Main Category: Lymphoma / Leukemia / Myeloma
Also Included In: Stem Cell Research;  Transplants / Organ Donations;  Blood / Hematology
Article Date: 11 Oct 2013 – 0:00 PDT

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

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“We basically sat down in a room and we brainstormed a clinical trial based on their scientific discovery, right then and there,” said Farber oncologist Corey Cutler. “They knew that it was something they could bring to the clinic, but they just didn’t know where it would fit. We said, if this molecule does what you say it does, significant utility would lie in umbilical cord blood transplants.”

A cord blood transplant is similar to a bone marrow transplant, however the blood stem cells are derived from the umbilical cord blood of a newborn, rather than from an adult donor. One of the advantages of umbilical cord blood is that matching between donor and recipient does not need to be as exact because potentially fatal graft-versus-host disease is less common. Although about 10-20 percent of stem cell transplantation procedures now use umbilical cord blood, the downside is that engraftment is more difficult, because the number of stem cells in an umbilical cord blood donation is far fewer than in an adult stem cell donation.

• 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 Boston 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 translated the research findings from the laboratory into the clinical setting.

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Fate Therapeutics discovered that the human cord blood was being handled at temperatures too cold (4-degrees Celsius) for the prostaglandin to biologically activate the stem cells and improve their engraftment properties. Fate further demonstrated that performing the incubation of the hematopoietic stem cells at 37-degrees Celsius and increasing the incubation time from 1 hour to 2 hours elicited a much stronger gene and protein expression response that correlated with improved engraftment in animal models.

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The Phase 1b safety study, published in the journal Blood, included 12 adult patients undergoing umbilical cord blood transplantation for leukemia or lymphoma 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 dimethyl 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 dramatic effects of this molecule on blood stem cells made Zon, a pediatric hematologist, consider ways in which the prostaglandin could be applied to bone marrow transplantation, often used to treat blood cancers, including leukemia and lymphoma. Bone marrow contains the body’s most plentiful reservoir of blood stem cells, and so patients with these conditions may be given bone marrow transplants to reconstitute their immune systems after their cancer-ravaged systems are wiped out with chemotherapy and radiation.

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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 very satisfying.”

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 improve the success of blood stem cell transplantation. This marks the first time, just nine short years after Harvard’s major commitment to stem cell biology, that investigators have carried a discovery from the lab bench to the clinic – fulfilling the promise on which HSCI was founded.

Umbilical cord blood transplants fail about 10 percent of the time; so increasing the procedure’s success would significantly help patients who do not have adult bone marrow donors, including a disproportionate number of non-Caucasian patients in North America. Increasing the engraftment rate would also allow the use of smaller umbilical cord blood units that are potentially better matches to their recipients, increasing the number of donations that go on to help patients.

Once the go-ahead for the trial was received by Fate Therapeutics from the US Food and Drug Administration, and the DFCI Institutional Review Board, the umbilical cord blood processing was done by Dana-Farber’s Cell Manipulation Core Facility, directed by HSCI Executive Committee member Jerome Ritz, MD. The study hit a stumbling block, however, once the human trial was underway with the first nine patients. The protocol that produced the dramatic blood stem cell expansion in mice did not translate to improved engraftment in humans.

The research was funded by the National Institutes of Health, the Howard Hughes Medical Institute, the Stem Cell Cyclists of the Pan-Mass Challenge, and the Patrick Carney Foundation.

University, Harvard. “New method for improving cord blood transplant success.” Medical News Today. MediLexicon, Intl., 11 Oct. 2013. Web.
12 Oct. 2013. <http://www.medicalnewstoday.com/releases/267224.php>

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“What we found was the bone marrow stem cells that were treated with prostaglandin, even for just two hours, had a four times better chance of engrafting in the recipient’s marrow after transplant,” he said. “I was very excited to move this into the clinic because I knew it was an interesting molecule.”

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