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    Research Grants Awarded

    Enhancing Antitumor Cytotoxic T Lymphocyte Function Using HER-2/neu-Specific Monoclonal Antibodies

    Study Section:
    Tumor Cell Biology III

    Scientific Abstract:
    Background: Current HER-2/neu (neu)-directed therapies target the inhibition of neu signal transduction or the induction of antibody-dependent cell cytotoxicity. However, data from our laboratory demonstrate that the co-administration of neu-specific monoclonal antibodies (mAbs) with neu-targeted vaccine induces a potent T cell response that results in the elimination of established tumors. The mechanisms underlying this synergy are not yet defined, but the data indicate that the administration of neu-specific mAbs enhances the antitumor effector function of neu-specific CD8+ T cells. These data suggest an as-yet unexplored antitumor mechanism associated with the administration of neu-specific mAbs. Objective/Hypothesis: Antitumor T cells can be found in cancer patients without evidence of immune-mediated tumor destruction. Among the explanations for this paradoxical finding is the apparent inability of activated antitumor T cells in the periphery to migrate efficiently to sites of tumor. Based on our preliminary data, as well as data from others, we hypothesize that antigen-presenting cells (APC) located within the tumor recognize tumor cells that are opsinized with mAbs. Binding of the mAbs facilitates neu antigen acquisition by and maturation of the APC, which then move to the draining LN and activate vaccine-expanded tumor-specific T cells for trafficking to the tumor site. Specific Aims: To 1) Characterize the role of neu-specific mAbs in priming of antitumor CD8+ T cells. 2) Determine the effects of neu-specific mAbs on tumor-infiltration by antitumor CD8+ T cells. 3) Define the tissue-selective factors involved in the trafficking of antitumor CD8+ T cells to mammary tumors. Study Design: In the first Aim we will use in vitro co-culture assays as well as in vitro and in vivo T cell proliferation assays to characterize the role of neu-specific mAbs in enhancing DC phagocytosis of tumor cells and cross-priming of CD8+ T cells. In Aim II, we will isolate tumor-infiltrating CD8+ T cell in order to characterize the effects of neu-specific mAbs on CD8+ T cell infiltration into mammary tumors. In the final Aim, we will analyze activated neu-specific CD8+ T cells obtained from the tumor-draining lymph nodes of neu-N mice treated with neu-specific mAbs in order to characterize the expression of T cell tissue-selective factors. Potential Outcomes and Benefits of the Research: This proposal seeks to characterize antibody-mediated enhancement of CD8+ T cell function as a novel antitumor mechanism for neu-targeted mAbs. In addition, we propose to identify the tissue-selective factors that aid in T cell trafficking to mammary tumors. These studies will provide a solid mechanistic base upon which to move forward with clinical trials of neu-specific mAb with the neu-targeted vaccine that is currently in clinical development by our lab.

    Lay Abstract:
    Background: Current HER-2/neu (neu)-directed therapies have failed to explore the potential of neu-specific monoclonal antibodies (mAbs) to activate the T cell arm of the immune system for antitumor T cell effector function. However, data from our laboratory demonstrate that the co-administration of neu-specific monoclonal antibodies (mAbs) with neu-targeted vaccine induces a potent T cell response that results in the elimination of established tumors. The mechanisms underlying this synergy are not yet defined, but the data indicate that the administration of neu-specific mAbs enhances the antitumor effector function of neu-specific CD8+ T cells. These data suggest an as-yet unexplored antitumor mechanism associated with the administration of neu-specific mAbs. Objective/Hypothesis : Antitumor T cells can be found in cancer patients without evidence of immune-mediated tumor destruction. Among the explanations for this paradoxical finding is the apparent inability of activated antitumor T cells to migrate efficiently to sites of tumor. Based on our preliminary data, as well as data from others, we hypothesize that antigen-presenting cells (APC), which are the key initiators of T cell responses, located within the tumor recognize tumor cells that are coated with mAbs. Binding of the mAbs facilitates tumor cell engulfment by the APC. The APC are then able to activate antitumor T cells and direct their migration back to the tumor site. Specific Aims: To 1) Characterize the role of neu-specific mAbs in priming of antitumor T cells. 2) Determine the effects of neu-specific mAbs on tumor-infiltration by antitumor T cells. 3) Define the tissue-selective factors involved in the migration of antitumor T cells to mammary tumors. Study Design: In the first Aim we will characterize the ability of neu-specific mAbs to increase tumor cell engulfment by APC and assess the ability of the APC to activate antitumor T cells. In Aim II, we will analyze the ability of neu-specific mAbs to induce T cell migration to sites of mammary tumors. In the final Aim, we will isolate T cells from mice treated with neu-specific mAbs in order to identify the factors on the T cell surface that aid in their specific migration to mammary tumors. Potential Outcomes and Benefits of the Research: This proposal seeks to characterize antibody-mediated enhancement of antitumor T cell function as a novel antitumor mechanism for neu-targeted mAbs. In addition, we propose to identify the tissue-selective factors that aid in T cell trafficking to mammary tumors. These studies will provide a solid mechanistic base upon which to move forward with clinical trials of neu-specific mAb with the neu-targeted vaccine that is currently in clinical development by our lab.