Triple-negative breast cancers (TNBCs) occur in approximately 15%-20% of all patients with invasive breast cancer and are associated with a poor prognosis. There is significant need to identify targeted approaches for patient management, as the only currently available treatment is toxic chemotherapy. The outcome of patients with invasive TNBC, even after (neo) adjuvant chemotherapy and local therapies (surgery and/or radiation) is poor, with overall breast-specific survival of less than 50%. We seek to help change these statistics by incorporating state-of-the-art biological data and immune modulating approaches. Following standard of care, there are windows of opportunity to further and safely treat patients to prevent recurrence. We believe that stimulating the immune system to produce T cells specific for tumor antigens can significantly delay recurrence and potentially cure patients. The proposed project will focus on conducting a randomized Phase II trial testing the clinical efficacy of a vaccine designed to induce T cells to survey for the reemergence of TNBCs and to prevent disease recurrence. The vaccine strategy that we propose is antigen-specific and will target the folate receptor alpha (FRa). FRa is an ideal target because of its limited expression in the healthy tissues and it high expression in >80% of TNBCs, based on our own bench research and that of others. Studies have shown that FRa is a biologically relevant molecule that is associated with poorer outcome and is retained in recurrent and metastatic lesions. We have successfully identified immunogenic epitopes and developed vaccines that safely generate tissue-surveying CD4 T cell immune responses in patients examined in an ongoing Phase I clinical trial. Results from that clinical trial demonstrate that the vast majority of patients generated T cell immunity that recognized naturally processed and presented antigen. The research proposed will expand our understanding of vaccination targeting FRa and specifically prospectively test the clinical efficacy of this biologically based approach in a randomized Phase II post-chemotherapy adjuvant trial in patients with resected TNBC. Our preliminary data, which include immune responses and safety information, allow us to proceed with a second step, which is this proposed translational trial of the addition of this vaccine to otherwise standard of care. The proposed research strategy addresses many of the overarching challenges. By preventing tumor recurrence, the expectation is that metastatic disease will be significantly decreased. Furthermore, this will reduce exposure of the patient to subsequent life-threatening therapies. A thorough randomized Phase II study is proposed to determine the following factors: identify elements contributing to both tumor protection and adverse reactions and provide the needed information to determine whether a larger Phase III trial should be conducted. To produce such a safe and effective vaccine, several key milestones will be achieved: In Year 1, we propose to design the randomized Phase II and conduct preliminary work related to biomarker development and manufacturing. We are confident that we will be able to launch the trial beginning later in Year 1 or early in Year 2. The trial will address the clinical efficacy, immunogenicity (surrogate maker development), and safety in disease-free TNBC patients (current results demonstrate an outstanding safety profile. Clinical testing will be done at Mayo Clinic Florida (Perez, Partnering Principal Investigator [PI]) and at sites within the Mayo Clinic Academic and Community Cancer Research United (ACCRU) network of collaborating physicians and clinics, which includes the Mayo Clinic Rochester and Mayo Clinic Arizona as well as other select sites within Mayo Clinic's ACCRU network (enabling rapid accrual within the confines of the grant funding period). The expectation is that at the end of 5 years, we will have a TNBC-vaccine strategy ready for Phase III testing. Strengths of this application 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) an established clinical trials network ensuring adequate recruitment and accrual, (4) outstanding immune monitoring/biomarker development strategies, (5) an extensive [1700+ page] Food and Drug Administration-approved Investigational New Drug application with extensive data evaluating safety and toxicity associated with vaccine-induced generation of FRa immune responses in animal models, and (7) >/=10-month follow-up safety data from cancer patients immunized with an FRa vaccine. We propose three carefully thought out aims that will determine the clinical efficacy of the vaccine as well as provide important additional safety and biomarker information integrated for eventual translation into a Phase III trial. Specific Aim 1: To determine the safety profile of vaccination targeting the FRa. In our preliminary Phase I trial (n=22 patients), adverse events are generally minor with the vast majority manifesting as grades 1 and 2 injection site reactions and/or general fatigue. The proposed clinical trial will enable a better understanding of the potential for less frequent adverse events. Specific Aim 2: To identify surrogate markers of disease protection and immunogenicity. This aim will focus extensively on evaluating the surrogacy potential of the IFN-g ELIspot and FRa staining in primary lesions. Other candidate approaches such as multiplexed cytokine analysis, flow cytometry, and high avidity antibody ELISAs will also be secondarily examined. Specific Aim 3: To determine if vaccination prevents or delays disease recurrence in patients with TNBC. The primary outcome measurement will be prevention of disease recurrence in patients with resected TNBC who have completed standard of care. The trial will be a double-blind randomized trial enrolling a total of 280 patients at a 2:1 (vaccine:control) ratio. With this design, we will have nearly 90% power to detect a hazard ratio of 0.5 in vaccinated patients relative to unvaccinated patients.
|Effective start/end date||9/30/15 → 9/29/20|
- Congressionally Directed Medical Research Programs: $7,777,947.00