Immune Checkpoint Blockade, Immunogenic Chemotherapy or IFN-α Blockade Boost the Local and Abscopal Effects of Oncolytic Virotherapy
Immune Checkpoint Blockade, Immunogenic Chemotherapy or IFN-α Blockade Boost the Local and Abscopal Effects of Oncolytic Virotherapy
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DOI：
10.1158/0008-5472.can-16-2165
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发表时间：
2017-08-01
期刊：
影响因子：
11.2
通讯作者：
Zitvogel, Laurence
中科院分区：
文献类型：
--
作者：
Fend, Laetitia;Yamazaki, Takahiro;Zitvogel, Laurence
尽管溶瘤病毒的局部治疗的临床疗效已得到证实，但其诱导免疫介导的远处转移消退的能力仍缺乏文献记载。我们在这里报告，工程化的溶瘤痘苗病毒VVWR-TK- RR-Fcu 1可以诱导免疫原性细胞死亡，并产生全身免疫应答。对肿瘤生长和存活的影响主要由CD 8（+）T细胞驱动，肿瘤中的免疫细胞浸润可以重新编程为效应T细胞与调节性CD 4（+）T细胞的比例更高。1型IFN途径在溶瘤病毒治疗中的关键作用也被强调，因为我们在Ifnar（-/-）肿瘤中观察到强烈的远位应答。在该模型中，将病毒直接单次给予一侧侧腹的肿瘤导致对侧侧腹的消退。此外，当溶瘤治疗与免疫原性化疗或免疫检查点阻断相结合时，这些作用进一步增强。综上所述，我们的研究结果表明，如何安全地提高局部溶瘤病毒疗法在肿瘤特征为IFNa信号失调的患者中的疗效。(C)2017年AACR。
Athough the clinical efficacy of oncolytic viruses has been demonstrated for local treatment, the ability to induce immune-mediated regression of distant metastases is still poorly documented. We report here that the engineered oncolytic vaccinia virus VVWR- TK- RR- Fcu1 can induce immunogenic cell death and generate a systemic immune response. Effects on tumor growth and survival was largely driven by CD8(+) T cells, and immune cell infiltrate in the tumor could be reprogrammed toward a higher ratio of effector T cells to regulatory CD4(+) T cells. The key role of type 1 IFN pathway in oncolytic virotherapy was also highlighted, as we observed a strong abscopal response in Ifnar(-/-) tumors. In this model, single administration of virus directly into the tumors on one flank led to regression in the contralateral flank. Moreover, these effects were further enhanced when oncolytic treatment was combined with immunogenic chemotherapy or with immune checkpoint blockade. Taken together, our results suggest how to safely improve the efficacy of local oncolytic virotherapy in patients whose tumors are characterized by dysregulated IFNa signaling. (C) 2017 AACR.