The immune status of the tumor microenvironment is a key indicator in determining the antitumor effectiveness of immunotherapies. Data support the role of activation and expansion of tumor-infiltrating lymphocytes (TILs) in increasing the benefit of immunotherapies in patients with solid tumors. We found that intratumoral injection of a tumor-selective oncolytic vaccinia virus encoding interleukin-7 (IL-7) and IL-12 into tumor-bearing immunocompetent mice activated the inflammatory immune status of previously poorly immunogenic tumors and resulted in complete tumor regression, even in distant tumor deposits. Mice achieving complete tumor regression resisted rechallenge with the same tumor cells, suggesting establishment of long-term tumor-specific immune memory. Combining this virotherapy with anti-programmed cell death-1 (PD-1) or anti-cytotoxic T lymphocyte antigen 4 (CTLA4) antibody further increased the antitumor activity as compared to virotherapy alone, in tumor models unresponsive to either of the checkpoint inhibitor monotherapies. These findings suggest that administration of an oncolytic vaccinia virus carrying genes encoding for IL-7 and IL-12 has antitumor activity in both directly injected and distant noninjected tumors through immune status changes rendering tumors sensitive to immune checkpoint blockade. The benefit of intratumoral IL-7 and IL-12 expression was also observed in humanized mice bearing human cancer cells. These data support further investigation in patients with non-inflamed solid tumors.

中文翻译：

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使用溶瘤病毒在肿瘤内表达IL-7和IL-12可提高对免疫检查点封锁的全身敏感性。

肿瘤微环境的免疫状态是确定免疫疗法抗肿瘤有效性的关键指标。数据支持肿瘤浸润淋巴细胞（TIL）的激活和扩展在增加实体瘤患者免疫疗法的获益方面的作用。我们发现向荷瘤免疫能力强的小鼠瘤内注射编码白介素7（IL-7）和IL-12的肿瘤选择性溶瘤牛痘病毒激活了先前免疫原性差的肿瘤的炎性免疫状态，甚至导致肿瘤完全消退，甚至在远处的肿瘤中。获得完全肿瘤消退的小鼠抵抗相同肿瘤细胞的再攻击，表明建立了长期肿瘤特异性免疫记忆。在仅对任何一种检查点抑制剂单一疗法无反应的肿瘤模型中，与单独使用病毒疗法相比，将这种病毒疗法与抗程序性细胞死亡1（PD-1）或抗细胞毒性T淋巴细胞抗原4（CTLA4）抗体相结合，可进一步提高抗肿瘤活性。这些发现表明，通过免疫状态改变，施用携带编码IL-7和IL-12的基因的溶瘤牛痘病毒在直接注射和远处未注射的肿瘤中均具有抗肿瘤活性，从而使肿瘤对免疫检查点阻断敏感。在携带人癌细胞的人源化小鼠中也观察到了肿瘤内IL-7和IL-12表达的益处。这些数据支持对未发炎的实体瘤患者的进一步研究。