Grant part of first time, $15 million, program to encourage physicians to choose careers in clinical research to reverse trend
Dr. Edus H. Warren, an immunologist at the Fred Hutchinson Cancer Research Center, is one of five recipients of the Cancer Research Fund grant. Citing a disturbing trend that threatens future breakthroughs in cancer and other diseases, the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation announced recently its plan to help reverse a 15-year decline in the number of physicians choosing careers in clinical research.
To address this issue over the long term, the Cancer Research Fund has established a new program which will award five outstanding young physicians and their research mentors a total of $1.2 million each over five years to provide the resources and training structure essential to becoming independent clinical investigators. The program's major sponsor is Eli Lilly & Company, which has pledged $15 million over five years to bring more physicians into the clinical research discipline.
Warren's research focuses on understanding the immune responses that mediate both graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect that occur following allogeneic bone marrow or stem cell transplantation. Both GVHD and the GVL effect are thought to be mediated by T cells derived from the donor that recognize minor histocompatibility antigens (mHA) of the recipient. Warren's research goal is to improve the outcome of allogeneic stem cell transplantation by selectively enhancing the GVL effect without inducing GVHD.
Despite the critical role of T cell responses to mHA in marrow transplantation, the genes encoding mHA and their expression in leukemic progenitor cells or tissues that are the targets of GVHD remain largely undefined.
Over the last five years, Warren and his colleagues in Dr. Stanley Riddell's laboratory in the Center's program in immunology have begun to identify the molecular nature of human mHA and to elucidate the roles of individual mHA in triggering both the GVL effect and GVHD. Warren proposes to continue this research and to use the results of these studies to develop strategies employing a technique called adoptive T cell therapy for selectively enhancing the GVL effect. Riddell and Dr. Philip Greenberg, head of the Center's program in immunology, have pioneered the use of adoptive T cell therapy for the treatment of human viral and malignant disease.
Warren's research involves the isolation of T cells that recognize mHA expressed in the leukemic cells of patients that are undergoing allogeneic stem cell transplantation. Transplant patients are typically matched with their donors for the genetic characteristics encoded by the major histocompatibility complex (MHC), but may differ from their donors for minor mHA. Differences between donors and recipients for mHA can give rise to GVHD but also make possible the GVL effect. His approach involves cloning T cells that recognize mHA of the patient, expanding them to large numbers in the laboratory, and giving the cloned T cells back to the patient. Warren believes that this technique, known as adoptive T cell therapy, will allow him to take advantage of the tremendous specificity of the immune system to target the patient's leukemia cells without harming normal tissues, such as skin, the gastrointestinal tract, and liver.
"My colleagues at the Hutchinson Center have made major progress in improving the success rate of marrow transplantation and decreasing the post-transplant complications," says Warren. "My goal is to further improve techniques to reduce the rate of posttransplant relapse and therefore increase the survival for those undergoing a transplant."
Bone marrow transplantation has been proven as a successful treatment for many people diagnosed with leukemia, lymphoma and a number of other blood and genetic disorders. While long-term survival after marrow transplantation has increased significantly over the years and many people survive to live healthy, happy and productive lives, a number have difficult recoveries due to GVHD or, in some cases, the treatment fails and disease returns. Improving bone marrow and stem cell transplantation is a major objective at the Hutchinson Center.
The Fred Hutchinson Cancer Research Center is recognized as a leader in the field of marrow transplantation. More than 400 marrow or stem cell transplants are performed each year for a number of diseases. Researchers at the Hutchinson Center have worked for the past 25 years to improve and further develop transplantation therapies. Are large part of this research is focused on to finding ways to reduce complications and improve long-term survival.
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