Clinical application of umbilical cord blood (UCB) as a source of hematopoietic stem cells for transplantation is limited by low CD34+ cell dose, increased risk of graft failure, and slow hematopoietic recovery. While the cell dose limitation is partially mitigated by using two UCB units, larger-dosed single units would be preferable. We have evaluated the feasibility and safety of StemRegenin-1 (SR-1), an aryl hydrocarbon receptor antagonist that expands CD34+ cells, by placing one of the two units in expansion culture. SR-1 produced a 330-fold increase in CD34+ cells and led to engraftment in 17/17 patients at a median of 15 days for neutrophils and 49 days for platelets, significantly faster than in patients treated with unmanipulated UCB. Taken together, the marked expansion, absence of graft failure, and enhanced hematopoietic recovery support testing of SR-1 expansion as a stand-alone graft and suggest it may ameliorate a limitation of UCB transplant.
Bibliographical noteFunding Information:
The project was supported by Novartis Corporation and a grant from the National Cancer Institute (P01 CA065493-20; J.E.W., C.G.B., T.E.D., D.M., B.R.B., J.T., and C.L.). We wish to thank Diane Kadidlo, Fran Rabe, and staff of the Cell Therapy Laboratory at the Molecular and Cellular Therapeutics Facility for their efforts in product manufacturing, development, and monitoring; Dr. Eros Lazzerini Denchi for his investigations on telomere length; Stefanie Hage of the University of Minnesota and Suzanne Maahs and Shazia Ali of the Novartis Institutes for Biomedical Research for their critical assistance in patient monitoring and moving the clinical trial forward; Albert E. Parker for performing the T cell alloreactivity assays; Stephanie Fiola for qualification of the media and cytokines; and the faculty, advanced practice providers, unit and clinic nurses, pharmacists, and social workers of the Blood and Marrow Transplant Program who cared for the 20 patients on this phase I clinical trial at the University of Minnesota Medical Center and Masonic Children''s Hospital. Specific authors are employees and shareholders of Novartis (J.J. and C.C.B.) and the Genomics Institute of the Novartis Foundation (A.E.B. and M.P.C.).