Corporate Banner
Satellite Banner
Pharma Outsourcing
Scientific Community
Become a Member | Sign in
Home>News>This Article

Improving Cord Blood Transplants

Published: Tuesday, October 15, 2013
Last Updated: Tuesday, October 15, 2013
Bookmark and Share
Researchers have published initial results of a Phase Ib human clinical trial of a therapeutic that could improve the success of blood stem cell transplantation.

This marks the first time that HSCI has carried a discovery from the lab bench to the clinic, fulfilling the promise of Harvard’s major commitment to such research by founding the institute nine years ago.

The Phase Ib 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 (MGH). Each patient received two umbilical cord blood units, one untreated and the other 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 had blood formation derived solely from the kdmPGE2-treated umbilical cord blood unit.

The clinical testing is now entering Phase II, which will assess the treatment’s efficacy at eight medical centers with 60 patients. Results are expected in 18–24 months.

Like much of the work conducted under the HSCI umbrella, this “first” depended on 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, chair of the HSCI Executive Committee and professor of stem cell and regenerative biology at Harvard, who studies blood formation in zebrafish at Children’s Hospital Boston;
•    Clinical research was conducted at Dana-Farber and MGH, led by hematologic oncologist and HSCI-affiliated faculty member Corey Cutler; and
•    Fate Therapeutics, 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 studied dmPGE2 for decades because of its ability to protect the intestinal lining from stress. However, its ability to amplify stem cell populations — the first molecule discovered in any system to have such an effect — was identified in 2005 during a chemical screen exposing 5,000 known drugs to zebrafish embryos. That work, published in the journal Nature in 2007, was conducted by Wolfram Goessling and Trista North, both former Zon postdoctoral fellows and current HSCI principal faculty members.

“We were interested in finding a chemical that could amplify blood stem cells, and we realized in 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 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 made Zon, a pediatric hematologist, consider ways in which 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, so patients with these conditions may be given bone marrow transplants to reconstitute their immune systems after their cancer-ravaged systems are wiped out by chemotherapy and radiation.

Zon designed a preclinical experiment, similar to 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 the other untreated.

“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.”

The next step for Zon and his team was to visit Dana-Farber, where 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 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.

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 could be better matches to their recipients, increasing the number of donations that go on to help patients.

Once Fate Therapeutics received the go-ahead for the trial from the U.S. Food and Drug Administration and Dana-Farber’s Institutional Review Board, the umbilical cord blood processing was done by the hospital’s Cell Manipulation Core Facility, directed by HSCI Executive Committee member Jerome Ritz. The study hit a stumbling block, however, once the human trial with the first nine patients got under way. The protocol that produced the dramatic blood stem cell expansion 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 of 4 degrees Celsius — too cold for the prostaglandin to biologically activate the stem cells and improve their engraftment properties. The company further demonstrated that performing the incubation of the hematopoietic stem cells at 37 degrees Celsius and increasing the incubation time from one to two 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.”

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,800+ scientific posters on ePosters
  • More than 4,000+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Scientific News
Lucentis Effective for Proliferative Diabetic Retinopathy
NIH-funded clinical trial marks first major advance in therapy in 40 years.
Blocking the Transmission Of Malaria Parasites
Vaccine candidate administered for the first time in humans in a phase I clinical trial led by Oxford University’s Jenner Institute, with partners Imaxio and GSK.
First Therapy Appearing to Reverse Decline in Parkinson’s
An FDA-approved drug for leukemia improved cognition, motor skills and non-motor function in patients with Parkinson’s disease and Lewy body dementia in a small clinical trial, say researchers at Georgetown University Medical Center (GUMC).
Gene Therapy Staves Off Blindness from Retinitis Pigmentosa in Canine Model
NIH-funded study suggests therapeutic window may extend to later-stage disease.
Treatment for Rare Bleeding Disorder is Effective
Researchers in Manchester have demonstrated for the first time the relative safety and effectiveness of treatment, eltrombopag, in children with persistent or chronic immune thrombocytopenia (ITP), as part of an international duo of studies.
HIV Vaccine Human Trials Begin
Baltimore-based Institute has begun enrolling volunteers for initial phase 1 clinical trials.
New Therapy Reduces Symptoms of Inherited Enzyme Deficiency
A phase three clinical trial of a new enzyme replacement medication, sebelipase alfa, showed a reduction in multiple disease-related symptoms in children and adults with lysosomal acid lipase deficiency, an inherited enzyme deficiency that can result in scarring of the liver and high cholesterol.
Fixing Holes in the Heart Without Invasive Surgery
UV-light enabled catheter is a medical device which represents a major shift in how cardiac defects are repaired.
Atriva Therapeutics GmbH Develops Innovative Flu Drug
Highly effective against seasonal and pandemic influenza.
Study Removes Cancer Doubt for Multiple Sclerosis Drug
Researchers from Queen Mary University of London are calling on the medical community to reconsider developing a known drug to treat people with relapsing Multiple sclerosis after new evidence shows it does not increase the risk of cancer as previously thought.
Scroll Up
Scroll Down

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,800+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,000+ scientific videos