Stem cell transplants are the best chance of cures for many blood cancer patients and for some patients with auto-immune diseases. Now, a Leukemia and Lymphoma Society-funded researcher, H. Lee Moffitt Cancer Center & Research Institute's William Kerr Ph.D., is working to bring this potentially curative option to more patients. His latest research breakthroughs will be published this month in the Journal of Immunology.
In "allogeneic" transplants, patients receive a healthy individual's blood stem cells, called a graft. Not only do the transplanted cells replace critical blood cells lost during high-dose pre-transplant chemotherapies, designed to kill most of the cancer cells, but they can also help kill any remaining cancer cells to prevent relapse. Unfortunately, when the donor graft is not a good match with the patient's immune cells, the transplanted cells can be rejected, providing no benefit. Or, a patient can develop a life-threatening condition called Graft vs. Host disease (GVHD) in which the donor's immune cells attack the patient's healthy tissue as well as the cancer cells.
Currently, suitable donors can only be found for 20-30% of patients who might be cured by allogeneic transplants. If we learned which genes controlled graft rejection and GVHD, new "targeted" treatments might be used to make transplants successful and safe for more patients.
Previously, Kerr discovered one gene (SHIP) with critical roles in both rejection and GVHD. He and his colleagues at Moffitt created mice that lacked this gene and showed last year that SHIP-deficient immune cells in a transplant recipient are far less likely to reject normal cells from an unrelated donor than recipient immune cells that still carry the SHIP gene (Journal of Immunology 2006, 176(12):7165-9).
Now, Kerr and colleagues have used another genetically engineered mouse model to show that removing SHIP for just one week protects transplant recipients from acute GVHD. This protection is seen even when the graft contains extra immune cells to help the graft "take" or when the graft cells are completely mismatched to the recipient.
Since the SHIP gene is also present in humans, Kerr says their findings have several implications for cancer and other human diseases.
"If we can identify approaches to reversibly inhibit SHIP in patients, then we could potentially: (1) reduce the risk of GVHD in matched transplants that are currently used to treat blood cancer patients, (2) perform allogeneic transplants even when a matched donor cannot be found, and (3) increase the number of donor immune cells that can be given to patients post-transplant to combat cancer relapse," said Kerr.
SHIP inhibitor drugs are already being developed and Kerr has shown that a genetic treatment strategy called RNA interference (RNAi) might also work. Other scientists have shown that RNAi can be used to turn-off specific genes in mice and non-human primates.
"These strategies are likely to be tested clinically, perhaps even within one to two years" said Kerr, "It's all about money - if there are more dollars then things will move faster."
The Leukemia and Lymphoma Society is trying to help make that happen.
About H. Lee Moffitt Cancer Center & Research Institute
Located in Tampa, Florida on the University of South Florida campus, H. Lee Moffitt Cancer Center & Research Institute (www.moffitt) is the only Florida-based cancer center with the NCI designation as a Comprehensive Cancer Center for its excellence in research and contributions to clinical trials, prevention and cancer control. Moffitt currently has 15 affiliates in Florida, one in Georgia and two in Puerto Rico. Additionally, Moffitt is a member of the National Comprehensive Cancer Network, a prestigious alliance of the country's leading cancer centers, and is listed in U.S. News & World Report as one of America's Best Hospitals for cancer. Moffitt's sole mission is to contribute to the prevention and cure of cancer.
H. Lee Moffitt Cancer Center & Research Institute
12902 Magnolia Dr., MBC-PR
Tampa, FL 33612-9497
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