In Vivo Expansion of Melanoma-Specific T Cells Using Microneedle Arrays Coated with Immune-Polyelectrolyte Multilayers.
In Vivo Expansion of Melanoma-Specific T Cells Using Microneedle Arrays Coated with Immune-Polyelectrolyte Multilayers.
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DOI：
10.1021/acsbiomaterials.6b00414
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发表时间：
2017-02-13
影响因子：
5.8
通讯作者：
Jewell CM
中科院分区：
文献类型：
--
作者：
Zeng Q;Gammon JM;Tostanoski LH;Chiu YC;Jewell CM
微针（MN）是微米级的聚合物或金属结构，通过有效靶向皮肤驻留免疫细胞，消除注射相关疼痛，提高患者依从性，为疫苗提供独特的优势。这些优点，沿着最近的研究显示使用传统皮内注射在人类癌症患者中实现的治疗益处，表明MN递送可能增强癌症疫苗和免疫疗法。我们最近开发了一类新的基于模型肽抗原和分子Toll样受体激动剂（TLRa）自组装成纳米共形涂层的纳米多层膜。在这里，我们推断，这些免疫粘附多层膜（iPEM）可能是一个有用的平台，用于组装癌症疫苗组件的MN阵列从这些基板的皮内递送。使用保守的人黑色素瘤抗原和有效的TLRa疫苗佐剂CpG，我们表明iPEM可以以自动化的方式组装在MN上。这些膜由多达128层制备，约200 nm厚，但提供>225 μg/cm 2的癌症疫苗负载。在细胞培养中，从MN释放的iPEM货物被原代树突状细胞内化，促进这些细胞的活化，并在共培养期间扩增T细胞。在小鼠中，iPEM包被的MN的应用导致肿瘤抗原和CpG通过皮肤的共递送，在初始MN应用期间扩增肿瘤特异性T细胞，并在随后的加强MN应用期间导致更大的记忆回忆反应。这项研究支持用由肿瘤疫苗组分构建的PEM包被的MN作为一种定义明确的模块化系统，用于产生肿瘤特异性免疫应答，从而实现可以与检查点阻断或其他组合癌症疗法相结合探索的新方法。
Microneedles (MNs) are micron-scale polymeric or metallic structures that offer distinct advantages for vaccines by efficiently targeting skin-resident immune cells, eliminating injection-associated pain, and improving patient compliance. These advantages, along with recent studies showing therapeutic benefits achieved using traditional intradermal injections in human cancer patients, suggest MN delivery might enhance cancer vaccines and immunotherapies. We recently developed a new class of polyelectrolyte multilayers based on the self-assembly of model peptide antigens and molecular toll-like receptor agonists (TLRa) into ultrathin, conformal coatings. Here, we reasoned that these immune polyelectrolyte multilayers (iPEMs) might be a useful platform for assembling cancer vaccine components on MN arrays for intradermal delivery from these substrates. Using conserved human melanoma antigens and a potent TLRa vaccine adjuvant, CpG, we show that iPEMs can be assembled on MNs in an automated fashion. These films, prepared with up to 128 layers, are approximately 200 nm thick but provide cancer vaccine cargo loading >225 μg/cm2. In cell culture, iPEM cargo released from MNs is internalized by primary dendritic cells, promotes activation of these cells, and expands T cells during coculture. In mice, application of iPEM-coated MNs results in the codelivery of tumor antigen and CpG through the skin, expanding tumor-specific T cells during initial MN applications and resulting in larger memory recall responses during a subsequent booster MN application. This study support MNs coated with PEMs built from tumor vaccine components as a well-defined, modular system for generating tumor-specific immune responses, enabling new approaches that can be explored in combination with checkpoint blockade or other combination cancer therapies.