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  • br Bo Sun br Laboratory of Nano and Translational

    2020-08-07


    Bo Sun
    Laboratory of Nano- and Translational Medicine
    Carolina Center for Cancer Nanotechnology Excellence Carolina Institute of Nanomedicine Lineberger Comprehensive Cancer Center
    Department of Radiation Oncology University of North Carolina at Chapel Hill
    Yanfei Qi
    School of Public Health
    Jilin University Changchun, Jilin, P. R. China
    Kyle Wagner
    Laboratory of Nano- and Translational Medicine Carolina Center for Cancer Nanotechnology Excellence
    Carolina Institute of Nanomedicine Lineberger Comprehensive Cancer Center Department of Radiation Oncology
    University of North Carolina at Chapel Hill
    Stephanie Montgomery
    Department of Pathology and Laboratory Medicine University of North Carolina at Chapel Hill
    Tian Zhang
    Department of Medicine Duke University Medical Center
    Andrew Z. Wang
    Laboratory of Nano- and Translational Medicine Carolina Center for Cancer Nanotechnology Excellence Carolina Institute of Nanomedicine
    Lineberger Comprehensive Cancer Center Department of Radiation Oncology University of North Carolina at Chapel Hill
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    Optimizing Advances in Nanoparticle Delivery for Cancer Immunotherapy
    Joseph M. Caster, MD/PhD; Cameron Callaghan, MD; Steven N. Seyedin, MD; Kelly Henderson, MS, MBA; Bo Sun, PhD; Andrew Z. Wang, MD
    Table of Contents
    1. Introduction
    2. Overcoming Barriers to Nanoparticle (NP) Delivery 2.1 Targeting Specific Cell Populations
    2.2 Enhancing Endosomal Escape
    3. Using NPs to Enhance Cancer Immunotherapy
    3.1 Enhancing Antigen Delivery
    3.1.1 Co-Delivery of Exogenous Antigens and Immune Adjuvants to antigen presenting 147852-83-3 (APCs)
    3.1.2 Enhancing Antigenic Presentation of Endogenous Tumor Neoantigens
    3.2 Activating Effector Cells
    3.2.1 Enhancing T-cell Checkpoint Inhibition
    3.2.2 NP Delivery of T-cell Activators
    3.3 Modulating the Tumor Microenvironment
    3.3.1 Targeting Tumor Associated Macrophages (TAMs)
    3.3.3 Targeting Tumor Associated Fibroblasts (TAFs)
    3.4 Targeting Tumor Cells
    4. Enhancing T-cell Therapy
    5. Summary and Conclusions
    1. Introduction
    Cancer immunotherapy is one of the most rapidly evolving fields in clinical medicine. Cancer immunotherapy includes a broad collection of therapies which aim to improve the ability of the immune system to recognize and eliminate tumors. Enthusiasm for cancer immunotherapy is well-supported by the clinical literature. T-cell checkpoint inhibitors, drugs that prevent CD8+ T-cell inactivation by blocking specific inhibitory receptors on the T-cell surface, have produced remarkable improvements in long-term survival for patients with aggressive cancers including metastatic melanoma and non-small cell lung cancer (NSCLC) not seen with traditional chemotherapies1-4. However, there are a number of challenges facing the field of cancer immunotherapy. Many common cancers, including microsatellite stable (MSS) colorectal cancers, are poorly responsive to T-cell checkpoint inhibitors5. Even among highly immunogenic histologies like melanoma, less than half of patients can expect to achieve long-term disease control. Numerous mechanisms of resistance to current cancer immunotherapies have been identified including the presence of numerous immunosuppressive cell populations in the tumor microenvironment (TME), poor tumor infiltration by activated CD8+ T-cells, and cytokine-mediated conversion of mesenchymal or immunogenic cell populations into immunosuppressive variants6-8. Many novel drugs (including cytokines and immune-stimulators) and nucleic acid therapies have been proposed as potential solutions to these mechanisms of resistance. However, their clinical translation with conventional drug delivery has been challenging. Immune stimulating drugs can be very toxic when administered systemically. Selectively depleting immunosuppressive cell populations without concomitantly depleting pro-immunogenic populations that are necessary for establishing sustained
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    antitumor immunity is difficult. Nucleic acids and recombinant proteins require targeted and efficient intracellular delivery to relevant cell populations in order to be effective. Finally, many immune modulators require simultaneous or near-simultaneous activation of multiple signals in target cells to exert their maximal effect. Intensive research efforts have been devoted to finding appropriate drug delivery solutions and novel nanomedicines appear well-positioned to meet many of these challenges.