Engineering approaches for innate immune-mediated tumor microenvironment remodeling.
Engineering approaches for innate immune-mediated tumor microenvironment remodeling.
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DOI：
10.1016/j.iotech.2023.100406
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发表时间：
2024-03
期刊：
影响因子：
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通讯作者：
Atukorale, P U
中科院分区：
文献类型：
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作者：
Kane, G I;Lusi, C F;Brassil, M L;Atukorale, P U
癌症免疫疗法具有变革性的前景，尤其在致命癌症的治疗方面，因为经过正确训练的免疫系统能够全面协调肿瘤清除，无需持续的治疗干预。从历史上看，大多数免疫疗法都以T细胞为重点，包括免疫检查点抑制剂、嵌合抗原受体T细胞和T细胞疫苗。不幸的是，以T细胞为重点的疗法在大多数实体瘤中未能达到最佳疗效，这主要是因为存在高度免疫抑制的“冷”肿瘤微环境或免疫排斥的肿瘤微环境（TME）。最近，一种快速发展的治疗模式出现了，它侧重于激活肿瘤内驻留的先天性抗原呈递细胞，如树突状细胞和巨噬细胞，这些细胞能够驱动促炎免疫反应，将肿瘤微环境从“冷”或免疫排斥重塑为“热”。肿瘤微环境重塑的早期策略以游离细胞因子和激动剂为中心，但这些方法在递送和疗效方面都面临重大障碍。脱靶炎症导致的全身毒性是这些疗法中至关重要的问题。为了解决这一关键差距，工程方法为细胞因子、激动剂和其他治疗剂提供了增加“内置”功能的机会，以提高递送效率和疗效。这些功能包括保护性封装以防止其降解、靶向使其高特异性地导向肿瘤，以及共递送策略以利用协同促炎途径。在此，我们综述了以细胞因子、先天性免疫激动剂、免疫原性病毒和基于细胞的方法为重点的先天性免疫介导的肿瘤微环境重塑工程方法，强调了新兴的临床前方法和策略，这些方法和策略要么正在临床试验中接受测试，要么已经获得美国食品药品监督管理局批准。
先天性免疫介导的肿瘤微环境重塑可能对招募细胞毒性CD8 + T淋巴细胞并维持其功能至关重要。
工程方法相对于游离免疫刺激剂具有关键优势。
仔细考虑肿瘤微环境的生物学、物理学和化学特性对于制定有效的设计原则是必要的。
给药方法，包括瘤内给药或全身给药，也能提高疗效。
我们描述了以细胞因子、先天性免疫激动剂、病毒和全细胞递送为重点的工程方法。
Cancer immunotherapy offers transformative promise particularly for the treatment of lethal cancers, since a correctly trained immune system can comprehensively orchestrate tumor clearance with no need for continued therapeutic intervention. Historically, the majority of immunotherapies have been T cell-focused and have included immune checkpoint inhibitors, chimeric antigen receptor T cells, and T-cell vaccines. Unfortunately T-cell-focused therapies have failed to achieve optimal efficacy in most solid tumors largely because of a highly immunosuppressed ‘cold’ or immune-excluded tumor microenvironment (TME). Recently, a rapidly growing treatment paradigm has emerged that focuses on activation of tumor-resident innate antigen-presenting cells, such as dendritic cells and macrophages, which can drive a proinflammatory immune response to remodel the TME from ‘cold’ or immune-excluded to ‘hot’. Early strategies for TME remodeling centered on free cytokines and agonists, but these approaches have faced significant hurdles in both delivery and efficacy. Systemic toxicity from off-target inflammation is a paramount concern in these therapies. To address this critical gap, engineering approaches have provided the opportunity to add ‘built-in’ capabilities to cytokines, agonists, and other therapeutic agents to mediate improved delivery and efficacy. Such capabilities have included protective encapsulation to shield them from degradation, targeting to direct them with high specificity to tumors, and co-delivery strategies to harness synergistic proinflammatory pathways. Here, we review innate immune-mediated TME remodeling engineering approaches that focus on cytokines, innate immune agonists, immunogenic viruses, and cell-based methods, highlighting emerging preclinical approaches and strategies that are either being tested in clinical trials or already Food and Drug Administration approved. Innate immune-mediated TME remodeling may be pivotal to recruiting cytotoxic CD8+ T lymphocytes and sustaining their function. Engineering approaches provide key advantages over free immunostimulatory agents. Careful consideration of TME biological, physical, and chemical attributes is necessary to inform effective design principles. Method of administration, including intratumoral or systemic delivery, can also drive efficacy. We describe engineering approaches focused on delivery of cytokines, innate immune agonists, viruses, and whole cells.