Overriding Systemic and Local Immunologic Checkpoints To Maximize Breast Cancer Immunotherapy

Principal Investigator: EMENS, LEISHA A
Institution Receiving Award: JOHNS HOPKINS UNIVERSITY
Program: BCRP
Proposal Number: BC060229
Award Number: W81XWH-07-1-0485
Funding Mechanism: Clinical Translational Research Award
Partnering Awards:
Award Amount: $1,979,902.00


Intensive research over the last 25 years has optimized the use of surgery, radiation, and systemic therapy to reduce the morbidity and mortality of breast cancer. However, up to 40% of women diagnosed with this disease still eventually relapse and die from breast cancer. This failure is thought to be due to the outgrowth of cells inherently resistant to standard therapy, highlighting the pressing need for innovative therapeutic strategies. Cancer vaccines are an attractive approach, and they offer numerous advantages over modalities in current use for breast cancer management. They are highly specific, resulting in a favorable side effect profile that does not impair quality of life. Moreover, they have the potential to induce long-lasting systemic immunity by virtue of the immunologic memory response, resulting in a durable therapeutic effect with the potential for containing disease at the first sign of relapse. This project will develop a strategy for integrating a novel breast tumor vaccine with standard breast cancer drugs to capitalize on both their cytoreductive potential and the ability of the drugs to prime immunoregulatory pathways to maximize the vaccine-induced immune response. We aim to strategically combine vaccination with the chemotherapy drug Cyclophosphamide (CY) and the therapeutic monoclonal antibody Trastuzumab (Herceptin), both of which are a standard part of breast cancer therapy.

We will test a novel, HER-2/neu-expressing, cell-based granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting breast tumor vaccine given in sequence with low, immune-modulating doses of CY and standard dose Trastuzumab (Herceptin) to patients with HER-2/neu-overexpressing metastatic breast cancer. Our preclinical modeling using the neu transgenic mouse model of breast cancer reveals that giving a low dose of CY 1 day prior to vaccination can relieve the suppressive influence of CD4+CD25+ regulatory T cells, facilitating a productive vaccine-induced immune response that is curative in about 30% of animals (compared to 0% of animals receiving only vaccination). Adding weekly antibody therapy with HER-2/neu-specific monoclonal antibodies augments antigen processing and presentation at the tumor site to further augment the vaccine-induced immune response, resulting in the cure of almost 70% of tumor-bearing mice. In this proposal, we will conduct studies in year 1 to further examine the activity of CY-modulated vaccination in the setting of weekly therapy with the monoclonal antibody 7.16.4, a mouse monoclonal antibody that recapitulates the essential features of Trastuzumab. These experiments will characterize the following activities of the vaccination regimen: (1) its antitumor activity; (2) the magnitude of HER-2/neu-specific immune responses; and (3) alterations in regulatory signaling within the tumor microenvironment (both immune-based and HER-2/neu pathway specific). These preclinical data will be used to guide the development and conduct of a clinical study testing CY-modulated vaccination in the setting of weekly Trastuzumab therapy in 20 women with HER-2/neu-overexpressing metastatic breast cancer during years 1 through 4. Study participants will receive three monthly cycles of combination vaccine therapy, with a fourth (boost) cycle given about 6 months after study entry. Primary study outcomes will include safety and clinical benefit, and additional outcomes will include an analysis of immune priming by vaccine site biopsies and vaccine-induced HER-2/neu-specific T cell responses by ELISPOT, tetramer analysis, and lytic potential. We will also assess tumor biopsies for changes in HER-2/neu signaling, antigen-processing pathways, and immune cell infiltrates as directed by the preclinical modeling.

These studies should lend insight into the potentially therapeutic immune-based interactions between CY, Trastuzumab, and vaccine in patients with HER-2/neu-expressing metastatic breast cancer. Characterizing the magnitude and quality of the immune response should lend insight into what is required for a therapeutic benefit from vaccine-based cancer treatment. Successful immune priming by this treatment approach would support using this vaccine strategy as a form of secondary immunoprevention to decrease the risk of relapse after standard Trastuzumab-based chemotherapy for HER-2/neu-positive early breast cancer. In addition, the identification of novel breast tumor antigens may lead to the development of recombinant vaccines that are highly effective in patients with breast cancer, and they might have a role in the primary immunoprevention of breast cancer in high-risk individuals.