A fully-virulent retargeted oncolytic HSV armed with IL-12 elicits local immunity and vaccine therapy towards distant tumors
A fully-virulent retargeted oncolytic HSV armed with IL-12 elicits local immunity and vaccine therapy towards distant tumors
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DOI：
10.1371/journal.ppat.1007209
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发表时间：
2018-08-01
期刊：
影响因子：
6.7
通讯作者：
Campadelli-Fiume, Gabriella
中科院分区：
文献类型：
--
作者：
Leoni, Valerio;Vannini, Andrea;Campadelli-Fiume, Gabriella
溶瘤单纯疱疹病毒(OHSV)在临床试验和实践中显示出良好的疗效。它们中的大多数通过抵消宿主反应的基因的缺失/突变获得癌症特异性，并选择性地在抗病毒反应缺陷的癌细胞中生长。由于缺失/突变，它们经常被减弱或过度减弱。我们开发了新一代OHSV，它没有缺失/突变，通过与肿瘤细胞受体的特异性重定向获得癌症特异性--例如。HER2(人表皮生长因子受体2)-因此在目标癌细胞中是完全毒力的。它们诱导的免疫疗法的类型是不可预测的，因为非减毒HSV诱导并随后抑制固有反应，而删除/减毒病毒无法对比剂，而且由于重定向OHSV在肿瘤细胞中有效复制，但不影响肿瘤中的其他细胞。我们报道了HER2重定向、全毒力OHSV在免疫活性小鼠中的首次有效性研究。他们的安全级别非常高。未携带IL-12的R-LM113和携带IL-12的R-115对HER2-Lewis肺癌-1(HER2-LLC1)的生长均有抑制作用，且R115的作用持续增强。所有没有因为主要治疗的肿瘤而死亡的小鼠，都被保护免受对侧未治疗的肿瘤的生长。长期存活的患者免受第二个对侧肿瘤的侵袭，这为非内窥镜免疫治疗效果提供了额外的证据。对局部反应的分析强调，特别是R-115释放了免疫抑制的肿瘤微环境，即诱导的免疫调节细胞因子，包括促进Th1极化的IFNy、T-bet。无论使用哪种病毒，在所有应答小鼠的肿瘤中，CD8+、Foxp3+、CD141+细胞明显增多，而CD11b+细胞优先减少。持久的反应包括打破了对HER2和wt肿瘤细胞的耐受性，并强调了系统性免疫治疗性疫苗反应。
Oncolytic herpes simplex viruses (oHSVs) showed efficacy in clinical trials and practice. Most of them gain cancer-specificity from deletions/mutations in genes that counteract the host response, and grow selectively in cancer cells defective in anti-viral response. Because of the deletions/mutations, they are frequently attenuated or over-attenuated. We developed next-generation oHSVs, which carry no deletion/mutation, gain cancer-specificity from specific retargeting to tumor cell receptors-e.g. HER2 (human epidermal growth factor receptor 2)-hence are fully-virulent in the targeted cancer cells. The type of immunotherapy they elicit was not predictable, since non-attenuated HSVs induce and then dampen the innate response, whereas deleted/attenuated viruses fail to contrast it, and since the retargeted oHSVs replicate efficiently in tumor cells, but spare other cells in the tumor. We report on the first efficacy study of HER2-retargeted, fully-virulent oHSVs in immunocompetent mice. Their safety profile was very high. Both the unarmed R-LM113 and the IL-12-armed R-115 inhibited the growth of the primary HER2-Lewis lung carcinoma-1 (HER2-LLC1) tumor, R115 being constantly more efficacious. All the mice that did not die because of the primary treated tumors, were protected from the growth of contralateral untreated tumors. The long-term survivors were protected from a second contralateral tumor, providing additional evidence for an abscopal immunotherapeutic effect. Analysis of the local response highlighted that particularly R-115 unleashed the immunosuppressive tumor microenvironment, i.e. induced immunomodulatory cytokines, including IFNy, T-bet which promoted Thl polarization. Some of the tumor infiltrating cells, e.g. CD4+, CD335+ cells were increased in the tumors of all responders mice, irrespective of which virus was employed, whereas CD8+, Foxp3+, CD141+ were increased and CD11 b+ cells were decreased preferentially in R115-treated mice. The durable response included a breakage of tolerance towards both HER2 and the wt tumor cells, and underscored a systemic immunotherapeutic vaccine response.