Relapse after optimal treatment is a major clinical problem in preventing our ability to cure breast cancer. Even patients with advanced stages of breast cancer can be treated to the point that their tumor is no longer detectable. Most assuredly, however, there are still some breast cancer cells present that have escaped standard treatment, as these patients will eventually relapse. A treatment designed to prevent breast cancer relapse would have the potential for significantly extending survival in such patients. We hypothesize that a breast cancer vaccine designed to stimulate a tumor specific immune response would allow the body's own immune system to completely eradicate the small number of breast cancer cells left after optimal therapy.

The ability to construct such a vaccine has become possible over the last decade due to several advances in immunology. First, we know to generate long-lasting immunity we need to stimulate tumor-specific T cells. Secondly, we know that certain types of cells, called antigen presenting cells (APC), are needed to stimulate tumor-specific T cells. The most potent APC are dendritic cells (DC). Several methods have been developed to harness the immunogenic power of the DC and improve the ability of tumor vaccines to elicit immunity. Finally, in the last several years many tumor antigens have been discovered. Tumor antigens are proteins that are expressed in a patient's tumor that can elicit an immune response in that patient. Our group has been working on identifying breast cancer tumor antigens for more than a decade. We found that patients with HER-2/neu (HER2) positive breast cancer have low levels of immunity to HER2. We thought that if we could boost those weak immune responses to the level of tetanus immunity after a tetanus shot, for instance, that perhaps HER2 immunity could kill HER2 tumors.

Working in rodents, we found a vaccine that specifically stimulated CD4+ T cell immunity, those T cells involved in increasing or augmenting immune responses, was effective in preventing HER2 tumor growth. The vaccine was made with peptides, or fragments, of the HER2 protein encompassing the most immunogenic proteins of the HER2 intracellular domain (ICD). We mixed the peptide vaccine with GM-CSF, a substance that causes skin DC to infiltrate the area of the vaccine. This approach resulted in the HER2 peptides being presented to T cells by DC, generating significant HER2-specific T cell immunity. We developed a similar HER2 ICD vaccine for a Phase I study in women with breast cancer. Our trial enrolled 20 patients; results demonstrated that the vaccine was safe and immunogenic and that immunity persisted after vaccination for over 5 years in many patients. In addition, after vaccination, patients also began to develop immunity to other cancer-related proteins in their tumors (epitope spreading). Demonstration of epitope spreading means that patients were developing robust immunity on their own. There was no toxicity associated with the vaccine, particularly no cardiac or autoimmune toxicity. We now know that the abundance of the HER2 protein in cancer cells, where it is upregulated and associated with tumor growth, makes the immune system recognize HER2 in a different way than when the protein is present at normal levels in other tissues.

We now propose a Phase II study of the HER2 ICD vaccine. Since our initial trial was completed, trastuzumab (Herceptin) has become a standard of care for HER2 positive advanced stage breast cancer patients. Studies have shown that incubation of trastuzumab with tumor cells enhances the ability of HER2-specific T cells to kill tumor. We will vaccinate patients while they receive trastuzumab, and our expectation is that HER2-specific T cell immunity will be enhanced compared to vaccination alone. Our main goal is to determine if there is a survival benefit to vaccination. A secondary goal will be to determine whether the generation of HER2-specific immunity or the broadening of the immune response to other tumor proteins, epitope spreading, is associated with improved survival. We will use quantitative measures for evaluating T cell immunity to HER2 and other proteins associated with breast cancer. These data would be important in the development of a Phase III randomized study of the vaccine added to standard treatment vs. standard treatment alone, if this Phase II study demonstrated efficacy. Although HER2 is overexpressed in a minority of patients with breast cancer, expression of the protein is associated with a poor prognosis; therefore, this group of women is in need of more effective therapies. Furthermore, if this study suggests that vaccinating against breast cancer in the adjuvant setting prevents or slows disease recurrence resulting in improved survival, more universal vaccine approaches can be rapidly developed and tested for the adjuvant treatment of all breast cancers.