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Localized Multi-Component Delivery Platform Generates Local and Systemic Anti-Tumor Immunity

机译：本地化多成分递送平台可产生局部和全身性抗肿瘤免疫力

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摘要

As tumors employ complementary overlapping and/or independent mechanisms to evade immune surveillance, many emerging cancer immunotherapies attempt to target multiple pathways to eradicate malignant cells. Although modulation of independent pathways by simultaneous administration of multiple immune modulators (e.g., checkpoint inhibitors, cytokines, and growth factors) has shown great promise, the clinical impact remains limited due to severe toxicity associated with high systemic levels of many of these drugs. Therefore, novel platforms for efficient delivery of multicomponent therapies at lower effective doses would be enabling. Here, a drug delivery platform called immunomodulatory molecule delivery system (iMods), which provides sustained extracellular delivery of a checkpoint inhibitor (antiPD-L1) and simultaneously, targeted intracellular delivery of a tumor antigen (OVA) along with adjuvant (poly(I: C)), and the indoleamine deoxygenase inhibitor 1-MT is described. In melanoma tumor-bearing mice, combinatorial delivery of these factors with iMods leads to regression of both treated and untreated (contralateral) melanoma tumors and 100% survival. These promising therapeutic outcomes are attributed to significantly enhanced ratios of anti-tumor CD8 T-cell/tumor-protective regulatory T-cell (Treg) in tumors and tumor draining lymph nodes. Overall, the iMods delivery platform described here represents a promising advance in multi-factor cancer immunotherapy.
机译：由于肿瘤采用互补的重叠和/或独立机制来逃避免疫监视，因此许多新兴的癌症免疫疗法试图靶向多种途径根除恶性细胞。尽管通过同时施用多种免疫调节剂（例如检查点抑制剂，细胞因子和生长因子）来调节独立途径已显示出巨大的希望，但由于与许多这类药物的高全身性相关的严重毒性，临床影响仍然有限。因此，以较低有效剂量有效递送多组分疗法的新型平台将成为可能。在这里，一个称为免疫调节分子递送系统（iMods）的药物递送平台可提供检查点抑制剂（antiPD-L1）的持续细胞外递送，并同时提供肿瘤抗原（OVA）和佐剂（poly（I： C）），并描述了吲哚胺脱氧酶抑制剂1-MT。在带有黑素瘤肿瘤的小鼠中，这些因子与iMods的组合递送可导致治疗和未治疗（对侧）黑素瘤肿瘤的消退和100％的存活率。这些有希望的治疗结果归因于肿瘤和引流淋巴结中抗肿瘤CD8 T细胞/肿瘤保护性调节性T细胞（Treg）的比率显着提高。总体而言，此处描述的iMods交付平台代表了多因素癌症免疫疗法中的有希望的进步。

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  • 来源
    《Advanced Functional Materials》 |2017年第5期|1604366.1-1604366.11|共11页
  • 作者

    Acharya Abhinav P.; Sinha Mantosh; Ratay Michelle L.; Ding Xiaochu; Balmert Stephen C.; Workman Creg J.; Wang Yadong; Vignali Dario A. A.; Little Steven R.;

  • 作者单位

    Univ Pittsburgh, Dept Chem & Petr Engn, Pittsburgh, PA 15231 USA;

    Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15231 USA;

    Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15231 USA;

    Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15231 USA;

    Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15231 USA;

    Univ Pittsburgh, Dept Immunol, Sch Med, Pittsburgh, PA 15231 USA|Univ Pittsburgh, Tumor Microenvironm Ctr, Canc Inst, Pittsburgh, PA 15231 USA;

    Univ Pittsburgh, Dept Chem & Petr Engn, Pittsburgh, PA 15231 USA|Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15231 USA|Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA 15231 USA;

    Univ Pittsburgh, Dept Immunol, Sch Med, Pittsburgh, PA 15231 USA|Univ Pittsburgh, Tumor Microenvironm Ctr, Canc Inst, Pittsburgh, PA 15231 USA;

    Univ Pittsburgh, Dept Chem & Petr Engn, Pittsburgh, PA 15231 USA|Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15231 USA|Univ Pittsburgh, Dept Immunol, Sch Med, Pittsburgh, PA 15231 USA|Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA 15231 USA|Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15231 USA|Univ Pittsburgh, Dept Ophthalmol, Pittsburgh, PA 15231 USA;

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