) It is now well accepted that T cells repesent a critical immunologic effector in the antitumor immune response produced by therapeutic cancer vaccines. The investigators participating in this NCDDG grant have all been involved in utilizing current molecular technology to develop novel approaches for inducing T cell mediated antitumor immune responses. Candidate tumor antigens have been identified for certain human cancers. An example, which the investigators in our NCDDG program have been evaluating, is the HER-2/neu gene product that is overexpressed in 30% of breast an ovarian cancers. HER-2/neu is one of a large category of recently identified tumor associated non-mutated self-antigens which is overexpressed by tumor cells relative to normal tissue. Although there are many examples of the induction of T cell responses against this category of antigens, currently employed vaccine approaches are not potent enough to overcome the mechanisms of peripheral tolerance that occur to these self-antigens. Therefore, it is necessary to utilize more clinically relevant animal models for identifying the most potent vaccine approaches that can overcome natural mechanisms of tolerance. Dr. Jaffee has been characterizing the immune responses to tumor in the HER-2/neu transgenic mouse model of mammary cancer. In this model, the rat proto-oncogene HER-2/neu, under the control of the MMTV promoter, is overexpressed by spontaneously developing tumors. These mice demonstrate peripheral tolerance to HER-/neu that is similar to what has been demonstrated in patients with HER-2/neu expressing tumors. Taking advantage of active scientific collaborations which have been ongoing over the past years, the NCDDG group now proposes to utilize this mouse model to evaluate and develop more potent antigen-specific vaccine strategies combined with immune modulators in the form of chemotherapy and biologics, that can overcome tolerance to tumor-associated self antigens. This development will follow a four step process: 1) Individual vaccine strategies under development by the NCDDG project leaders will be optimized for a number of parameters using transplantable HER-2/neu mammary tumors; 2) Baseline immunologic effect functions will be measured as an additional parameter for identifying the most potent vaccine approaches; 3) Optimized vaccine approaches will then be compared head-to-head for the ability to eradicate naturally developing mammary tumors; 4) A targeted evaluation of potential synergies between different vaccine strategies will be evaluated using potency against spontaneous arising tumors as the final outcome.
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