PROVIDED. 5. Specific Adoptive Immunotherapy of Leukemia The ability of T cells to mediate in vivo anti-tumor effects is now well-documented, particularly in the setting of allogeneic hematopoietic stem cell transplantation (HSCT) for leukemia. However, reproducibly narnessing this activity to provide therapeutic benefit requires identifying antigens expressed by leukemia cells that are immunogenic and can be safely targeted without toxicity to the host, characterizing the nature and magnitude of the T cell responses required to eradicate leukemia, and developing methods to achieve such responses in patients. Our laboratory has been addressing these issues by pursuing adoptive T cell therapy, a strategy in which T cells potentially reactive with a selected antigen are isolated from the blood, sensitized to the antigen and expanded in vitro to large numbers, and infused back into the patient. This approach overcomes many obstacles that limit vaccine strategies, and permits critical variables to be controlled and manipulated, including the magnitude of the in vivo response achieved and the phenotype and function of the tumor-reactive T cells, making it possible in a small set of patients to determine the - therapeutic potential and risks of targeting a protein and to define the parameters that must be achieved for a vaccine to be successful. The antigens we have chosen to target, WT1 and Proteinase 3, are overexpressed by leukemic cells, contribute to the leukemic phenotype, and are capable of inducing T cell responses. The proposed studies will explore the therapeutic activity and potential risks of establishing potent CD4* as well as CDS* T cell responses to leukemia antigens.
The specific aims are to: . . 1) Determine if donor-derived CD8* T cell clones specific for WT1 or PR3 transferred into patients with advanced leukemia or MDS after allogeneic HSCT is safe and can mediate an antitumor effect. 2) Determine if CD4+ T cell clones specific for WT1 can be reproducibly generated from an MHC diverse population of normal donors, .and if donor-derived CD4+ T cell clones transferred into patients with advanced leukemia after allogeneic HSCT are safe, can persist, and can mediate an antitumor effect. . '. 3) Develop methods to potentially improve the persistence and long-term therapeutic activity of transferred leukemia-reactive CD8+ T cells by generating not only effector T cells but also T cells with phenotypes/functions characteristic of central memory cells. Relevance of research to public health: The frequency of leukemic relapse after treatment with allogeneic hematopoietic stem cell transplantation dictates that additional therapies be developed. These studies will utilize the fine specificity of the immune system to selectively target leukemia cells after transplantation, and will develop principles for effectively applying such immunotherapy to broader treatment settings.
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