Project Summary Cancer and cardiovascular disease are leading causes of death in the United States. Given the high percentage of cancer patients with co-existing atherosclerosis, the development of cancer therapeutics that prevent progression of atherosclerosis have the potential to align cancer therapy goals with favorable cardiovascular outcomes. Hyaluronic acid (HA) has unique properties that are desirable for the development of biocompatible and biodegradable nanoparticle drug delivery systems for both cancer and atherosclerosis. We have developed a hyaluronic acid nanoparticle (HANP) conjugated with PD1 memetic peptides that target and block immune checkpoint protein PD-L1 and carry the cholesterol-lowering drug Avasimibe (PD1Y-HANP/Ava). Avasimibe is a multifunctional agent that decreases cholesterol accumulation, inhibits tumor cell growth, and enhances immune response by activating cytotoxic T cells. We found that systemic administrations of PD1Y-HANP/Ava led to targeted delivery into tumors and atherosclerotic plaques, inhibition of tumor growth and atherosclerosis progression, and significant improvement in mouse survival in a dual mouse cancer and atherosclerosis model. In this study, we hypothesize that systemic delivery of urokinase plasminogen activator receptor (uPAR), PD- L1 and CD44 co-targeted HANP carrying Avasimibe (ATF/PD1Y-HANP/Ava) leads to the efficient delivery of the HANP/Ava into tumors and atherosclerotic plaques, resulting in a significant anti-tumor growth effect by direct inhibition of tumor cell proliferation, activation of cytotoxic CD8+ T cells, and pro-immune modulatory effect of ATF/PD1Y-HANP/Ava in tumor microenvironment. We further hypothesize that delivery of targeted PD1Y- HANP/Ava into atherosclerotic plaques decreases cholesterol-rich macrophages and infiltrating immune cells, and thereby prevents atherosclerosis progression. To develop and validate the proposed immunotherapy, we will first develop ATF/PD1Y-HANP/Ava and examine the efficiency of targeted delivery in metastatic mouse colon cancer models (Aim 1). Therapeutic efficacy and immune responses following targeted PD1Y-HANP/Ava treatment, alone or in combination with a chemotherapy drug, irinotecan, will be evaluated in the mouse cancer models (Aim 1). We will then determine the effect of the targeted PD1Y-HANP/Ava on targeted delivery, immune responses and therapeutic efficacy in tumor and atherosclerotic plaques in a dual mouse colon cancer and atherosclerosis model (Aim 2). Immunological analysis of tumors and atherosclerotic plaques will allow us to determine therapy-related changes in immune cell types and functions, especially CD8+ T cell activity. We will then investigate the feasibility of translation in cancer patients by examining targeted delivery and direct cytotoxic effect of the targeted PD1Y-HANP/Ava in colon cancer patient derived xenograft models (Aim 3). Finally, pharmacokinetics, toxicity, biodistribution and systemic immune responses will be determined in mice (Aim 4). Results of this research should provide us with preclinical data for translational development of a phase 1 clinical trial using this novel targeted immunotherapy for metastatic colon cancer patients with comorbid atherosclerosis.

Project Narrative The overarching goal of this translational research project is to develop a new targeted cancer immunotherapy using a biocompatible and bioactive nanoparticle drug delivery system for the treatment of cancer patients with comorbid atherosclerosis or at a high risk of developing atherosclerosis. The proposed research project aims to develop a multifunctional immunomodulatory nanoparticle with the ability of targeted delivery into tumors and atherosclerotic plaques, inhibition of tumor cell growth, activation of anti-tumor immune responses and cytotoxic T cell function, and reduction of cholesterol-rich macrophages and effector T cells in atherosclerotic plaques. The effects of the targeted nanoparticle/drug on the inhibition of progression of metastatic colon cancer and atherosclerosis and the improvement of overall survival will be evaluated in mouse colon tumor models, dual mouse colon and atherosclerosis models, and human colon cancer patient derived xenograft models for feasibility of future clinical translation.