Exciting Advances in Stem Cell Transplantation
Many patients with high-risk or relapsed blood cancers cannot be cured by today's standard chemotherapies. These patients might be cured by more aggressive, higher dose treatments, but these treatments also kill normal blood cells - patients must receive new blood stem cells to survive. In "allogeneic" (from another) "hematopoietic" (blood forming) stem cell transplantation, blood stem cells from a healthy donor replace critical patient cells lost during pre-transplant chemotherapy. Some mature immune cells come along for the ride - they fight infections while the stem cells produce an all new immune system, and they can also ?see' any remaining cancer cells as foreign and destroy them, preventing early relapse.
Successful allogeneic transplantation requires finding a "well-matched" donor. This means that the patient's and the donor's cells are similar enough that they don't mind living and working together. Unfortunately, good matches can't always be found - patients who receive "mismatched" transplants can develop Graft versus Host disease (GvHD) in which the "graft" (donor immune cells) attacks the healthy tissues of the "host" (patient). GvHD can occur even with the best possible matches and can be life-threatening, especially in patients already weakened by multiple cancer treatments, but mismatching increases the risk of this serious side-effect.
Reducing GvHD would substantially increase the safety and success rate for transplants. There is currently no effective treatment for GvHD. It can be reduced by using powerful immunosuppressive drugs or by physically removing all the donor immune cells, but then their good effects (fighting infection and preventing relapse) are also lost. The problem could be solved by selectively disabling donor immune cells most likely to cause GvHD, whilst leaving the remaining cells functional. But, this requires knowing who's who.
And, now we think we know!
Jeff Davies, M.D., Ph.D. of Dana-Farber Cancer Institute has been funded by The Leukemia & Lymphoma Society (LLS) to pursue an exciting new approach to selectively incapacitating GVHD-causing cells. He and his colleagues describe their most recent findings in a manuscript currently in press at the prestigious new journal Science Translational Medicine.
Dr. Davies and his colleagues are using a sophisticated new method to inactivate only the troublesome immune cells in the donor graft, before it is used. The method basically over-stimulates the 'bad' immune T cells that could react against the patient's tissues, such that they are unable to react once transplanted along with the ?good' immune cells.
In 2008, the team got promising results in an early phase clinical trial - very little GvHD, despite mismatched transplantation. While studying samples from patients and donors, Dr. Davies discovered that their novel method not only inactivates dangerous T cells, but also unleashes a type of immune cells known as T regulatory cells, or Tregs, that expand over the months following transplant and further dampen GvHD.
Tregs were already known to have two important functions - they turn off immune reactions following a successful defense against infectious organisms, and they prevent immune cells from attacking the body's own tissues and causing "autoimmune diseases" like rheumatoid arthritis and lupus. But, how to effectively use them to block GvHD was not known.
Dr. Davies and his colleagues have now replaced the antibodies that they first used to deactivate the bad T cells with a new, commercially available reagent. They are using their optimized method in a new clinical trial for acute leukemia and myelodysplastic syndrome patients treated with mismatched bone marrow transplantation. Early results show that the technique is safe and that patients who receive bigger doses of the treated donor T cells recover immunity more rapidly.
Of note, Tregs can be the bad guys too, in that they can reduce the ability of a patient's immune system to respond to a cancer vaccine.
I have talked here before about cancer vaccines that can help a patient's own immune system find and fight cancer lymphoma, leukemia & myeloma. Another LLS-funded investigator, Robert Vonderheide M.D. of the University of Pennsylvania, has recently shown that a single intravenous dose of an antibody, daclizumab, can eliminate Tregs for prolonged periods and can allow patients with metastatic breast to make a productive anti-cancer vaccine response. Dr. Vonderheide is testing similar approaches for blood cancer patients. If confirmed in additional patients, his findings suggest that daclizumab might be an effective therapeutic agent for Treg modulation in vaccine treatments for a broad array of cancer patients.
Obviously, there is more to learn about Tregs, how to control them in transplantation versus vaccination settings, how to use them best to help patients. But, real progress is being made.
Laboratory research and clinical trials remain essential and will go on with LLS funding, made possible by our many supporters. Stay tuned!
