Novel Strategy to Enhance T cell Reconstitution Post Stem Cell Transplantation
Blood stem cells (BSC) within bone marrow, are responsible for producing all the cells found in blood, from red blood cells that carry oxygen, to disease fighting T cells. Many types of cancer, including leukemia, are treated by BSC transplantation, especially after treatment with chemotherapy or radiation. Ideally, a patient should use his own bone marrow for transplantation. However, this is not always possible; a significant number of patients receiving blood stem cell transplantation cannot find a related donor. Instead, they rely on blood stem cells donated by an unrelated donor.
Receiving blood stem cells from an unrelated donor has significant benefits, but might have some serious side effects. Often, there are donor T cells present in the blood stem cell sample. T cells uses markers called HLA antigens to recognize cells. Once inside the patient, donor T cells recognize the host HLA antigens as different and attack the patient’s cells. This is beneficial if the attacked cell is a lingering cancer cell, but it is harmful if the attacked cell is a normal cell. The beneficial anti-cancer response is called graft-versus-tumor (GVT) effect. Attacks on normal cells result in a serious condition called graft-versus-host disease or GVHD. Doctors can treat GVHD with drugs that will prevent T cell function. However, these treatments reduce the beneficial graft-versus-tumor effect and weaken the immune system, leaving the patient defenseless against infections.
The possibility of infection represents another complication resulting from blood stem cell transplantation. Blood stem cells take a long time to produce enough disease fighting T cells to protect the patient against infection, up to 2 years in some cases. Without T cells, the body does not have a way to fight off germs. This leaves the patient vulnerable to fungal and viral infections.
The possibilities of GVHD and infections offset the benefits of blood stem cell transplantation from unrelated donors. Therefore, it is imperative to figure out ways to reduce the possibility of GVHD and infections, while maintaining graft-versus-tumor activity. With this in mind, we intend to transplant human committed T cell progenitors (CTP), cells that are programmed to become T cells, together with unrelated blood stem cells. This treatment has several advantages over traditional blood stem cell transplantation: First, neither CTP nor the T cells they produce cause GVHD. Second, CTP can produce T cells faster than blood stem cells, rapidly providing an army of disease fighting T cells to the patient. These T cells could control lingering tumor cells too, allowing the blood stem cell to establish itself in the patient. Third, few CTPs are needed to achieve these beneficial results, making CTP transplantation feasible. Taken together, the simple addition of CTP to blood stem cell transplants could result in a significant increase in the success of blood stem cell transplantation from unrelated donors.
The State of California and its citizens will benefit from the proposed research in the following ways:
Direct impact: The National Marrow Donor Program reports that 2,198 unrelated blood stem cell transplants were conducted in 13 different transplant centers in California, from January 2001 to December 2005. These patients often suffer from devastating graft-versus-host disease and infection. The research proposed here has the potential to significantly increase the capacity of the immune system to fight viral infections, while significantly decreasing the severity of graft-versus-host disease. This will: 1) reduce the amount and time of use of drugs that control GVHD by suppressing the immune system, 2) reduce the rate of infections and 3) reduce the time of hospitalization. Together, these benefits expedite the time of recovery while reducing cost, resulting in a net improvement in quality of life for patients receiving blood stem cell transplants.
Health Care: We will test our hypothesis in well-characterized models of transplantation, leukemia and viral infection. If successful, this research would identify a novel developmental candidate that will improve immune function in patients receiving blood stem cell therapies. Most likely, Californians would be the primary recipients of life-saving therapies designed using my research. Moreover, my research is designed to have broad applicability, so that other conditions where T cells are dysfunctional could be tested and improved.
Biotechnology: My work already depends on a number of products and instruments made by California companies. If our proof-of-concept studies are successful, bringing this project to the clinic will require a scaled-up version of the protocols described in my studies, using Good Manufacturing Practices. This could attract new biotechnology companies in the state, boosting its tax revenue and providing new jobs for Californians.
Public opinion and educational benefits: If successful, my work has the potential to positively affect the public opinion and educational climate in the state of California. Patients who benefited from improved blood stem cell transplants, as well as their friends and family, would become advocates for stem cell research, encouraging the government to adopt better stem cell research policies. This will incite universities to promote science education, generating highly skilled graduates to fill the jobs created by stem cell research in the state. California and out-of-state students interested in biomedical research and health professions will remain in the state, reducing the brain drain of California’s talent. I foresee that K-12 education will also benefit, by receiving funding to improve and promote science education at all levels.