Immunostimulatory bacterial antigen-armed oncolytic measles virotherapy significantly increases the potency of anti-PD1 checkpoint therapy
Immunostimulatory bacterial antigen-armed oncolytic measles virotherapy significantly increases the potency of anti-PD1 checkpoint therapy
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DOI：
10.1172/jci141614
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发表时间：
2021-07-01
影响因子：
15.9
通讯作者：
Galanis, Evanthia
中科院分区：
文献类型：
--
作者：
Panagioti, Eleni;Kurokawa, Cheyne;Galanis, Evanthia
临床免疫治疗方法在治疗胶质母细胞瘤（GBM）方面缺乏疗效。在这项研究中，我们试图使用幽门螺杆菌中性粒细胞激活蛋白（NAP）（一种有效的 TLR2 激动剂）作为溶瘤麻疹病毒（MV）平台中表达的免疫刺激转基因，逆转局部和全身 GBM 诱导的免疫抑制，重新定位以允许病毒通过尿激酶型纤溶酶原激活剂受体（uPAR）进入。虽然单药鼠抗 PD1 治疗或用 MV-s-NAP-uPA 重复原位免疫在 MV 耐药同基因 GBM 模型中提供了一定的生存获益，但联合治疗产生了协同作用，颅内 GL261 肿瘤小鼠的治愈率为 80%，CT-2A 肿瘤小鼠的治愈率为 72%。 NAP-免疫病毒联合疗法诱导小鼠大脑中淋巴细胞大量涌入，其中 CD8+ T 细胞占主导地位；治疗效果依赖于 CD8+ T 细胞。使用 JAK1/JAK2 抑制剂鲁索替尼抑制 IFN 反应途径可降低大脑中骨髓源性抑制细胞的 PD-L1 表达，并进一步增强 MV-s-NAP-uPA 和抗 PD1 的治疗效果。我们的研究结果支持这样的观点，即携带细菌免疫刺激抗原的 MV 菌株代表了一种有效的策略，可以克服 GBM 中基于免疫检查点抑制剂的疗法的有限疗效，为这种致命的脑肿瘤创造一种有前途的转化策略。
Clinical immunotherapy approaches are lacking efficacy in the treatment of glioblastoma (GBM). In this study, we sought to reverse local and systemic GBM-induced immunosuppression using the Helicobacter pylori neutrophil-activating protein (NAP), a potent TLR2 agonist, as an immunostimulatory transgene expressed in an oncolytic measles virus (MV) platform, retargeted to allow viral entry through the urokinase-type plasminogen activator receptor (uPAR). While single-agent murine anti-PD1 treatment or repeat in situ immunization with MV-s-NAP-uPA provided modest survival benefit in MV-resistant syngeneic GBM models, the combination treatment led to synergy with a cure rate of 80% in mice bearing intracranial GL261 tumors and 72% in mice with CT-2A tumors. Combination NAP-immunovirotherapy induced massive influx of lymphoid cells in mouse brain, with CD8+ T cell predominance; therapeutic efficacy was CD8+ T cell dependent. Inhibition of the IFN response pathway using the JAK1/JAK2 inhibitor ruxolitinib decreased PD-L1 expression on myeloid-derived suppressor cells in the brain and further potentiated the therapeutic effect of MV-s-NAP-uPA and anti-PD1. Our findings support the notion that MV strains armed with bacterial immunostimulatory antigens represent an effective strategy to overcome the limited efficacy of immune checkpoint inhibitor-based therapies in GBM, creating a promising translational strategy for this lethal brain tumor.