Project 3

ABSTRACT Vaccine-based prevention of breast cancer is a promising strategy for substantially reducing the impact of disease incidence, treatment, and mortality because vaccines can induce highly specific immune responses that self-regulate in the absence of disease. Ongoing clinical trials of vaccines targeting antigens expressed by breast cancer cells, including ongoing trials from members of this research group, have shown that vaccines can induce T-cell-based immunity that can last for years. Effective implementation of a prevention vaccine will require identification of which antigens are associated with breast cancer risk and progression and definition of tissue- and blood-based metrics of vaccine response. The experiments presented in this project will pair with our new Phase Ib trial of a novel multi-antigen prevention vaccine to advance it toward a clinical prevention trial. In our first Specific Aim, we will draw upon an extensive tissue resource of women diagnosed with benign breast disease at the Mayo Clinic and at the Karmanos Cancer Center to assess which of the antigens in the prevention vaccine are expressed in premalignant breast tissue and which are most associated with subsequent breast cancer development. This information will be critical for identifying which antigens should be included in the future prevention trial and which patients are most likely to benefit from it. In our second Specific Aim, we will evaluate blood-based antibody and cellular immune responses to the multiantigen vaccine in our current Phase 1b clinical trial. We will use high dimensional cellular analysis and targeted sequencing approaches, information that will provide minimally invasive endpoints of immune response for a larger scale future prevention trial. In our third Specific Aim, we will assess pre- and post-vaccine background normal breast tissues from patients in the clinical trial to identify how changes in antigen expression are associated with activation of specific immune cell subtypes and changes in the T- and B-cell repertoire. This information will inform the future prevention trial by defining how the vaccine and its specific components impact antigen expression and immune response in nonmalignant breast tissue. Successful completion of this project will define which vaccine components should be advanced to a larger vaccine-based breast cancer prevention clinical trial, which has the potential to drive significant reductions in overall disease incidence, burden and mortality.