HER2-positive breast cancer (HER2+ BC) accounts for approximately 25% of all BCs. HER2 expression is associated with unfavorable pathologic features and aggressive disease, if untreated with targeted therapies, relative to other forms of BC. While the outcome of patients with HER2+ BC has significantly improved in the past few decades with an advent of anti-HER2 therapies, a substantial number of resected patients with HER2+ BC still subsequently develop metastatic disease. Complete pathological response (pCR) to neoadjuvant chemotherapy has been shown to be a good surrogate for favorable long-term outcomes in HER2+ BC, particularly in hormone receptor-negative HER2+ disease. Based on the recent clinical trials with neoadjuvant therapy with trastuzumab, pertuzumab, and chemotherapy, ~30% of patients who do not achieve pCR-developed recurrence or metastatic disease within the relatively short median follow-up of 5 years. Our group is interested in improving outcome and increasing the cure rate of patients with locally advanced HER2+ BC by boosting natural adaptive host immune defenses by either directly inducing tumor antigen-specific immune responses or by blocking/reversing immune suppressive mechanisms operating in the tumor microenvironment.The traditional paradigm is that the effects of trastuzumab are mediated either by direct blockade signaling or through the activation of cytotoxic natural killer (NK) cells. More recent evidence from our group (published and unpublished) suggests that an adaptive immune response is generated including activation of tumor-specific CD4 T cells and antibody-producing B cells. Importantly, our evidence strongly suggests that it is an endogenous antibody response that is responsible for the improved survival and that only 1/3 of patients develop these antibodies, leading us to speculate that boosting this immune response will reduce deaths. It is well known that CD4 helper T cells boost antibody production. We think that vaccination to boost HER2-specific T cells during trastuzumab-based therapy will improve survival by boosting anti-tumor immunity. We have recently identified a pool of four degenerate HER2 HLA-DR epitopes that we have formulated into a vaccine. Indeed, in an ongoing trial, we found that nearly 100% of vaccinated patients developed robust HER2-specific T cell immunity consistent with the degeneracy.Based on the strong background of our prior work, we propose to conduct a randomized Phase II clinical trial to ask whether the administration of vaccine during trastuzumab and pertuzumab maintenance therapy in patients with residual disease post-neoadjuvant chemotherapy blocks disease recurrence and the development of metastatic breast cancer. By prevention of recurrence and metastasis, the expectation is that mortality associated with BC will be decreased. Aside from the immunization component of the approach, another unique aspect is we will study the role of the immune response, induced by monoclonal antibody therapy, in the neoadjuvant setting by engaging the patients that demonstrated complete pathologic response to therapy but who do not get vaccine, potentially enabling a better understanding of mechanisms of immune escape.In Year 1, we will get U.S. Food and Drug Administration (FDA) approval for a Phase II clinical trial and begin testing. Clinical testing will continue in years 2-4. The primary objective is to determine if boosting CD4 helper T cell immunity boosts the therapeutic efficacy of HER2-specific monoclonal antibody therapy. Secondary objectives include: (1) determine the safety of HER2 immunization, (2) determine the persistence of the immune response, (3) determine if vaccine induces antigen loss, and (4) determine histologic genetic features that correlate with response and treatment failure. The expectation is that at 4 years, we will be ready for Phase III testing. There are significant strengths of this application, which include: (1) a strong Initiating Principal Investigator (PI) with several years of basic and clinical trial experience, (2) strong Partnering PI who is a breast cancer oncologist with research experience in benign breast disease and BC, (3) a strong collaborative team of BC researchers, (4) outstanding immune monitoring/biomarker development strategies, (5) 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 (6) 18-month follow-up data from BC patients immunized with the same vaccine. A positive outcome would facilitate the translation of a novel vaccine-based approach that could ultimately prevent disease recurrence and mortality associated with metastatic breast cancer in HER2+ BC patients.
|Effective start/end date||9/30/18 → 9/29/22|
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