NCI CLINICAL INVESTIGATOR AWARD

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The Abelson oncogene (abl) of the acutely transforming Abelson Murine Leukemia Virus (AMLV) has been intensively studied since its original discovery. The AMLV genome encodes a recombinant gag-abl protein with tyrosine kinase activity and belonging to the src family of oncogenes. In human chronic myelogenous leukemia (CML) an analagous recombinant bcr-abl protein is expressed resulting from the 9:22 chromosomal translocation forming the Philadelphia chromosome. While the gag-abl protein is detectable on the cell surface with specific antibody, it is not subject to surface labeling and is non-glycosylated. Thus from an immunologic perspective it, like most other oncogene products, is predominantly an intracellular protein. A number of recent studies have indicated that intracellular proteins are indeed accessible to T cell recognition probably after proteolysis, unfolding, or other processing and trafficking to the cell surface. Possible T cell immunity against proteins encoded by abl or other oncogenes has not been previously explored. The objectives of this project are: 1) to determine the extent of the murine T cell response to the Abelson oncogene product, 2) to determine the specificity of the response at the level of small peptides, 3) to determine the ability of such antigenic peptides to immunize mice for a response to the native protein, and finally 4) to evaluate the effectiveness of such an anti-peptide response in protecting mice from challenge with AMLV. The methods to be employed are an outgrowth of recent work identifying helper T cell sites in the AIDS virus envelope protein using synthetic peptides and applying recent insights into the structural features of immunodominant sites recognized by T cells. Both the helper and the cytolytic T cell responses will be studied. Selection of abl as a prototype for detailed characterization offers the opportunity to do careful studies in the mouse, including disease challenge and protection studies, focusing on a protein whose oncogene-encoded sequence is nearly identical to that associated with human malignancy. These studies may therefore generate the basic knowledge and reagents necessary for effectively studying the human T cell response to proteins encoded by abl and other oncogenes. It is hoped that such studies may eventually elucidate strategies for induction of antigen-specific T cell immunity to human malignancies.