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    Awarded Grants
    A Novel MUC1 Targeted Vaccine for the Treatment of Breast Cancer

    Scientific Abstract:
    A Novel MUC1-targeted Vaccine for the Treatment of Breast Cancer: A novel vaccine approach is the use of recombinant whole yeast Saccharomyces cerevisiae (Baker’s yeast) engineered to express tumor-associated antigens. Recombinant yeast is an ideal vector for vaccine development. It is non-immunogenic and non-pathologic to humans, it can accommodate multiple antigens for expression, is relatively easy to construct and low cost to produce on a large scale with biologic stability. Data from our laboratory has shown that recombinant S. cerevisiae are readily phagocytosed by immature dendritic cells (DC) resulting in their rapid maturation with prominent upregulation of costimulatory signals, increased IL-12 production, and expression of the tumor antigen. Humoral and cell mediated responses have been generated in response to recombinant yeast vaccination in other murine models. This proposal is a translational project aimed at studying the recombinant yeast model as treatment for breast cancer. Our hypothesis is that the MUC1 recombinant yeast vaccine will be, in essence, a DC based vaccine that bypasses the need for ex vivo manipulation of DC and will result in strong immunologic effects and anti-tumor efficacy due to its unique ability to induce prominent DC maturation. Using a validated transgenic murine model for MUC1 that expresses normal MUC1 in epithelial tissue and develops spontaneous MUC1 expressing mammary tumors in a manner that mimics the epithelial transformation pattern and subsequent metastasis of human breast cancer, we aim to quantitate the anti-tumor efficacy of the MUC1 recombinant yeast vaccine in the setting of existing tumor burden and in prevention of spontaneous tumor. We will quantitate humoral and cytotoxic immune responses via measurement of MUC1 antibody and MUC1 specific CTL and evaluate the safety profile of a recombinant MUC1 yeast vaccine, including on subsequent murine fetal development in successfully vaccinated mice, using the aforementioned validated transgenic model. In parallel, our aims include the demonstration of MUC1-specific humoral and cytotoxic immune responses in human breast cancer tissue using patient-derived T cells after exposure to vaccine-exposed or control autologous DC. MUC1 antibody levels, T cell proliferation, MUC1-specific CTL generation analyzed, and gamma interferon levels will be analyzed. The MUC1 recombinant yeast vaccine is highly relevant to the treatment and potential prevention of breast cancer and is poised to be rapidly advanced to the clinical setting.

    Lay Abstract:
    A Novel MUC1-targeted Vaccine for the Treatment of Breast Cancer: Breast cancer cells bear unique markers that distinguish them from healthy tissue and which could serve as targets for attack by immune cells. However, tumor cells present themselves to the immune system in the absence of signals that are important for stimulating proper killing responses. Baker’s yeast, technically known as Saccharomyces cerevisiae, can be engineered to express tumor markers. Research has shown that engineered yeast are readily eaten by dendritic cells, the tumor antigen is then presented to the immune system, and strong anti-tumor responses ensue. Laboratory animals have been protected from fatal doses with tumor cells by vaccination with such engineered yeast. This new approach to making a cancer vaccine spares the patient from having to undergo procedures to obtain immune system cells or tumor cells to create the vaccine, it is relatively easy and inexpensive, and ultimately could be tailored to an individual's tumor. In this project, yeast cells will be engineered to express the MUC1 tumor marker, which is present in more than 90% of breast cancers. Mice that both express normal levels of MUC1 in their tissues (like humans have) as well as develop MUC1 expressing tumors are an ideal model to test a MUC1 based vaccine because they mimic breast cancer development in humans. These mice will be vaccinated with the MUC1 expressing yeast cells (MUCVAX) both before and after tumor development to demonstrate benefit. Evidence for tumor-specific stimulation of the immune system to kill tumor cells will be studied. Long-term ability to provide continued anti-cancer protection through MUCVAX vaccination will be evaluated and a novel model for studying the potential impact of successful vaccination against a normal body marker on subsequent fetal development will be developed. The second part of this project will study the MUCVAX to demonstrate it efficacy against actual human cancer in a system that mimics human treatment. Woman with breast cancer undergoing surgery will be asked to donate some of their tumor tissue and blood. Then, evidence of strong immune responses specific to the MUC1 target will be looked for by exposing immune killer cells from their blood to the MUCVAX exposed dendritic cells and studying the ability of these killer cells to then successfully attack tumor cells taken from the same women. MUCVAX is poised for rapid advancement into breast cancer clinical trials and represents an important advancement in vaccine therapy for cancer.