Converting HR+ Breast Cancer into an Individualized Vaccine
Abstract
Approximately three-quarters of newly diagnosed invasive breast cancers (BC) in the U.S. are hormone receptor-positive (HR+) HER2-negative (hereafter, HR+). Despite therapeutic advances, one-third of HR+BC recurs and account for the most frequent cause of death from breast cancer. Immune checkpoint blockade (ICB) therapy has revolutionized the treatment of other deadly cancers, but the available data indicate that the response to ICB is limited to only 2%-5% of HR+BC patients. Response in HR+BC is hampered by a complex immunosuppressive tumor microenvironment that characterizes this disease. To address this barrier, we propose to use a multipronged approach to reset the cross-talk between the BC cells and the immune system of the patient. Endocrine therapy (NET) with aromatase inhibitors like letrozole has already shown to have a positive effect in recovering immune rejection, by reducing regulatory T cell (Treg), in addition to depriving HR+ BC cells of critical hormonal growth factors. NET is a standard treatment option for postmenopausal BC patients and can be safely used before surgery. Tumor radiotherapy (RT), equivalent to a “boost” dose of 8 Gy X 3 visits, can be used to elicit an immune response to the tumor. Similarly, in mice models and recently in patients, the growth factor FMS-like tyrosine kinase 3 ligand (FLT3L) has shown to potentiate tumor rejection. Finally, programmed cell death-1 (PD-1) and its ligand PDL-1 are known dominant obstacles to tumor rejection. While few HR+BCs are PDL-1+, upregulation of PDL-1 in the setting of radiation-induced anti-tumor responses was shown to impair tumor elimination, warranting to also block PD-1 pathway to induce effective immune responses. We are proposing a prospective randomized trial in postmenopausal HR+BC patients, to test standard therapy with immunotherapies targeting these barriers. All patients will undergo NET with letrozole and will be randomly assigned to combinations of letrozole and RT alone, or with FLT3L and/or anti-PD-1 antibody pembrolizumab. When they undergo surgery, 16 weeks later, tumor response will be assessed in the surgical specimen. The preoperative design of the trial will allow us to discern the contribution of each immunotherapy to tumor response assessed at surgery, while assuring that all patients also receive standard NET treatment. In addition to the baseline biopsy for cancer diagnosis, a tumor tissue biopsy will be conducted after 6 weeks of treatment. The latter is a standard assessment to measure tumor response to letrozole, protecting patients from delaying breast surgery in case their tumor is unresponsive. The trial requires acceptance of sequential blood sampling, by venipuncture, to study in the blood the anti-tumor immune responses induced by each treatment. Overarching Challenge: By attempting to immunize patients against their tumor the trial hopes to confer them the capacity of rejecting micrometastases, addressing the overarching challenge of reducing the mortality of breast cancer. Response to immunotherapy may avoid chemotherapy, possibly reducing morbidity of treatment. Hypothesis: We will test the hypothesis that in HR+ BC a multi-pronged strategy based on neoadjuvant endocrine therapy and focal RT enhances tumor immunogenicity and enables a response to immunotherapy. Objectives and Study Design: A multi-institutional randomized trial will enroll 64-100 postmenopausal patients with newly diagnosed stage II-III HR+ BC. All patients will receive neoadjuvant NET and tumor RT (either alone [Arm 1], or with addition of anti-PD-1 [Arm 2], FLT3L [Arm 3] or anti-PD-1 +FLT3L [Arm 4]). Objective 1: Safety and feasibility of adding immunotherapy to a combination of radiotherapy and endocrine therapy in the neoadjuvant setting of newly diagnosed HR+ BC patients. Tolerability will be demonstrated if no grade 3 or higher toxicities are observed in the first 8 patients of each arm of the trial.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910142
Entities
People
- Sandra Demaria
Organizations
- United States Army
- Weill Cornell Medicine