May 25, 1999 A research team from the Massachusetts General Hospital (MGH) has shown that it is possible to transplant bone marrow successfully from mismatched human donors without the usual pre-transplant destruction of the patient's own bone marrow. The report appears in the May 22 issue of The Lancet.
The scientists from the hospital's Bone Marrow Transplant Program and Transplantation Biology Research Center (TBRC) successfully induced a state of mixed chimerism - in which the immune systems from both donor and recipient are blended - in four patients with aggressive non-Hodgkins lymphomas that resisted other treatment methods. Two of those patients have achieved long-term remission without significant graft-versus-host disease, a dangerous complication of bone marrow transplantation.
"This proof-of-principal study has shown that we can achieve a lasting combination of donor and recipient immune systems without the kind of toxic treatment usually used to wipe out the recipient's bone marrow," says Megan Sykes, M.D., of the TBRC, the paper's lead author. "We are intrigued by the powerful anti-tumor effect observed in several patients."
Thomas Spitzer, M.D., director of the Bone Marrow Transplant Program and principal investigator of the study described in the Lancet paper, adds, "While it's much too early to say whether this approach will benefit and be safe for all patients with advanced blood-cell cancers, we're very encouraged by the results we've seen."
In standard bone marrow transplantation, patients undergo a pre-transplant process called ablation in which their diseased bone marrow is destroyed by either intense radiation or chemotherapy, essentially wiping out their immune system. Depending on the patient's particular illness, replacement marrow may come from a donor or may be the patient's own marrow treated to remove any malignant cells (an autologous transplant). In the case of treatment-resistant non-Hodgkins lymphoma, a blood-cell cancer that affects several thousand Americans annually, both autologous transplants and those from closely-matched donors have been successful less than 25 percent of the time, the authors note.
"It really has been an all-or-nothing situation, with patients facing two hazards," says Spitzer. "If the transplanted marrow doesn't take or is rejected, patients are left with no immune system. When patients receive transplants from less closely matched donors, they risk graft-versus-host disease, a life-threating complication that develops when the donor marrow attacks the recipient's tissues."
Mixed chimerism represents a balanced state in which elements from both the donor and recipient immune systems successfully coexist. It was originally achieved in animal studies in the laboratory of David Sachs, M.D., director of the MGH-TBRC and a co-author of the Lancet paper. Mixed chimerism now is being extensively studied by Sachs and his colleagues for its potential to allow transplantation of organs without long-term use of immunosuppressive drugs.
Sykes developed the concept of applying the mixed chimerism work to treatment-resistant lymphomas. She made the original observation in animal studies that administration of donor lymphocytes (white blood cells) to mixed chimeras could induce an anti-tumor effect without causing severe graft-versus-host disease. Her team collaborated with Spitzer's bone marrow transplant group to develop a strategy for replicating this response in human recipients of mismatched bone marrow transplants who received a milder course of pretransplant chemotherapy, combined with monoclonal antibodies against T cells, the specific type of lymphocyte involved in rejecting transplanted tissues.
The current study is the first to achieve intentional mixed chimerism in human patients receiving mismatched marrow transplants without intensive pretransplant preparation. The technique was applied in five patients with advanced, treatment-resistant non-Hodgkins lymphoma who had no closely matched donor available. All patients were considered terminally ill at the time of the transplant and had no other treatment options.
In two patients the transplants were successful, both producing mixed chimerism - shown by the presence of both donor and recipient cells in their bone marrow - and long-term remission from their cancers. While two other patients died in the months following their procedure of causes related to their illness, studies of their marrow showed a level of mixed chimerism had been achieved. The fifth patient died from a cause unrelated to the transplant (pulmonary hemorrhage) 12 days after the procedure, too early to judge whether or not the donor marrow had engrafted. The two surviving patients are still in remission up to two years after receiving their transplants.
Sykes notes that this less toxic approach to bone marrow transplantation may open the technique up to individuals - particularly the elderly - who could not withstand the harsh conventional regimens. Follow-up studies are investigating the additional anti-cancer effect of a post-transplant infusion of donor white blood cells, a technique shown in Sykes' laboratory to enhance the attack on the recipient's malignant blood cells.
The TBRC-developed techniques for inducing mixed chimerism and exploiting the anti-cancer effects of donor immune system cells have been licensed to BioTransplant Incorporated (Nasdaq:BTRN) of Charlestown, which also has supported much of the basic research conducted at the TBRC. Coauthor Sachs is chairman of BioTransplant's scientific advisory board. Additional coauthors of the Lancet paper are Frederic Preffer, Ph.D.; Steven McAfee, M.D.; Susan Saidman, Ph.D.; Dina Weymouth; David Andrews, M.D.; Christine Colby, PharmD, and Robert Sackstein, M.D., all of the MGH. The Lancet study was supported by a grant from the National Institutes of Health.
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