Neoadjuvant Use of Oncolytic Herpes Virus G47Δ Enhances the Antitumor Efficacy of Radiofrequency Ablation.
Neoadjuvant Use of Oncolytic Herpes Virus G47Δ Enhances the Antitumor Efficacy of Radiofrequency Ablation.
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DOI：
10.1016/j.omto.2020.08.010
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发表时间：
2020-09-25
期刊：
影响因子：
--
通讯作者：
Todo T
中科院分区：
文献类型：
--
作者：
Yamada T;Tateishi R;Iwai M;Koike K;Todo T
G47Δ是一种三重突变的溶瘤性单纯疱疹病毒1型，旨在有效诱导抗肿瘤免疫应答。我们研究了G47Δ作为射频消融（RFA）新辅助治疗的有效性，RFA是某些癌症（如肝癌）的标准局部治疗，但同一器官内的远端复发经常发生。在具有双侧皮下Neuro 2a肿瘤的A/J小鼠中，左侧肿瘤用G47Δ瘤内注射治疗，然后进行RFA。尽管RFA治疗的肿瘤全部被根除，但评估右侧肿瘤的生长并分析肿瘤浸润淋巴细胞。与G47Δ单药治疗相比，G47Δ+RFA治疗导致右侧肿瘤体积更小，同时伴有CD 8 +/CD 45 + T细胞增加。在耗尽CD 8 + T细胞后，对对侧肿瘤的增强功效完全消除。新佐剂G47Δ导致再攻击肿瘤的排斥反应，这是由酶联免疫斑点（ELISPOT）测定显示的有效诱导特异性抗肿瘤免疫应答引起的。用抗程序性细胞死亡1配体1（PD-L1）抗体治疗携带肿瘤的动物，对对侧肿瘤的疗效甚至更高。我们的研究表明，G47Δ的新辅助使用通过CD 8 + T细胞依赖性免疫有效地增强了RFA的疗效，免疫检查点抑制剂进一步增强了这种免疫。射频消融是一种有效的局部治疗方法，但常发生远端复发。在患有双侧皮下肿瘤的免疫活性小鼠中，RFA前使用溶瘤性疱疹G47Δ治疗可增强对远端肿瘤的疗效，并增加免疫应答，随后使用抗PD-L1抗体进一步增强。这种连续治疗应该是有用的。
G47Δ is a triple-mutated oncolytic herpes simplex virus type 1 designed to induce antitumor immune responses efficiently. We examine the usefulness of G47Δ as a neoadjuvant therapy for radiofrequency ablation (RFA), a standard local treatment for certain cancers such as liver cancer, but remote recurrences within the same organ often occur. In A/J mice harboring bilateral subcutaneous Neuro2a tumors, the left tumors were treated with G47Δ intratumoral injections followed by RFA. Whereas the RFA-treated tumors were all eradicated, the growth of the right tumors was evaluated and tumor-infiltrating lymphocytes were analyzed. The G47Δ+RFA treatment caused smaller volumes of right tumors, accompanied by increased CD8+/CD45+ T cells, compared with G47Δ monotherapy. After depletion of CD8+ T cells, the enhanced efficacy on the contralateral tumors was completely abolished. Neoadjuvant G47Δ led to rejection of rechallenged tumors, which was caused by efficient induction of specific antitumor immune responses shown by enzyme-linked immunospot (ELISPOT) assays. Treatment of tumor-harboring animals with an anti-programmed cell death 1 ligand 1 (PD-L1) antibody led to even greater efficacy on contralateral tumors. Our study indicates that the neoadjuvant use of G47Δ effectively enhances the efficacy of RFA via CD8+ T cell-dependent immunity that is further augmented by an immune checkpoint inhibitor. Radiofrequency ablation (RFA) is an effective local treatment, but remote recurrences often occur. In immunocompetent mice harboring bilateral subcutaneous tumors, treatment with oncolytic herpes G47Δ prior to RFA causes enhanced efficacy on remote tumors with increased immune responses, further boosted by following with anti-PD-L1 antibody. Such sequential treatments should be useful.
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