Most tumor specific antigens (TAA) represent proteins also expressed at some level by normal cells. Self-tolerance would necessarily prohibit responsiveness by the host to such TAA. This is a proposal to obtain CTL specific for TAA by allo or xeno-immunization with tumor cells. Recent studies have demonstrated that allospecific CTL recognize not just the allogeneic class I MHC molecule but also the myriad of endogenous peptides bound in the antigen binding groove of the class I molecule, including peptides that can serve as TAA. Therefore, by appropriate screening of allospecific clones, CTL specific for TAA can be found. To obtain CTL specific for TAA on human tumors we will use a recently constructed transgenic line that expresses human CD8 and responds as efficiently to HLA class I molecules as it does to mouse H-2. CTL specific for TAA will be used for tumor cell elimination in two complementary approaches. First, recognition by TAA specific CTL clones will be used as an assay in the purification of TAA peptides extracted directly from the groove of class I molecules. Such peptides will be sequenced and used to generate synthetic peptides that will serve as the basis for vaccine development and for immunotherapy. In a second approach, the genes encoding the variable regions of T cell receptors from TAA peptide specific CTL will be transferred into a retroviral vector that contains the sequences for human T cell receptor genes and used to transduce T cells derived from the tumor bearing host.
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