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Targeting Langerhans Cells for Therapeutic Vaccination in Breast Cancer
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Targeting Langerhans Cells for Therapeutic Vaccination in Breast Cancer
PI: Karolina Palucka
Funding Organization: Susan G. Komen for the Cure
Project Start: May 1, 2007
Project End: April 30, 2009

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. In this context, we have developed prototype human vaccines that are based on targeting DCs. 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-LCs-antigen fusion proteins consisting of anti-ASGPR mAbs and cyclin B1 protein.  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.