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

Abstract

BACKGROUNDIn preclinical murine and early clinical studies of hematopoietic cell transplantation, engineering of donor grafts with defined 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 purified 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.METHODSWe 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 purified by immunomagnetic selection and high-speed cell sorting.RESULTSHere we report results for the first 12 patients who received Tregs of between 91% and 96% purity. Greater than grade II GVHD was noted in 2 patients in the first 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.CONCLUSIONOur study shows that the use of highly purified fresh Tregs is clinically feasible and supports continued investigation of the strategy.TRIAL REGISTRATIONClinicalTrials.gov NCT01660607.FUNDINGNIH NHBLI R01 HL114591 and K08HL119590.

• Authors: 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 Muffly, Andrew R Rezvani, Judith Shizuru, Wen-Kai Weng, Kevin Sheehan, David Miklos, Robert S Negrin
• Journal: JCI insight (JCI Insight) Vol. 4 Issue 10 (05 16 2019) ISSN: 2379-3708 [Electronic] United States
• PMID: 31092732 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Topics

• Adult
• Aged
• Bone Marrow Transplantation (methods)
• Female
• Graft vs Host Disease (immunology)
• Hematologic Neoplasms (immunology, therapy)
• Hematopoietic Stem Cell Transplantation (methods)
• Humans
• Male
• Middle Aged
• T-Lymphocytes, Regulatory (immunology)
• Tissue Donors
• Young Adult