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HSCI's first stem cell clinical trial finds new method for improving cord blood transplant success.

Starting with a discovery in zebrafish in 2007, Harvard Stem Cell Institute (HSCI) researchers have published initial results of a Phase Ib human clinical trial of a therapeutic that has the potential to improved the success of blood stem cell transplantation. The results mark the first time, just nine short years after Harvard's major commitment to stem cell biology, that invetigators have carried a discovery from the laboratory bench to the clinic thus fulfilling the promise on which HSCI was founded.

The Phase 1b safety study, published in the current issue of the journal Blood, included 12 adult patients undergoing umbilical cord blood transplantation for leukemia at the Dana Farber Cancer Institute and Massachusetts General Hospital. Each of the patients received two umbilical cord blood units, one untreated and another treated with the small molecule, 16, 16 dimenthyl prostaglandin E2 (dmPGE2). All 12 patients had reconstitution of their immune systems and renewed blood formation, and 10 of the 12 patients had blood formation derived solely from the dmPGE2-treated umbilical cord blood unit.

The clinical testing is now entering Phase II, which will assess the treatment's efficacy at 8 medical centers with 60 patients. Results are expected within 18-24 months.

Like much of the work conducted under the HSCI umbrella, the "first" depended upon the collaboration of scientists at different Harvard-affiliated institutions, and, in this case, an industrial partner.

The initial finding occurred in the laboratory of Leonard Zon, MD, chair of the HSCI Executive Committee and Professor of Stem Cell and Regenerative Biology at Harvard, who studies blood formation in zebrafish at Boson Children's Hospital.; clinical research was conducted at Dana-Farber Cancer Institute and Massachusetts General Hospital, led by hematologic oncologist and HSCI Affiliated Faculty member Corey Cutler, MD, MPH; and Fate Therapeutics, Inc., a San Diego-based biopharmaceutical company of which Zon is a founder, sponsored the Investigational New Drug Application, under which the clinical program was conducted, and transplanted the research from the laboratory into the clinical setting.

"The initial results were very disappointing," Cutler said. "We went back to the drawing board and tried to figure out why, and it turned out some of the laboratory-based conditions were simply not optimized, and that was largely because when you do something in the lab, the conditions are a little bit different when you do it in a human."

Fate Therapeutics discovered that the human cord blood was being handled at temperatures too cold for the prostaglandin to biologically activate the stem cells and improve their engraftment properties. Fate further demonstrated that performing incubation of the hematopoietic stem cells at 38-degrees Celsius and increasing the incubation time from 1 to 2 hours elicited a much stronger gene and protein expression response that correlated with improved engraftment in animal models.

In running a second cohort of the Phase IB trial, which included 12 patients, dmPGE2 appeared to enhance the engraftment properties of the blood stem cells in humans and was deemed safe to continue into Phase II. "It's probably the most exciting thing I've ever done," Zon said. "Basically, to watch something come from your laboratory and then go all the way to a clinical trial is quite remarkable and satisfying."
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Title Annotation:Stem Cell News
Publication:Transplant News
Date:Oct 1, 2013
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