Transplantation of donor grafts with defined ratio of conventional and regulatory T cells in HLA-matched recipients

Everett H. Meyer, Ginna Laport, Bryan J. Xie, Kate MacDonald, Kartoosh Heydari, Bita Sahaf, Sai Wen Tang, Jeanette Baker, Randall Armstrong, Keri Tate, Cynthia Tadisco, Sally Arai, Laura Johnston, Robert Lowsky, Lori Mufy, Andrew R. Rezvani, Judith Shizuru, Wen Kai Weng, Kevin Sheehan, David MiklosRobert S. Negrin

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

BACKGROUND. In preclinical murine and early clinical studies of hematopoietic cell transplantation, engineering of donor grafts with defned ratios of CD4+CD25+FoxP3+ Tregs to conventional T cells (Tcons) results in the prevention of graft-versus-host disease and improved immune reconstitution. The use of highly purifed primary graft Tregs for direct cell infusion has potential advantages over impure immunomagnetic selection or culture expansion, but has not been tested clinically. We performed a phase I study of the timed addition of CD34-selected hematopoietic stem cells and Tregs, followed by Tcons for the treatment of patients with high-risk hematological malignancies. METHODS. We present interim evaluation of a single-center open phase I/II study of administration of human leukocyte-matched Tregs and CD34-selected hematopoietic cells, followed by infusion of an equal ratio of Tcons in adult patients undergoing myeloablative hematopoietic stem cell transplantation (HCT) for high-risk or active hematological malignancies. Tregs were purifed by immunomagnetic selection and high-speed cell sorting. RESULTS. Here we report results for the frst 12 patients who received Tregs of between 91% and 96% purity. Greater than grade II GVHD was noted in 2 patients in the frst cohort of 5 patients, who received cryopreserved Tregs, but neither acute nor chronic GVHD was noted in the second cohort of 7 patients, who received fresh Tregs and single-agent GVHD prophylaxis. Patients in the second cohort appeared to have normal immune reconstitution compared with patients who underwent transplantation and did not develop GVHD. CONCLUSION. Our study shows that the use of highly purifed fresh Tregs is clinically feasible and supports continued investigation of the strategy.

Original languageEnglish (US)
Article numbere127244
JournalJCI Insight
Volume4
Issue number10
DOIs
StatePublished - 2019

ASJC Scopus subject areas

  • Medicine(all)

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