Advancing CD8+ Treg cell therapy to the clinic for the treatment of kidney transplanted patients
Severine Bezie1, Sonia Salle1, Mariane Lucazeau1, Soraya Saiagh2, Marie-Christine Leveque2, Cécile Braudeau1,4, Mina Benjelloun Zahar2, Florence Vrignaud2, Cecile Guillot-Gueguen5, Emmanuelle Papuchon5, Béatrice Clémenceau2,3, Maëlle Ningre6, Régis Josien1,4, Gilles Blancho1,5, Diego Cantarovich1,5, Ignacio Anegon1, Carole Guillonneau 1.
1Center for Research in Transplantation and Translational Immunology (CR2TI), Nantes University, Nantes, France; 2Unité de Thérapie Cellulaire et Génique, CHU Nantes, Nantes, France; 3CRCI2NA, INSERM, Nantes, France; 4CIMNA, CHU Nantes, Nantes, France; 5Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France; 6Direction de la Recherche, CHU Nantes, Nantes, France
CD8+ Treg cell therapy is effective in preclinical models but has never been evaluated in a clinical trial. We designed a phase 1/2a clinical trial of cell therapy using GMP manufactured autologous polyclonal CD8+ Tregs to treat kidney transplanted patients from living donors.
First, we set up a method for the isolation of CD8+Tregs from peripheral blood of healthy individuals using positive magnetic selection and flow cytometry in a safe closed system. We determined optimal clinical-grade culture conditions to preserve high proliferation rate, baseline phenotypic profile, and suppressive function in vitro and in vivo in a model of acute GVHD in NSG mice. We verified that they were resistant to classic maintenance immunosuppressive drugs, persistent and efficient in vivo but not cytotoxic. The method was validated on cells from patients with renal insufficiency, then transferred in the GMP facility with 3 validation runs demonstrating the phenotypic and functional stability of CD8+ Treg, meeting quality controls and release criteria.
The clinical study is a first-in-human, one-arm, open-label, prospective trial in patients with end-stage chronic renal failure requiring primary kidney transplantation, with 3 escalating doses of CD8+ Tregs administered the day before the transplantation without induction treatment and associated with classic maintenance immunosuppression. Patients are monitored for long-term safety, immunosuppression burden and occurrences of infections. Transcriptomic and proteomic analyses on blood, biopsy, and urine samples will inform on persistence and migration of Tregs to the graft. Recruitment will start mid-2024.
This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 825392 “RESHAPE”. This work was partially funded by the Labex IGO program supported by the National Research Agency via the investment of the future program ANR-11-LABX-0016-01. This work was also realized in the context of the support provided by the Fondation Progreffe.
[1] Cell therapy
[2] Regulatory T cell
[3] Tolerance
[4] Clinical trial
[5] Safety
[6] Autologous
[7] Induction treatment