Nanoparticle-Modulated Response Against Tumor-Associated Antigens

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DESCRIPTION (provided by applicant): Treatment for cancer has improved survival and delayed tumor recurrence, but challenges such as multidrug resistance and metastasis can still undermine standard therapies. For this reason, immune-mediated approaches focus on recruiting the body's native immune system to recognize and destroy cancer cells. Clinical trials have investigated the feasibility of using peptide epitopes from tumor-associated antigens. Although these approaches have been promising, they rarely invoke a sufficiently strong response. Our long-term goal is to develop a protein nanoparticle technology platform designed to increase the immune system's native ability to recognize and destroy cancer cells expressing tumor-associated antigens. Specifically, we are focused on targeting the cancer/testis (CT) class of antigens. In this proposed work, we will examine the premise that the magnitude and type of immune responses against cancer cells can be more effectively elicited when CT antigens are coupled to nanoparticles of optimal uptake size that are simultaneously functionalized with a dendritic cell-activator molecule. We expect that by combining these elements in a nanoparticle, simultaneous spatial and temporal dosing will yield synergistic effects, thereby improving therapeutic efficacy significantly. To examine this hypothesis, we propose the following specific aims: (1) Fabrication of protein nanoparticles that are functionalized with both CT antigens and a dendritic cell activator; (2) Evaluation of the cytotoxi T-lymphocyte response, in vivo cytokine production, and regulatory T cell activity due to protein nanoparticles bearing a single CT antigen epitope; and (3) Evaluation of the cytotoxic T- lymphocyte response, in vivo cytokine production, and regulatory T cell activity due to protein nanoparticles bearing multiple CT antigen epitopes. This work will evaluate the feasibility of using a nanoparticle-based strategy that has the potential to significantly increase treatment efficacy and to generate general principles for improving cancer vaccines using such technologies. It will determine whether more effective immunotherapy can be achieved by integrating antigens, immune activator, and passive targeting within a single entity. Ultimately, i can potentially provide a new, more effective therapeutic strategy applicable for cancer states that are conventionally difficult to treat.