Phase 1 Clinical Trial of a Novel HER2 Vaccine for Patients with DCIS

Ductal carcinoma in situ (DCIS) is a non-cancer tumor that must be treated because it can lead to the develop breast cancer. In the United States in 2014, it is estimated that 63,000 women were diagnosed with DCIS, thus making the tumor a major health challenge. Over the next 20 years, the incidence of DCIS will increase due to a greater number of older women in the population. Even though not a cancer, it is counted in the overall incidence of breast cancer representing about a quarter of new breast cancers the in the United States. If not treated, about 40% will ultimately give rise to breast cancer. Since there is no standard marker of which DCIS tumors will progress to breast cancer, all patients are similarly treated with mastectomy or lumpectomy along with radiation. In cases where the estrogen receptor is expressed, patients can also be treated with estrogen antagonists such as tamoxifen or aromatase inhibitors. These treatments are very effective and do quite well at reducing the chances of getting breast cancer. However, in general, DCIS is associated with high cost and later adverse health effects. For example, patients treated for DCIS frequently experience decreased physical activity, high rates of weight gain, and depression. There are also several problems associated with the long-term use of tamoxifen such as an increased risk of developing endometrial cancer (cancer of the lining of the uterus) and blood clots in the lung. With the increased incidence, the high cost of management, and the risk of future adverse health problems, it makes sense to continue to develop other alternative, safer, and less invasive approaches to treat DCIS. Boosting natural host immune defenses represents an area of active interest in the patient communities. Recent scientific research shows that immunization alone with a vaccine can eradicate small deposits of tumor tissue, whether premalignant or malignant. Early-stage breast cancer patients for example are protected from relapse when given vaccines after regular surgery and chemotherapy. In another example, studies have demonstrated that HER2-based vaccines given prior to surgical removal of DCIS can completely shrink the lesion, obviating the need for surgery. In yet another example, cervical abnormalities that are risk factors for cervical cancer also regress after immunization with peptides derived from HPV oncoproteins. Thus, immunization against early/small lesions is a candidate strategy for replacing costly, toxic treatments, affording patients with immune system protection that potentially could be sustained for years.

We propose to develop a HER2 vaccine that is useful in patients with DCIS to eliminate disease and protect from progression, possibly leading to implementation of an approach that is a safe and effective alternative to surgery, chemotherapy, and hormonal treatment. HER2 is expressed in about ~60% of DCIS lesions and is associated with development of cancer. In contrast to previous HER2 vaccines, we have recently developed an improved HER2 vaccine, designed to stimulate immunity in nearly 100% of individuals. We are currently running a Phase I trial in patients with resected HER2 invasive breast cancer, and the interim results show outstanding safety and immunogenicity with the robust generation of host immunity against tumors. We will test the hypothesis that vaccination of DCIS patients, prior to standard treatment, will safely induce persistent immunity and result in regression of DCIS, thereby affording protection from progression.

Preliminary data from our Phase I clinical trial eliminates the early risks associated with development of this vaccine making this an ideal application for a Level 3 Breast Cancer Research Program Breakthrough Award. In Year 1, we will get Institutional Review Board approval and Food and Drug Administration (FDA) authorization for a Phase 1b clinical trial and begin testing. Clinical testing will continue in years 2-5. The design of the trial will be Phase Ib trial, which is a two-step design. The first step will be a dose-finding step in which patients will be vaccinated every 2 weeks over the course of 6 weeks with vaccine with one of three doses of vaccine. The reason for the dose-finding step is that we may need to increase the dose, relative to our current ongoing trial, because we will need to immunize the DCIS patients over 6 weeks rather than 6 months, which may require higher doses of vaccine to achieve maximal immunity. Vaccinations will be given in the prior to treatment followed by standard of care. Eligible patients will be those with some level of HER2, which should be the majority. We will test three doses with nine patients per dose arm. Once the dose is established, the second step will expand the ideal dose cohort to attain enrollment of 25 patients. Primary objectives in this step will include: (1) determine the safety of HER2 immunization in patients with DCIS, (2) determin .......