DEVELOPMENT OF IMMUNOTHERAPIES FOR CHRONIC MYELOID LEUKEMIA

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At present, curative therapy for CML is limited primarily to the small fraction of patients with stable phase disease who are eligible for an HLA- matched bone marrow transplant. There has recently been renewed interest in developing immunotherapies for cancer because of a number of discoveries in basic immunology. These discoveries include major advances in the understanding of antigen presentation, T cell regulation, and the mechanisms of tolerance or anergy. In theory, many cancers have potential tumor antigens in the form of mutations in dominant oncogenes, viral oncogenes, or other neoantigens. CML is an example, where the p210 BCR/ABL oncogene itself is a possible tumor antigen, as are mutations in other proto-oncogenes such as p53 and p21 ras which are commonly observed in advanced forms of the disease. It is evident that most or all patients with CML generate either no immune response to athe tumor or an ineffective immune response. The immune response to leukemia cells may be impaired because leukemic antigens are typically presented to T cells in such a manner as to force the development of tolerance rather than active immunity. Tolerance is believed to be caused by the presentation of antigen to T cells in the absence of a costimulatory signal through CD28. The goals of this project will be to develop animal models to explore the immune response to a leukemia antigen (p210BCR/ABL), to investigate ways of manipulating the immune response in vivo as a correlate to in vitro studies with human cells conducted in other projects, to find novel ways to induce an effective immune response in leukemic animal which could lead to clinical trials, and to generate new animal models of CML which more accurately reflect human disease. This models produced by this project will also be used by investigators in other projects to test new concepts about tolerance or techniques for altering immune responses to tumors. Over the long term, this project should contribute tot he development of novel therapies for human leukemias and lymphomas.