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

James M. Mathew*, Jessica H-Voss, Ann LeFever, Iwona Konieczna, Cheryl Stratton, Jie He, Xuemei Huang, Lorenzo Gallon, Anton Skaro, Mohammed Javeed Ansari, Joseph R. Leventhal

*Corresponding author for this work

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number7428
JournalScientific reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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Living Donors
Regulatory T-Lymphocytes
Clinical Trials
Transplants
Kidney
Safety
Poisons
Immunosuppressive Agents
Cell- and Tissue-Based Therapy
Hematopoietic Stem Cells
Morbidity
Mortality
Therapeutics
Infection
Transplant Recipients

ASJC Scopus subject areas

  • General

Cite this

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. / A Phase i Clinical Trial with Ex Vivo Expanded Recipient Regulatory T cells in Living Donor Kidney Transplants. In: Scientific reports. 2018 ; Vol. 8, No. 1.
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A Phase i Clinical Trial with Ex Vivo Expanded Recipient Regulatory T cells in Living Donor Kidney Transplants. / 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.

In: Scientific reports, Vol. 8, No. 1, 7428, 01.12.2018.

Research output: Contribution to journalArticle

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AU - Stratton, Cheryl

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AU - Huang, Xuemei

AU - Gallon, Lorenzo

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AU - Ansari, Mohammed Javeed

AU - Leventhal, Joseph R.

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