten. CAR-T-Zellen sind dabei als Letztlinientherapie für fortgeschrittene B‑Zelllymphome und die B‑Zellleukämie etabliert und zugelassen. TCR-basierte T‑Zellen als Behandlungsoption verschiedener hämatologischer und solider Tumoren befinden sich in der klinischen Entwicklung. Genetisch modifizierte regulatorische T‑Zellen stehen dagegen noch am Anfang ihrer klinischen Entwicklung zur Induktion von Immuntoleranz in einer Vielzahl von Anwendungsgebieten. In diesem Artikel wird zunächst ein Überblick über die Funktion der regulatorischen T‑Zellen für die Induktion der Immuntoleranz sowie über ihre Rolle im Pathomechanismus bestimmter Immunerkrankungen gegeben und der aktuelle Stand der klinischen Entwicklungen von therapeutischen Ansätzen auf Basis genetisch modifizierter regulatorischer T‑Zellen zusammengefasst. Im Weiteren werden die regulatorisch-wissenschaftlichen Anforderungen und Herausforderungen hinsichtlich Herstellung und Qualitätskontrolle sowie nichtklinischer und klinischer Testung genetisch modifizierter regulatorischer T‑Zellen als Arzneimittel für neuartige Therapien diskutiert.

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Toward an Optimized Process for Clinical Manufacturing of CAR-Treg Cell Therapy

Cited by 76 publications

References 104 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

Antigen presentation, autoantibody production, and therapeutic targets in autoimmune liver disease

Genetisch modifizierte regulatorische T-Zellen: Therapiekonzepte und ihr regulatorischer Rahmen

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