PROVIDED.5. Specific Adoptive Immunotherapy of LeukemiaThe ability of T cells to mediate in vivo anti-tumor effects is now well-documented, particularly in the settingof allogeneic hematopoietic stem cell transplantation (HSCT) for leukemia. However, reproduciblynarnessing this activity to provide therapeutic benefit requires identifying antigens expressed by leukemiacells that are immunogenic and can be safely targeted without toxicity to the host, characterizing the natureand magnitude of the T cell responses required to eradicate leukemia, and developing methods to achievesuch responses in patients. Our laboratory has been addressing these issues by pursuing adoptive T celltherapy, 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. Thisapproach overcomes many obstacles that limit vaccine strategies, and permits critical variables to becontrolled and manipulated, including the magnitude of the in vivo response achieved and the phenotypeand 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 avaccine to be successful. The antigens we have chosen to target, WT1 and Proteinase 3, are overexpressedby leukemic cells, contribute to the leukemic phenotype, and are capable of inducing T cell responses. Theproposed studies will explore the therapeutic activity and potential risks of establishing potent CD4* as wellas 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 withadvanced 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 diversepopulation of normal donors, .and if donor-derived CD4+ T cell clones transferred into patients with advancedleukemia 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 oftransferred leukemia-reactive CD8+ T cells by generating not only effector T cells but also T cells withphenotypes/functions characteristic of central memory cells.Relevance of research to public health: The frequency of leukemic relapse after treatment with allogeneichematopoietic stem cell transplantation dictates that additional therapies be developed. These studies willutilize the fine specificity of the immune system to selectively target leukemia cells after transplantation, andwill develop principles for effectively applying such immunotherapy to broader treatment settings.
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