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WIREs Nanomed Nanobiotechnol
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Combining nanomedicine and immune checkpoint therapy for cancer immunotherapy

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Abstract Cancer immunotherapy has emerged as a pillar of the cancer therapy armamentarium. Immune checkpoint therapy (ICT) is a mainstay of modern immunotherapy. Although ICT monotherapy has demonstrated remarkable clinical efficacy in some patients, the majority do not respond to treatment. In addition, many patients eventually develop resistance to ICT, disease recurrence, and toxicity from off‐target effects. Combination therapy is a keystone strategy to overcome the limitations of monotherapy. With the integration of ICT and any therapy that induces tumor cell lysis and release of tumor‐associated antigens (TAAs), ICT is expected to strengthen the coordinated innate and adaptive immune responses to TAA release and promote systemic, cellular antitumor immunity. Nanomedicine is well poised to facilitate combination ICT. Nanoparticles with delivery and/or immunomodulation capacities have been successfully combined with ICT in preclinical applications. Delivery nanoparticles protect and control the targeted release of their cargo. Inherently immunomodulatory nanoparticles can facilitate immunogenic cell death, modification of the tumor microenvironment, immune cell mimicry and modulation, and/or in situ vaccination. Nanoparticles are frequently multifunctional, combining multiple treatment strategies into a single platform with ICT. Nanomedicine and ICT combinations have great potential to yield novel, powerful treatments for patients with cancer. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies
Cancer‐immunity cycle and checkpoint immunotherapy targets. Schematic view of the cyclic process through which the immune system generates a response to cancer. Checkpoints within this cycle provide regulatory negative (inhibitory checkpoints, red inhibition symbols) or positive (stimulatory checkpoints, green arrows) feedback mechanisms to attenuate or augment to anti‐tumor immune response. Key steps include tumor lysis (1), which can be induced by cytotoxic immune cells or by cancer therapies (radiation, chemotherapy, heat or cryoablation are shown here). Damaged tumor cells release TAAs into the tumor microenvironment. With local inflammation, APCs process and transport TAAs to draining lymph nodes (2, 3). Cross‐presentation of antigens to T cells leads to activation of tumor‐reactive T cells (4). Circulating activated tumor‐reactive T cells migrate to and infiltrate tumors (5, 6). Interactions with the TME may suppress or promote their anti‐tumor effector functions, mediated through immune checkpoint signaling. APC, antigen presenting cell; B7, B7 co‐stimulatory protein; CTLA‐4, cytotoxic T‐lymphocyte‐associated antigen 4; LAG‐3, lymphocyte‐activation gene 3; MHC, major histocompatibility complex molecule; OX40, OX40 co‐stimulatory receptor; OX40L, OX40 ligand; PD‐1, programmed cell death‐1 receptor; PD‐L1, programmed cell death‐1 ligand; TAA, tumor‐associated antigen; TIM‐3, T‐cell immunoglobulin and mucin‐domain containing molecule 3; TIGIT, T‐cell immunoreceptor with immunoglobulin and ITIM domains; TCR, T‐cell receptor; TIL, tumor‐infiltrating lymphocyte; VISTA, V‐domain Ig‐containing Suppressor of T‐cell Activation; 4‐1BB, 4‐1BB co‐stimulatory receptor; 4‐1BBL, 4‐1BB ligand. Created with BioRender.com
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Nanomedicine and ICT combination strategies aim to improve therapeutic efficacy and reduce systemic toxicity of ICT. Different types of ICT (left circle) can be integrated with a variety of nanoparticle types (right circle) utilizing key design features (intersection of circles). These combinations approaches can use passive targeting, active targeting, and immunomodulation to improve efficacy and decrease toxicity. Abbreviations are as follows: siRNA, small interfering RNA; ICD, immunogenic cell death; TME, tumor microenvironment. Created with BioRender.com
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Schematic overview of nanoparticle strategies for ICT combination. Nanoparticle strategies can be primarily categorized as delivery and immunomodulation approaches. Within delivery strategies, nanoparticles may be designed with active targeting and passive targeting capabilities. Nanoparticles with immunomodulatory function may mimic or modify immune cell function, possess inherent immunogenicity, modify the TME, or induce immunogenic cell death. aAPCs, artificial antigen‐presenting cells; NIR, near infrared; NP, nanoparticle; PTT, photothermal therapy; ROS, reactive oxygen species; TME, tumor microenvironment. Image of plant virus nanoparticle (cowpea mosaic virus) was reproduced from the VIPER database (www.viperdb.scripps.edu). Created with BioRender.com
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An overview of several nanoparticles in development for combination ICT applications. A wide array of nanoparticles and design features are being developed for combination ICT. Synthetic: polymeric lipid and proteinaceous nanoparticles, metallic nanoparticles, liposomes, micelles, and carbon nanotubes. Viral vectors: Adeno‐associated virus. Plant virus‐based nanoparticles: cowpea mosaic virus and tobacco mosaic virus. Multifunctional nanoparticles: multi‐layered nanoparticle containing ICI and chemotherapy‐loaded micelles and magnetic fucodian‐dextran‐iron oxide nanoparticle displaying ICI and T‐cell activator antibodies. Schematic images are not to scale. ICI, immune checkpoint inhibitor; ICT, immune checkpoint therapy. Image of cowpea mosaic virus was reproduced from the VIPER database (www.viperdb.scripps.edu). Created with BioRender.com
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Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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