PHASE 1 CLINICAL TRIAL OF A NOVEL HER2 VACCINE FOR PATIENTS WITH DCIS

Project: Research project

Project Details

Description

Ductal carcinoma in situ (DCIS) is a non-obligate precursor lesion to invasive breast cancer. In the United States in 2014, it is estimated that 63,000 women were diagnosed with DCIS, thus making the pre-invasive disease a major health challenge. Over the next 20 years, the incidence of DCIS is expected to increase another 26% due to a greater number of older women in the population. The diagnosis of DCIS accounts for ~27% of new breast cancers (BC) annually in the United States. DCIS is a heterogeneous disease and in the absence of treatment, the risk of transformation is ~40%. There is no standard marker that helps to predict progression. Thus, all diagnosed patients are obligatorily treated with surgery followed by radiation. Furthermore, due to high risk of developing new primary breast cancer, patients with hormone receptor-positive (HR+) DCIS are also offered hormone therapy. Currently, there is no standard adjuvant systemic treatment for patients with HR-negative DCIS. Despite the improved disease-free outcomes however, in general, DCIS diagnosis and treatment are associated with high cost and adverse health effects among patients. Survivors report decreased physical activity, high rates of weight gain, and elevated use of antidepressants. Identifying strategies to more effectively diagnose and treat DCIS with a particular focus on mitigating long-term adverse effects, while preventing disease recurrence and progression, seems essential. Boosting natural host immune defenses represents an area of active interest in the scientific and patient communities. Recent studies are suggesting that immunization alone with a vaccine can eradicate small deposits of tumor tissue, whether premalignant or malignant. For example, in a landmark 24-month analysis of disease-free survival, Drs. Mittendorf and Peoples reported on early-stage BC patients immunized against HER2 in the adjuvant setting. Disease-free survival (DFS) at 24 months was 94.3% in the vaccinated group (n=106) versus 86.8% among controls. In another example, Dr. Czerneicki (University of Pennsylvania) has observed that HER2-based dendritic cell vaccines in the neoadjuvant setting can induce regression of ~30% of DCIS lesions, and preliminary evidence suggests improved survival. In gynecology, cervical intraepithelial neoplasia also regresses 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 endogenous host protection that potentially could be sustained for years.We propose to develop a HER2 vaccine strategy that is useful in patients with DCIS to eliminate disease and protect from recurrence, possibly leading to implementation of an approach that is a safe and effective alternative to current treatment strategies. HER2 is expressed in about ~60% of unselected DCIS lesions and is associated with high-grade disease and disease recurrence. In contrast to previous HLA-specific HER2 vaccines, which are restricted to ~50% of the population, we have recently developed an improved HER2 subdominant degenerate epitope-based vaccine designed to augment HER2-specific CD4 T cell immunity that is useful in nearly 100% of individuals. We are conducting a Phase I trial in patients with resected HER2+ breast cancer, and the interim results show outstanding safety and immunogenicity with the robust generation of HER2-specific CD4 T cells. We will test the hypothesis that neoadjuvant vaccination of DCIS patients will safely induce persistent immunity and result in regression of DCIS, thereby affording protection from recurrence. Preliminary data on safety and immunogenicity eliminate 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 Phase Ib trial will be designed in two steps. The first step will be dose-finding. Patients will be vaccinated every 2 weeks over the course of 6 weeks with vaccine (epitopes with GMC-SF as adjuvant) with one of three doses (500, 1000, or 1500 ug/peptide) of vaccine. Vaccinations will be given in the neoadjuvant setting followed by standard of care surgical resection and physician's choice of adjuvant treatment. Eligible patients will be those with HER2 1+, 2+, or 3+ DCIS lesions (either ER+ or ER-). Once the dose is established, the second step will expand the ideal dose cohort to attain enrollment of 25 patients. Primary objectives will include: (1) determine the safety of HER2 immunization in patients with DCIS, (2) determine the frequency of immune responses, and (3) determine if vaccination induces T cell infiltration. Secondary objectives include: (1) determine the persistence of the immune response, (2) determine if vaccine induces antigen loss, (3) determine histologic features that correlate with response, and (4) if vaccine induces regression. The expectation is that at 5 years, we will be ready for Phase II testing. Strengths of this application include (1) strong Initiating Principal Investigator (PI) with several years of basic and clinical trial experience, (2) strong Partnering PI who is a breast surgeon with research experience in benign breast disease and BC, (3) a strong collaborative team of BC researchers, (3) outstanding immune monitoring/biomarker development strategies, and (4) an extensive FDA-approved Investigational New Drug (IND) with extensive review of safety data evaluating safety and toxicity associated with vaccine-induced generation of HER2 immune responses in animal models and in human, and (5) 18-month follow-up data from BC patients immunized with the same vaccine. A positive outcome would facilitate a translation of a novel vaccine-based approach that could prevent invasive disease and ultimately replace less safe therapeutic approaches commonly observed to reduce quality of life.

StatusFinished
Effective start/end date9/30/169/29/21

Funding

  • Congressionally Directed Medical Research Programs: $1,228,897.00

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