CD8+ T CELL ACTIVATION AND INFILTRATION INTO BREAST TUMORS POST PEPTIDE VACCINE

University Of Virginia, Charlottesville VA

Investigators

Linked publications & trials

Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Breast cancer is diagnosed in over 200,000 American women each year, and remains a leading cause of cancer death despite advances in diagnosis and treatment. It is the leading cause of death in women between the ages of 40 and 44. In the United States, 32% of all new cancers and 18% of cancer deaths in women are related to breast cancer. Existing therapy includes surgical resection, monoclonal antibody therapy, chemotherapy, radiation therapy and hormonal therapy. Resistance of tumor cells to standard treatments is thought to be the major cause of the failure of current management approaches. Thus, there is a need for new strategies in addition to existing therapy. Increasingly, therapies directed at improving immune responses to cancer are being employed, and there is evidence that breast cancer can be targeted by antigen-specific T cells. Multiple breast cancer-relevant antigens for T cells have been defined, but few have been studied in breast cancer patients to date. Immunotherapeutic approaches offer a potentially useful treatment for breast cancer patients because breast tumors 1) express MHC Class I molecules allowing for their recognition by CD8+ T lymphocytes and 2) express mutated versions of proteins associated with cellular proliferation such as BRCA-1, BRCA-2, and p53, elevated levels of aberrantly glycosylated proteins such as MUC-1, and elevated levels of non-mutated proteins such as Her-2/neu, carcinoembryonic antigen (CEA,) MAGE antigens, or NY-ESO-1, which could serve as targets for cellular and humoral immune responses. Indeed, tumor-associated lymphocytes and antibodies specific for some tumor antigens have been isolated from breast cancer patients. More importantly, recent studies have identified antigenic fragments, epitopes, from these proteins capable of stimulating immunological responses, which can be incorporated in novel vaccine designs. The goals of the proposed study are to assess whether vaccination with a multipeptide vaccine induces T cell responses to the vaccinating peptides, and importantly to characterize the phenotype of responding T cells with respect to differentiation and chemokine receptor (CCR) expression patterns. The epitopes were chosen based on 1) their MHC restriction (approximately 60-80% of the breast cancer patient population will express HLA-A1, -A2, -A3, or -A31), 2) the frequency of expression of the parent protein in adenocarcinomas of the breast, and 3) for the majority of the epitopes, their proven immunogenicity in vivo. There are several advantages associated with the development of this proposed peptide-based vaccine. First, the breast cancer-associated peptides to be used in this study are usually encoded by non-mutated genes, which lack tumor-specific mutations. Therefore, epitopes derived from these molecules could be useful in a vaccine for a large population of breast cancer patients. Second, since we are vaccinating with defined breast cancer-associated epitopes as opposed to a whole cell vaccine, immunological responses to the vaccinating peptides can be easily monitored. Third, metastases may be comprised of a heterogenous population of cells, which express a different profile of tumor-associated antigens. Thus, vaccines incorporating a single breast cancer-associated epitope may be inadequate in generating a complete immune response against tumor. Ideally, the proposed polyvalent vaccine incorporating epitopes derived from multiple antigens would compensate for the differential display of tumor-associated antigens. The following study incorporates nine epitopes derived from six different breast cancer associated proteins, MAGE-A1, -A3, -A10, CEA, NY-ESO-1, and Her-2/Neu. The proposed analyses are designed to test the hypotheses that vaccination 1) enhances T cell infiltration into tumor and 2) induces T cells to become activated and fully differentiate into effector cells. The proposed study is unique among breast vaccine trials proposed to date in that we will define the extent to which these two processes occur following vaccination and identify opportunities for improving tumor targeting and T cell effector function in human breast cancer.