Ras proto-oncogenes encode a highly conserved family of 21kD proteins collectively designated as p21. In animals, carcinogens induce very specific and predictable nucleotide substitutions in ras genomic DNA, usually at or near codons 12 or 61. The resultant single amino acid substitutions in the primary protein structure alter the tertiary structure and impart transforming activity. In humans, a substantial proportion of malignancies of a variety of histologic types are associated with activating mutations in the same codons of ras. In preliminary studies the applicant has demonstrated that specific T cell immunity to mutated ras p21 protein can be elicited by immunization with synthetic peptides constructed to be identical to the mutated portion of the ras protein. Thus, the protein products of mutated ras proto-oncogenes represent potential tumor-specific antigens both related to the oncogenic event and """"""""shared"""""""" by many tumors. The goal of the proposed studies is to develop in murine models the principles and methodologies for generating and for utilizing ras-specific T cell immunity in cancer therapy.
The specific aims of this application are: (1) To develop methods of generating CD4+ helper/inducer T cells immune to mutated ras protein. (2) To develop methods for generating CD8+ T cells specifically cytolytic to tumor cells expressing mutated ras proteins. (3) To determine the therapeutic potential of ras-specific T cells against transplanted tumors in adoptive therapy models. (4) To examine the diagnostic and therapeutic potential of ras-specific immunity in hosts bearing primary carcinogen-induced malignancies. (5) To develop the use of primary in vitro immunization with dendritic antigen presenting cells as a means for generating ras-specific T cells and for determining which ras peptides and proteins are recognized by host T cells.
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