Expansion technique triggered notch-signaling pathway, according to a study in Nature Medicine.

Investigators report what they claim is the first successful engraftment of ex vivo-expanded human umbilical cord blood stem/progenitor cells in patients with leukemia. The Fred Hutchinson Cancer Research Center team used a notch-signaling pathway activation method to expand the number of stem/progenitor cells in cord blood ex vivo. Subsequent infusion of a unit of expanded cord blood into leukemia patients led to rapid, successful engraftment, they report. 

The researchers, led by Colleen Delaney, M.D., claim the approach could make the use of umbilical cord blood transplantation far more widely applicable for the treatment of leukemia and other blood cancers. Their results are reported in Nature Medicine in a paper titled “Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution.”

Cord blood represents a promising source of stem cells for treating blood cancers and immune system disorders because there is no need for a perfect donor-recipient match, according to Dr. Delaney et al. However, cord blood transplants generally take much longer to engraft than standard stem cell transplants from donors because a unit of umbilical cord blood contains only about 1/10th the number of stem cells as a conventional transplant. The delay in engraftment thus increases the likelihood that immunocompromised patients will acquire serious infections.

Dr. Delaney’s group used a notch-signaling pathway activation approach to trigger cord blood stem cell expansion. The technique uses an engineered protein to activate the notch pathway in stem cells in the laboratory and trigger their expansion in culture. It was originally developed by Irwin Bernstein, M.D., from the Hutchinson Center’s clinical research division, and first reported in 2000.

Dr. Delaney’s latest research showed the method boosted the number of CD34+ hematopoietic cells in cord blood by an average of 164-fold. While a typical unit of cord blood usually contains less than 200,000 stem cells per kg of the recipient’s bodyweight, the expanded units contained an average of 6 million CD34+ cells per kg bodyweight.

The expanded cord blood was then used to treat leukemia patients participating in an ongoing Phase I trial. Each of the 10 patients received one unit of nonmanipulated cord blood and one unit of expanded cord blood. The results showed it took an average of 14 days for transplanted cells from the expanded unit to engraft, compared with an average of four weeks for engraftment when nonexpanded units were used. Tests also showed that white blood cells recovered from patients during the early post-transplant period were derived primarily from the expanded cord blood unit.

“To our knowledge, this is the first demonstration of rapid hematopoietic engraftment derived from ex vivo-expanded hematopoietic progenitors,” the authors state. “However, although rapid neutrophil engraftment has been shown in the patients treated to date, larger Phase II–III studies will be required to test the hypothesis that the observed enhanced kinetics of engraftment will improve patient outcomes including effects on overall survival, incidence of clinically important infections, and time spent in the hospital.”

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