Immunotherapeutic effects of intratumoral nanoplexed poly I:C
Immunotherapeutic effects of intratumoral nanoplexed poly I:C
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DOI：
10.1186/s40425-019-0568-2
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发表时间：
2019-05-02
影响因子：
10.9
通讯作者：
Melero, Ignacio
中科院分区：
文献类型：
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作者：
Angela Aznar, M.;Planelles, Lourdes;Melero, Ignacio
Poly I：C由于其对TLR-3、MDA 5和RIG-I的激动剂活性而成为强大的免疫佐剂。BO-112是聚I：C与聚乙烯亚胺复合的纳米复合物制剂，其引起肿瘤细胞凋亡，显示免疫原性细胞死亡特征，并且在肿瘤内释放后导致T淋巴细胞更显著的肿瘤浸润。用BO-112对源自MC 38、4 T1和B16-F10的皮下肿瘤进行瘤内治疗导致依赖于1型干扰素和γ-干扰素的显著的局部疾病控制。在携带双侧B16-OVA黑色素瘤的小鼠中发现BO-112瘤内治疗后对非注射肿瘤病变的一定程度的控制，用全身性抗CD 137和抗PD-L1 mAb共治疗增强了该活性。在B16-OVA肿瘤引流淋巴结和肿瘤内BO-112治疗后的肿瘤微环境中发现更丰富的CD 8（+）T淋巴细胞，肿瘤抗原特异性细胞毒性T淋巴细胞的数量增加。注射肿瘤病灶的全基因组转录组分析与I型干扰素途径的显著上调一致。受这些数据的启发，肿瘤内递送的BO-112正在癌症患者中进行测试（NCT 02828098）。
Poly I:C is a powerful immune adjuvant as a result of its agonist activities on TLR-3, MDA5 and RIG-I. BO-112 is a nanoplexed formulation of Poly I:C complexed with polyethylenimine that causes tumor cell apoptosis showing immunogenic cell death features and which upon intratumoral release results in more prominent tumor infiltration by T lymphocytes. Intratumoral treatment with BO-112 of subcutaneous tumors derived from MC38, 4T1 and B16-F10 leads to remarkable local disease control dependent on type-1 interferon and gamma-interferon. Some degree of control of non-injected tumor lesions following BO-112 intratumoral treatment was found in mice bearing bilateral B16-OVA melanomas, an activity which was enhanced with co-treatment with systemic anti-CD137 and anti-PD-L1 mAbs. More abundant CD8(+) T lymphocytes were found in B16-OVA tumor-draining lymph nodes and in the tumor microenvironment following intratumoral BO-112 treatment, with enhanced numbers of tumor antigen-specific cytotoxic T lymphocytes. Genome-wide transcriptome analyses of injected tumor lesions were consistent with a marked upregulation of the type-I interferon pathway. Inspired by these data, intratumorally delivered BO-112 is being tested in cancer patients (NCT02828098).