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 publication marks a success for the HSCI and their ability to carry a discovery from the lab bench to the clinic. This was actually the mandate for the HSCI when it was founded.
This Phase 1b safety study was published in the journal Blood, and it included 12 adult patients who underwent umbilical cord blood transplantation for leukemia or lymphoma at the Dana Farber Cancer Institute and Massachusetts General Hospital. Each patient received two umbilical cord blood units; one of which was untreated and another that was treated with a small molecule called 16,16 dimethyl prostaglandin E2 (dmPGE2). The immune systems of all 12 patients were successfully reconstituted and their bone marrow tissues were able to make blood cells. However, 10 of the 12 patients had blood formation that was solely derived from those umbilical cord blood cells that had been treated with dmPGE2.
This clinical test is now entering Phase II, during which the HSCI scientists will determine the efficacy of this treatment in 60 patients at 8 different medical centers. They expect results from this trial within 18-24 months.
The success of the HSCI depended on collaborations with scientists at different Harvard-affiliated institutions. These collaborations included 1) Leonard Zon, chair of the HSCI Executive Committee and Professor of Stem Cell and Regenerative Biology at Harvard, and his colleagues, 2) Dana-Farber Cancer Institute and Massachusetts General Hospital, led by hematologic oncologist and HSCI Affiliated Faculty member Corey Cutler, and 3) 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.
“The exciting part of this was the laboratory, industry, and clinical collaboration, because one would not expect that much close interplay in a very exploratory trial,” Cutler said. “The fact that we were able to translate someone’s scientific discovery from down the hall into a patient just a few hundred yards away is the beauty of working here.”
Gastroenterologists have been interested in dmPGE2 for decades, because it has the ability to protect the intestinal lining from stress. However, its ability to amplify stem cell populations was identified in 2005 during a chemical screen exposing 5,000 known drugs to zebrafish embryos. Wolfram Goessling, MD, PhD, and Trista North, PhD former Zon postdoctoral fellows, were involved in that work.
“We were interested in finding a chemical that could amplify blood stem cells and we realized looking at zebrafish embryos that you could actually see blood stem cells budding from the animal’s aorta,” Zon said. “So, we elected to add chemicals to the water of fish embryos, and when we took them out and stained the aortas for blood stem cells, there was one of the chemicals, which is this 16,16 dimethyl prostaglandin E2, that gave an incredible expansion of stem cells—about a 300 to 400 percent increase.”
The dramatic effects of this molecule on blood stem cells causes Zon, who practices as a pediatric hematologist, consider how this prostaglandin could be applied to bone marrow transplantation. Bone marrow transplantations are 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 bone marrow has been wiped out with chemotherapy and radiation.
Zon designed a preclinical experiment, similar to the one later done with cord blood patients, in which mice undergoing bone marrow transplants received two sets of competing bone marrow stem cells, one set treated with dmPGE2 and a second untreated set.
“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.”
Zon and his team’s then visited the Dana Farber Cancer Institute (DFCI). There, they presented the mouse research at bone marrow transplant rounds and found physicians interested in giving the prostaglandin to patients.
“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, but the blood stem cells are not from an adult donor but from the umbilical cord blood of a newborn. The degree of tissue matching is less in an umbilical cord blood transplant than in a bone marrow transplant. The umbilical cord stem cells are young and incipient and the immune system simply does not recognize them as readily as adult cells. Therefore, potentially fatal graft-versus-host disease is less common with umbilical cord blood transplants. About 10-20 percent of stem cell transplantation procedures now use umbilical cord blood. However the main disadvantage of umbilical cord blood transplantations is that the cord blood contains uses smaller amounts of cells, which makes engraftment is more difficult.
Umbilical cord blood transplants fail about 10 percent of the time. Therefore, 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.
Fate Therapeutics received the first green light from the US Food and Drug Administration, and the DFCI Institutional Review Board for this clinical trial. Umbilical cord blood processing was done by Dana-Farber’s Cell Manipulation Core Facility, directed by HSCI Executive Committee member Jerome Ritz, MD. There was a stumbling block in that once the human trial was underway with the first nine patients in that the protocol in use, which was developed in mice, did not translate to improved engraftment in humans.
“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 than when you do it in a human.”
Fate Therapeutics discovered that the human cord blood was being handled at temperatures that were too cold (4-degrees Celsius) for the prostaglandin to biologically activate the stem cells. Therefore even after prostaglandin treatment, the umbilical cord blood did not show enhanced engraftment rates. 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.
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.”