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Immunotherapeutic Synergy Between Chemotherapy and A Breast Cancer Vaccine
Tumor Cell Biology IV
Background: The success of therapeutic breast cancer vaccines is potentially limited by both redundant mechanisms of immune tolerance, and established burdens of disease. Combining a HER-2/neu-targeted, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting vaccine with low dose Cyclophosphamide (CY) and Doxorubicin (DOX) overcomes immune tolerance in neu mice, curing up to 40% of mice compared to chemotherapy (0%) or vaccination (0%) alone. CY abrogates the negative influence of CD4+CD25+ regulatory T cells (Tregs), facilitating the de novo recruitment of highly avid T cells specific for an immunodominant HER-2/neu epitope. We are now testing this promising vaccination strategy in an active clinical trial. Objective/Hypothesis: The overarching objective of this proposal is to develop an effective vaccination strategy that abrogates immune tolerance in breast cancer patients, thereby enhancing the magnitude and quality of vaccine-induced CD8+ T cell responses. Specific Aims: (1) Determine the impact of CY on vaccine-mediated immune priming; and (2) Characterize the magnitude and quality of the systemic HER-2/neu-specific CD8+ T cell response by measuring their function and avidity. Study Design: We have an ongoing Phase I clinical study evaluating a human allogeneic GM-CSF-secreting breast tumor vaccine (given Day 0) in a specifically timed sequence with CY (given Day -1) and DOX (given Day +7) in 30 patients with stable metastatic breast cancer. The study design is a 3 X 3 factorial designed to identify the optimal combination of CY (250, 350, and 450 mg/m2) and DOX (15, 25, and 35 mg/m2) that maximize vaccine-induced immune responses. Here, we will analyze the impact of CY on immune priming by characterizing CY-mediated changes in Tregs by flow cytometry, and the evolution of cellular infiltrates with and without CY in vaccine site biopsies by immunohistochemistry. We will also characterize HER-2/neu-specific CD8+ T cell immune responses by ELISPOT (cytokine secretion), tetramer analysis (T cell avidity), and CD107a assay (lytic activity). Immune responses will be modeled as a quadratic or cubic, and fit to the trial design matrix as an immune response surface in a third dimension. The maximum will identify the optimal combination of CY, DOX, and vaccine. Potential Outcomes and Benefits of the Research: An innovative feature of this work is the continued translation of data between the laboratory and the patient bedside. This proposal aims to characterize immunoregulatory pathways that impact the vaccine-induced immune response directly in patients with stable metastatic breast cancer. The knowledge gained should lay the groundwork for incisively manipulating the key regulatory pathways controlling vaccine-induced antitumor immune responses, and guide the development of future trials evaluating vaccines for the secondary and primary prevention of breast cancer.
Breast cancer vaccines offer a unique strategy for breast cancer treatment, aiming to re-educate the patients own immune system (T cells) to seek out and destroy breast cancer cells. Using vaccines to treat cancer (as compared to preventing it) presents two major challenges. First, the amount of tumor with progressing disease most often outmatches the ability of the immune system to respond. Second, the immune system has adapted to the breast cancer by the time it is widespread, developing multiple ways to "tolerate" the breast cancer cells. We have developed a strategy for treatment with a granulocyte-macrophage colony-stimulating factor- GM-CSF-secreting breast tumor vaccine combined with low doses of chemotherapy (Cyclophosphamide and Doxorubicin) in patients with stable (non-progressing) metastatic breast cancer. In this case, the chemotherapy is given prior to vaccination in order to knock out the regulatory T cells that turn the antitumor immune response off, allowing the vaccine to induce a stronger, higher quality tumor-specific T cell response that can kill breast tumor cells. Here, we propose a series of laboratory studies using the blood from patients treated with chemotherapy-modulated vaccination to dissect the way in which the chemotherapy and vaccine interact to improve the T cell response. What we learn from these studies should help us to develop practical strategies for incorporating breast tumor vaccines into standard approaches for treating patients with metastatic breast cancer, early breast cancer at high risk for relapse, and ultimately for applying vaccination to breast cancer prevention.