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    Research Grants Awarded

    Targeting Langerhans cells for therapeutic vaccination in breast cancer

    Study Section:
    Treatment

    Scientific Abstract:
    Background: Subsets of patients with breast cancer continue to have a great unmet medical need as there is no known therapy which can improve clinical outcome. There is substantial evidence from murine and human studies that the immune system can be mobilized to control cancer. This might be best achieved through vaccination, which aims to induce tumor-specific effector T cells that can reduce tumor mass and tumor-specific memory T cells that can control tumor relapse. Owing to their capacity to regulate T-cell immunity, dendritic cells (DCs) are increasingly used as adjuvants for vaccination, and the immunogenicity of antigens delivered on DCs has now been shown in cancer patients. Recent studies in mice demonstrate that the specific targeting of antigen to DCs in vivo results in dramatic improvement of antigen-specific CD4+ and CD8+ T cell immunity (1, 2). In this context, we have developed prototype human vaccines that are based on DC targeting. Furthermore, our studies demonstrate that distinct DC subsets differentially affect lymphocyte differentiation and function. Objective/Hypothesis: Therefore, we propose to develop novel vaccines against breast cancer that will be based on targeting Langerhans cells (LCs), which are particularly efficient in priming specific CD8+ cytotoxic T lymphocytes (CTLs). These novel vaccines consist of recombinant anti-LC monoclonal antibody ? antigen fusion proteins. Specific Aims/Study Design: Aim 1: Construct anti-LC-antigen fusion proteins consisting of anti-ASGPR mAbs and cyclin B1. We will select vaccines in vitro by testing the capacity of ex vivo generated LCs exposed to vaccines to prime antigen-specific CTLs. Aim 2: We will analyze priming of breast cancer antigen-specific CTLs in vivo in humanized mice. Potential Outcomes and Benefits of the Research: This proposal seeks to determine the optimal combination of anti-DC antibody and breast cancer antigen that would permit induction of therapeutic immunity against breast cancer. This will be further developed into clinical grade vaccines that will be tested in human clinical trials.

    Lay Abstract:
    Background: Patients with breast cancer continue to have a great unmet medical need and for some of them there is no known therapy which can improve their clinical outcome. We now know from the research done in the laboratory and in the clinic that the immune systems of the patients can be mobilized to control cancer. This might be best achieved through vaccination. A special type of white blood cell, called dendritic cells (DCs), is increasingly used for vaccination of patients with cancer. Objective/Hypothesis: Research in the past few years has shown that special proteins, called antibodies, can be decorated with pieces of cancer proteins (antigens) and this combination can be taken up by DCs in the body. We have also learned that there are different types of DCs that may have specific functions, and we now know how to distinguish them. Therefore, we want to use this way of making vaccines to develop novel vaccines against breast cancer. Specific Aims/Study Design: In Aim 1, we will make these novel vaccines and select those that work best for further analysis. This selection will be based on studying how these vaccines can educate T cells to kill cancer cells. In Aim 2, we test the selected vaccines in an in vivo model that mimics the cancer in patients to see if these vaccines can educate T cells in the body and if these T cells can kill cancer cells. Potential Outcomes and Benefits of the Research: We will develop novel vaccines against breast cancer. This will be further developed into clinical grade vaccines that will be tested in human clinical trials.