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Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation

Corey Cutler, Pratik Multani, David Robbins, Haesook T. Kim, Thuy Le, Jonathan Hoggatt, Louis M. Pelus, Caroline Desponts, Yi-Bin Chen, Betsy Rezner, Philippe Armand, John Koreth, Brett Glotzbecker, Vincent T. Ho, Edwin Alyea, Marlisa Isom, Grace Kao, Myriam Armant, Leslie Silberstein, Peirong Hu, Robert J. Soiffer, David T. Scadden, Jerome Ritz, Wolfram Goessling, Trista E. North, John Mendlein, Karen Ballen, Leonard I. Zon, Joseph H. Antin and Daniel D. Shoemaker

Key points

  • Molecular profiling was used to optimize an ex vivo modulation protocol with dmPGE2 for UCB transplantation.

  • Pulse treatment of UCB with dmPGE2 is safe and may lead to accelerated UCB engraftment and preferential cord chimerism.

Abstract

Umbilical cord blood (UCB) is a valuable source of hematopoietic stem cells (HSCs) for use in allogeneic transplantation. Key advantages of UCB are rapid availability and less stringent requirements for HLA matching. However, UCB contains an inherently limited HSC count, which is associated with delayed time to engraftment, high graft failure rates and early mortality. 16,16 dimethyl prostaglandin E2 (dmPGE2) was previously identified to be a critical regulator of HSC homeostasis and we hypothesized that a brief ex vivo modulation with dmPGE2 could improve patient outcomes by increasing the "effective dose" of HSCs. Molecular profiling approaches were used to determine the optimal ex vivo modulation conditions (temperature, time, concentration and media) for use in the clinical setting. A phase I trial was performed to evaluate the safety and therapeutic potential of ex vivo modulation of a single UCB unit using dmPGE2 prior to reduced intensity, double UCB transplantation. Results from this study demonstrated clear safety with durable, multilineage engraftment of dmPGE2-treated UCB units. We observed encouraging trends in efficacy, with accelerated neutrophil recovery (17.5 vs. 21 days, p=0.045), coupled with preferential, long-term engraftment of the dmPGE2 treated UCB unit in 10 of 12 treated subjects.

  • Submitted May 16, 2013.
  • Accepted August 20, 2013.