New Stem Cell Transplantation Techniques
Last month, I let you know about some exciting advances reported by LLS-funded investigators at the recent American Society of Hematology (ASH) meeting. There was so much to tell you that I left some news for this month. So, here's some of what is happening in transplantation research - advances that are likely to help many patients.
Of course, stem cell transplantation is an important option for patients with high-risk or relapsed blood cancers that are unlikely to be cured by standard chemotherapies but can be cured by intensive, high dose treatments. Because the high dose treatments also kill critical normal blood cells, to survive patients must receive healthy cells in what is known as a hematopoietic stem cell transplant. This potentially lifesaving procedure was previously called a "bone marrow transplant" when the blood stem cells (and some mature immune cells) were collected from the cell-rich center of a donor's bones. Doctors have since learned how to coax those cells out into a donor's blood where they can be more easily collected. Now, we usually call these procedures "stem cell transplants".
Most recently, umbilical cord blood (UCB) has been shown to have real advantages as a stem cell source. Usually more than one umbilical cord is needed to successfully transplant an older child or adult, owing to the relatively small stem cell numbers. Colleen Delaney, M.D., M.S.C., of Fred Hutchinson Cancer Research Center, works closely with LLS-funded Specialized Center of Research (SCOR) team leader Irwin Bernstein, M.D. and is a leader in the advance of UCB transplantation. At this year's ASH meeting, she described a way to productively increase the number of cells that can be recovered from UCB.
Building on a new understanding of stem cell biology, Dr. Delaney uses an engineered molecule called Delta1 with other stem cell growth factors to generate increased numbers of stem cells in the laboratory before using them in transplantation. She first showed that this worked in mice, and has now gotten positive results in a Phase I clinical trial designed to evaluate the safety and potential efficacy of this new method.
All six patients enrolled in this trial so far have been successfully engrafted. Accelerated engraftment has been observed in the majority of patients as a direct result of the expansion method. Importantly, no potentially dangerous immune T-cells were generated during the laboratory expansion phase and no toxicities have been attributed to the transplanted cells, including acute graft-versus-host disease (GVHD), in which donor T-cells attack a patient's healthy tissue. These promising studies continue.
I previously described so-called "mini-transplants" that use less toxic pre-transplant treatments than those used in standard transplantation procedures. These transplants are being developed to help improve outcomes especially for older and otherwise weakened blood cancer patients who are not candidates for conventional, high-dose chemotherapy/transplants. But extra immune cell treatments may be needed to prevent relapse when less intense pre-transplant therapies are used.
Progress is being made by LLS Specialized Center of Research (SCOR) team leader Carl June M.D., University of Pennsylvania. His colleagues, include SCOR team members Edward Stadtmauer, M.D. and David Porter, M.D., as well as LLS-funded Selina Luger, M.D., Alexander Perl, M.D., Alison Loren, M.D. and Noelle Frey, M.D. Steven Goldstein, M.D., presented the team's findings for the prophylactic administration of donor immune cells (lymphocytes) after mini-transplants.
The researchers activated donor T-cells in the laboratory with a special method and gave these engineered donor lymphocyte infusions (DLI) to patients with particularly aggressive, high-risk blood cancers at four and six months after transplantation. Laboratory tests showed that the DLI did enhance anti-cancer immune responses with no evidence of increased GVHD. Eight of 16 patients enrolled in this trial are still in remission, suggesting that this approach is safe and feasible with real potential for reducing relapse without increasing GvHD. Studies are ongoing.
GVHD can occur even without DLI, when the original donor cells attack the patient's normal cells as well as the cancer cells. When GVHD occurs months after transplantiation it is known as "chronic GVHD," and can be just as life-threatening as "acute GVHD" that occurs soon after a patient receives blood cells from a healthy individual. LLS-funded David Miklos, M.D., and his Stanford University colleagues are working on a novel strategy to prevent chronic GVHD. Their goal is to make potentially curative transplants available to more patients, including those who need reduced intensity transplants and do not have access to optimally-matched donors.
Immune B-cells are implicated in the development of chronic GVHD; Rituxan® is a drug approved to treat B-cell malignancies. Therefore, Dr. Miklos reasoned that Rituxan might prevent chronic GVHD and prevent relapse after transplantation for patients with B cell malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL).
His LLS-supported laboratory investigations strongly support his novel idea. Sally Arai, M.D., presented the findings from the team's clinical trial, in which 36 patients, including 22 high risk CLL patients, underwent mini transplants and received post-transplant Rituxan treatments.
Thirty-four patients received all four planned Rituxan treatments, which were well tolerated. Consistent with Dr. Miklos' laboratory findings, donor B-cells were safely depleted without decreasing engraftment or increasing infection incidence in the treated patients. The incidence of chronic GVHD was lower than patients who received similar transplants without prophylactic Rituxan treatments, while relapse rates were not affected. The group recommends that this approach now be tested in a large, randomized trial to prove its value to patients.
Deborah Banker, Ph.D.