To reduce the mortality and morbidity of HER2+ breast cancer, we must reduce recurrence of the disease, which is associated with metastasis to distant organs and treatment resistance. As opposed to standard approach of treating existing disease, a prevention strategy acts by deterring cancer reformation. Several drugs on the market, such as tamoxifen/raloxifene and trastuzumab are good examples of agents that are useful in preventing disease recurrence in ER+ and HER2+ breast cancer, respectively. We aim to build upon and enhance these approaches’ success. Specially, to stop the recurrence of HER2+ triple-negative breast cancer, we propose a novel vaccine that stimulates immunity to the HER2 protein. We have already developed the vaccine and have tested it in 22 patients in a Phase I clinical trial to determine that it is safe and immunogenic. Now, we need to answer the most important question, that is, “Does this vaccine safely prevent HER2+ from recurring?” To answer, we will accomplish the following:

(1) Determine if vaccination prevents or delays disease recurrence in patients with HER2+ breast cancer. We will conduct a “Phase II” trial. There will be two groups of patients enrolled: those that receive the vaccine and those that receive a placebo. We will enroll 190 women total between the 2 groups. The vaccine group will be double the size of the placebo (i.e., the majority of women will receive the vaccine). Vaccine will be given with standard of treatment trastuzumab and pertuzumab therapy. To be eligible, women must be free of all disease. We will follow the groups and evaluate relapse.

(2) Determine the safety profile of vaccination targeting HER2. In our prior Phase I trial (n=22 patients), side effects have been generally minor with the vast majority manifesting as minor injection site reactions and/or general fatigue. That is similar to what we see with regular vaccines. These new safety studies proposed are important because they will help us understand if there are other side effects that may be less frequent.

(3) To identify markers of disease protection. When it recurs, HER2+ breast cancer can take anywhere up to about 4-5 years to come back. We need to have a blood measurement to determine if a patient generates protective immunity. This is similar to a variety of blood tests that are performed with other infectious disease vaccines. Plus, they will allow us to determine how long the immunity lasts and whether or not booster shots should be given. We have identified several blood tests that we will optimize and perfect that could be applied to an eventual Phase III clinical trial. Additionally, we will also examine tumor tissue derived from the time of surgery to determine what tumor characteristics contribute to the success or failure of therapy.

Our preliminary data, which include immune responses and safety information, allow us to proceed with this second step of a Phase II trial. The proposed research strategy addresses many of the overarching challenges. By preventing tumor from coming back, the expectation is that metastatic disease will be decreased. If tumor recurrence is prevented, this will also reduce exposure of the patient to toxic debilitating therapies. Clinical testing will be done at Mayo Clinic Florida with Dr. Sara Chumsri, the Partnering Principal Investigator (PI). We will take advantage of one of the most admirable and efficient clinical trials networks on the face of the planet, specifically conducting the trial through the Mayo Clinic collaborating physicians and clinics, which include the Mayo Clinic Rochester and Mayo Clinic Arizona as well as other select sites within the network to ensure rapid accrual within the confines of the grant funding period. The expectation is that at the end of 4-5 years, we will have a HER2-vaccine strategy ready for Phase III testing. Strengths of this application, which mitigate much of the risks of failure, include: (1) strong PIs with several years of combined basic, toxicological and translational clinical trial experience, (2) a strong collaborative team of breast cancer researchers, (3) established clinical trials networks ensuring adequate recruitment and accrual, (4) outstanding immune monitoring/biomarker development strategies, (5) an extensive U.S. Food and Drug Administration (FDA)-approved Investigational New Drug (IND) with extensive data evaluating safety and toxicity associated with vaccine-induced generation of FRa immune responses in animal models, and (7) 24-month follow-up safety data from 22 breast cancer patients immunized with the same vaccine.