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    Awarded Grants
    Toward Complete Inhibition of Spontaneous Mammary Tumors by a Combinational HSP110-HER-2/neu Chaperone Vaccine

    Scientific Abstract:
    Toward complete inhibition of spontaneous mammary tumors by a combinational HSP110-HER-2/neu chaperone vaccine Background: We have shown that heat shock complex of HSP110 and intracellular domain of HER-2/neu (ICD) elicits strong ICD-specific T cell responses, which leads to a significant inhibition of spontaneous mammary tumor growth in vivo. However, complete eradication of neu-overexpressing mammary tumors requires improvement in vaccine formulation. We extend our earlier studies to enhance/improve anti-tumor efficacy of our HSP110-ICD chaperone vaccine by designing a combinational HSP110-based chaperone vaccine that generates both cell-mediated and antibody responses. This combinational vaccine would also overcome the immunosuppression induced by CD4+ CD25+ regulatory T cells. Objective/Hypothesis: We hypothesize that a combinational vaccine of HSP110-ICD (to generate anti-tumor T cell responses) plus HSP110-p628 (to generate anti-tumor antibody responses) would result in prevention and/or complete eradication of spontaneous mammary tumors. We also hypothesize that HSP110-p628 component of the vaccine that induces anti-neu antibodies would inhibit neu shedding thereby restraining stimulation of regulatory/suppressor T cells by the shed neu ECD. Specific Aims: (1) To determine whether generation of neu-specific cell-mediated and humoral immune responses by HSP110-ICD/p628 complexes may lead to prevention and/or complete eradication of spontaneous mammary tumors in FVB-neu transgenic mice; and (2) To determine whether HSP110-p628 complex may downregulate neu expression in mammary tumors and inhibit elevation of CD4+ CD25+ regulatory T cells. Study Design: We will generate heat shock complexes of HSP110-ICD plus HSP110-p628 and evaluate the binding complex by immunoprecipitation and Western blot analysis. We will then use ELISPOT and ELISA assays to evaluate the immunogenicity of this chaperone complex, and also tumor protection studies to prevent and/or eradicate mammary tumors in vivo. We will also evaluate the potency of HSP110-p628 complex to downregulate neu expression in mammary tumors and inhibit elevation of CD4+ CD25+ regulatory T cells using immunohistochemistry, Western blot and flow cytometry. Potential Outcomes and Benefits of the Research: These studies will define a new direction for the immunotherapy of breast cancer in preventive and therapeutic settings. We anticipate that our proposed studies in rodents would result in similar effects in humans because we are using a transgenic mouse model of human breast cancer.

    Lay Abstract:
    Toward complete inhibition of spontaneous mammary tumors by a combinational HSP110-HER-2/neu chaperone vaccine Advances in our understanding of tumor immunology is now leading to a greater interest in new approaches for cancer treatment based upon manipulation of the patient’s immune response against her own cancer. Using the body’s own protective mechanisms is attractive for a number of reasons, including low toxicity, a high degree of specificity and a long lasting immunity that would have therapeutic and preventive values in high risk populations. Induction of specific anti-tumor immune responses requires a proper adjuvant to be used in combination with a tumor antigen. We have previously demonstrated that heat shock protein 110 (HSP110) can be used as a strong adjuvant to induce anti-tumor immunity when complexed with intracellular domain (ICD) of HER-2/neu. This immunity was capable of significant inhibition of spontaneous mammary tumors in the FVB-neu transgenic mouse model of human breast cancer. However, complete eradication of breast tumors requires improvement in the vaccine formulation. In addition, breast cancer patients and FVB-neu transgenic mice have elevated suppressor T cells, which cause inhibition of anti-tumor immune responses. Therefore, an ideal vaccine against breast cancer should not only induce anti-tumor immunity but also prevent elevation of suppressor T cells. To prevent and/or completely eradicate spontaneous mammary tumors, we propose to use a combinational vaccine of HSP110-ICD (to generated anti-tumor cell-mediated immunity) plus HSP110-p628 (a peptide from HER-2/neu that induces the anti-tumor antibody response). This combinational vaccine not only generates anti-HER-2/neu cell-mediated immune responses but should also induce anti-HER-2/neu antibodies, which downregulates neu protein in mammary tumors and prevents elevation of suppressor T cells. These hypotheses will be examined in the present application. This proposal will foster a new direction for immunotherapy of breast cancer that may be effective in both preventive and therapeutic settings. We anticipate that our proposed studies in rodents would result in similar effects in humans because we are using a transgenic mouse model of human breast cancer. Anti-her-2/neu antibody (Herceptin) has been successful in the clinic supporting that our approach would be effective in humans. This combinational vaccine would be applicable to the high risk population with family histories of breast cancer as well as to breast cancer patients either before or after surgery.