A Phase I Clinical Trial with Ex Vivo Expanded Recipient Regulatory T cells in Living Donor Kidney Transplants

• Published in: Scientific reports Vol. 8; no. 1; pp. 7428 - 12
• Main Authors: Mathew, James M., H.-Voss, Jessica, LeFever, Ann, Konieczna, Iwona, Stratton, Cheryl, He, Jie, Huang, Xuemei, Gallon, Lorenzo, Skaro, Anton, Ansari, Mohammed Javeed, Leventhal, Joseph R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.05.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/107; 13/21; 13/31; 631/250/1854/2812; 692/308/2779/109/1940; CD19 antigen; CD25 antigen; CD4 antigen; CD8 antigen; Clinical trials; Contamination; Demethylation; Diabetes mellitus; Foxp3 protein; Graft rejection; Hematopoietic stem cells; Humanities and Social Sciences; Hypotheses; Immune response; Immunological tolerance; Immunoregulation; Immunosuppressive agents; Kidney transplantation; Kidney transplants; Lymphocytes T; Morbidity; multidisciplinary; Safety; Science; Science (multidisciplinary); Side effects; Stem cell transplantation; Stem cells; Transplants & implants
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-25574-7

There is considerable interest in therapeutic transfer of regulatory T cells (Tregs) for controlling aberrant immune responses. Initial clinical trials have shown the safety of Tregs in hematopoietic stem cell transplant recipients and subjects with juvenile diabetes. Our hypothesis is that infusion(s) of Tregs may induce transplant tolerance thus avoiding long-term use of toxic immunosuppressive agents that cause increased morbidity/mortality. Towards testing our hypothesis, we conducted a phase I dose escalation safety trial infusing billions of ex vivo expanded recipient polyclonal Tregs into living donor kidney transplant recipients. Despite variability in recipient’s renal disease, our expansion protocol produced Tregs which met all release criteria, expressing >98% CD4 + CD25 + with <1% CD8 + and CD19 + contamination. Our product displayed >80% FOXP3 expression with stable demethylation in the FOXP3 promoter. Functionally, expanded Tregs potently suppressed allogeneic responses and induced the generation of new Tregs in the recipient’s allo-responders in vitro . Within recipients, expanded Tregs amplified circulating Treg levels in a sustained manner. Clinically, all doses of Treg therapy tested were safe with no adverse infusion related side effects, infections or rejection events up to two years post-transplant. This study provides the necessary safety data to advance Treg cell therapy to phase II efficacy trials.