Public Health Challenge

Approximately 40% of women diagnosed with breast cancer ultimately relapse. When relapse occurs, their disease is considered incurable. The challenge is to decrease the rate of relapse and develop better drug therapies for managing metastatic disease so that people can live longer. Dr. Emens is interested in developing a new approach to treating breast cancer by engaging the patients’ own immune system to seek out and destroy cancer cells. Emens and her team have developed a breast cancer vaccine for clinical investigation, and are exploring strategies for integrating cell-based vaccination strategically with established breast cancer therapeutics (chemotherapy and Trastuzumab). They are also developing immunotherapeutic strategies that target proteins within the breast tumor microenvironment (VEGFR2 and grp78).

Research Findings

Dr. Emens and her team have completed the first clinical study testing the vaccine in sequence with low dose chemotherapy. The objectives of the clinical trial were to determine the doses of CY and DOX that maximize vaccine-activated immunity as measured by the immune response to HER-2, evaluate the safety of the vaccination regimen, assess the in vivo immune responses, and assess time to disease progression in treated patients. The eligibility criteria for the trial were women with histologically confirmed breast cancer that is metastatic, stable disease of at least one month, allowable concurrent treatment with bisphosphonates and/or endocrine therapy and adequate cardiac function (LVEF > 45%). Vaccine-related toxicities involved local injection site reactions, rash/hives beyond vaccine site, fever/myalgia, fatigue, eczema, late hives/vaccine site flares. Importantly, there was no evidence of cardiac dysfunction. Vaccine alone induced new HER-2-specific immunity; this was augmented by the lowest dose of CY tested (200 mg/m2) and the highest dose of DOX tested (35 mg/m2). Notably, doses of CY higher than 200 mg/m2 suppressed vaccine-induced immunity, defining a very narrow therapeutic window for the immune-modulating activity of low dose CY. The laboratory and clinical data together show that low dose Cyclophosphamide can abrogate suppression of anti-tumor T cells by regulatory T cells; cancer therapeutics have immune effects even in the absence of active vaccination; and abrogating the influence of regulatory T cells can release the immune-activating potential of distinctly targeted cancer therapeutics. The data strongly argues for the scientifically-based integration of tumor vaccines into standard therapies for early and late stage cancer to maximally harness the therapeutic host immune response.

Possible Directions

Dr. Emens currently has three active clinical trials testing the vaccine with CY and Trastuzumab. Understanding the mechanisms of immunoregulation in breast cancer patients is essential to the successful development of therapeutic breast cancer vaccines.

Future Research Opportunities

Further investigation of the impact of chemotherapy and newer targeted therapies for breast cancer on distinct aspects of vaccine-induced immunity is warranted. The sera and lymphocytes of patients who develop an effective response to the vaccine provide powerful tools for the identification and development of novel targets for breast cancer treatment by strategies involving the immune system, or targeted therapy with antibodies or small molecule inhibitors.