The University of Minnesota Cancer Center's transplant biology and therapy researchers are exploring the spectrum of the stem cell transplantation process, from investigating new approaches to preparing patients for transplantation. Their goal: improve outcomes for patients diagnosed with hematological malignancies by making more options available for treatment.

From the start, the University of Minnesota has been a pioneer in the field of blood and marrow transplantation (BMT). Physicians here performed both the first successful human bone marrow transplant in the world and the first successful bone marrow transplant to treat malignant lymphoma. Blood and marrow transplantation, now frequently referred to as stem cell transplantation, is an important therapeutic strategy worldwide for cancer treatment, particularly for hematological malignancies including leukemia, lymphoma, and multiple myeloma. Researchers at the University's Cancer Center continue to lead the way in developing innovative approaches for making stem cell transplantation safer, simpler, more effective, and available to more patients.

Putting white blood cells to work

Research teams led by Jeffrey Miller, M.D., co-leader of the Cancer Center's Transplant Biology and Therapy Research Program, are exploring how cellbased therapies using natural killer (NK) cells can be incorporated in stem cell transplantation protocols to improve outcomes hematological cancers.

NK cells are white blood cells in the immune system that target and kill infected and malignant cells. A Phase I clinical trial performed at the Cancer Center showed that a combination of chemotherapy and an infusion of NK cells from a family member can induce remissions in patients with advanced, resistant leukemia. Without remission, these patients would be ineligible for potentially life-saving transplants. Current clinical trials building upon these results include a trial in which this chemotherapy/NK cell treatment is directly followed by a transplant during the same hospitalization. Although it is too soon to tell if this consolidated regimen is more effective, it is much easier for patients.

According to Sarah Cooley, M.D., a hematology-oncology specialist working with Miller, "NK cells are the earliest white blood cell population to grow back in the recipient after transplant, and we think they are very important in mopping up any residual leukemia to prevent relapse."

First regulatory T cell clinical trial in the world

The use of regulatory T cells in conjunction with stem cell transplantation is another cell-based therapy approach being examined by Cancer Center researchers.** Regulatory T cells are a rare subset of white blood cells that act to suppress the immune response. Initial studies have demonstrated that administration of regulatory T cells can prevent the onset of graft-versus-host disease (GVHD) in a mouse model of bone marrow transplantation. GVHD, a life-threatening condition in which transplanted cells from a donor attack the recipient's tissues, is the most frequent complication of stem cell transplantation. If GVHD develops, it can require the use of intensive longterm immunosuppressive agents that can predispose patients to infections, necessitating prolonged hospitalization and potentially causing multiple side effects.

Cancer Center scientists have developed methods for isolating and growing regulatory T cells to increase their numbers for use in transplantation. A current clinical trial here is the first one worldwide to test if infusion of regulatory T cells at the time of stem cell transplant can prevent GVHD; two other related trials are soon to open.

"If these trials are successful, it would mean that we have a new way of preventing GVHD with cellular therapy that may ultimately avoid the need for intense immunosuppressive therapies," says Bruce Blazar, M.D., co-leader of the Cancer Center's Transplant Biology and Therapy Research Program. He notes that regulatory T cells are also to be explored for their effectiveness in other settings, such as autoimmune diseases like diabetes or in organ transplantation.

Bringing stem cell transplants to more patients

In the University of Minnesota's adult BMT program, the goal is to bring the curative potential of stem cell transplantation to more patients. Recent research has been investigating methods to make the transplant process safer through the use of a less toxic preparative step to destroy existing cancer as well as the patient's immune system cells prior to transplant. Known as reduced intensity conditioning, it uses far less radiation and it uses drugs that are less toxic but more immunosuppressive than in standard protocols.***

Although it had always been accepted that adults over a certain age with hematological malignancies like acute leukemia were not strong enough for a transplant, research results have indicated that reduced intensity conditioning allows potentially curative transplants to be performed even in patients up to 70 years of age.

"These results indicate that patients who didn't have transplant as an option in the past are now eligible," says Daniel J. Weisdorf, M.D., director of the adult BMT program.

Reduced intensity conditioning can also provide a transplant option to patients who were previously ineligible because of complications, prior therapies, or significant infections.

Largest center in the world investigating cord blood transplantation

The research advances in the adult BMT program have also improved availability of stem cell transplantation by finding more people an effective well-matched stem cell donor through the use of umbilical cord blood grafts. The use of umbilical cord blood stem cells for treating hematological cancers by transplantation has increased at the University of Minnesota in recent years.

Because cord blood is banked frozen, it is readily available if a match is made. According to John E. Wagner, M.D., director of the University's division of pediatric hematology-oncology and BMT and principal investigator of the cord blood transplant program, "Many patients would have died while waiting for a donor in the past, but cord blood has solved this problem."

The results of recent studies have indicated that transplants using cord blood stem cells, even if mismatched to the recipient, can provide outcomes that rival, if not surpass, that of bone marrow stem cells. These findings mean that cord blood should always be considered when searching for a stem cell donor, rather than only in circumstances where no match for a patient is found through bone marrow registries.

Current cord blood transplant research includes development of new approaches for expanding the number of stem cells used in transplants to treat hematological malignancies. Those studies build on previous work demonstrating that the number of stem cells infused predicts both the rate of recovery of the bone marrow and the survival rate (including work with transplanting two cord blood units in adults to boost cell numbers; see accompanying article on the "Minneapolis Regimen."

"We're still exploring different strategies because even though using two cord blood units gives us a tremendous advantage in terms of survival and rate of recovery, we can do even better," Wagner says. "We're the largest center in the world investigating cord blood transplantation and because we have so many patients coming from around the world for this therapy, we've been able to move the field forward at a faster pace."

* Members of the team working on the NK cell therapy studies include Jeff Miller, M.D., Sarah Cooley, M.D., and Daniel Weisdorf, M.D., who are conducting the clinical trials; Sue Fautsch and Julie Curtsinger, Ph.D., who are responsible for immune monitoring; and Dave McKenna, M.D., and Diane Kadidio, who are responsible for NK cell selection and activation for use in clinical trials.

** Members of the team working on the regulatory T cell-based therapy studies include Claudio Brunstein, M.D., and Margaret MacMillan, M.D., who are conducting the clinical trials; Patricia Taylor, Ph.D., who completed the mouse studies; and Keli Hippen, Ph.D., Steph Porter, Darin Sumstad, and John Wagner, M.D., who optimized the expansion of the cord blood regulatory T cells for clinical use.

*** Members of the team working on the reduced intensity conditioning transplant studies include Claudio Brunstein, M.D., and Marcie Tomblyn, M.D., who are conducting the clinical trials.

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This story was originally published in the University of Minnesota Cancer Center 2007 Annual Report.