Combining NanoKnife with M1 oncolytic virus enhances anticancer activity in pancreatic cancer
Authors: Xin Huang
Jiali Wu
Yuan Lin
Shuxin Sun
Chaobin He
Shengping Li
Wanming Hu
Wenfeng Liu
Chen Chen
Yang Liu
Jun Wang
Wenbo Zhu
Jing Cai
Fengxiao Xie
Guangmei Yan
Journal: Cancer Letters (2021)
Discipline: CLINICAL MEDICINE
Keywords: Apoptosis; Immune activation; Irreversible electroporation; Oncolytic-virotherapy; Reactive oxygen species.
Affiliations: Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, PR China; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China., Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, PR China., Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, PR China., Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, PR China. Electronic address: ., Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, PR China; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China. Electronic address: .

Abstract:  NanoKnife, a nonthermal ablation technique also termed irreversible electroporation (IRE), has been adopted in locally advanced pancreatic cancer (LAPC) treatment. However, reversible electroporation (RE) caused by heterogeneous electric field magnitude leads to inadequate ablation and tumor recurrence. Alphavirus M1 has been identified as a novel natural oncolytic virus which is nonpathogenic and with high tumor selectivity. This study evaluated improvements to therapeutic efficacy through combination therapy incorporating NanoKnife and M1 virus. We showed that IRE triggered reactive oxygen species (ROS)-dependent apoptosis in pancreatic cancer cells (PCCs) mediated by phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway suppression. When NanoKnife was combined with M1 virus, the therapeutic efficacy was synergistically enhanced. The combinatorial treatment further inhibited tumor proliferation and prolonged the survival of orthotopic pancreatic cancer (PC)-bearing immunocompetent mice. In depth, NanoKnife enhanced the oncolytic effect of M1 by promoting its infection. The combination turned immune-silent tumors into immune-inflamed tumors characterized by T cell activation. Clinicopathologic analysis of specific M1 oncolytic biomarkers indicated the potential of the combination regimen. The combinatorial therapy represents a promising therapeutic efficacy and may ultimately improve the prognosis of patients with LAPC. 

Retracted: No

PubPeer comments:
 Others have noted the high rate of preterm birth in the placebo group, high recruitment in a single centre, lack of stillbirths, and high rate of data completeness in this trial. https: obgyn.onlinelibrary.wiley.com doi 10.1111 aogs.13771. The lead author responded. https: obgyn.onlinelibrary.wiley.com doi 10.1111 aogs.13791 We note a different issue. Participants were recruited at 14 to 18 weeks gestation, and 18 of them (7 progesterone, 11 placebo) had a midtrimester miscarriage (Table 3) ![file] It is therefore odd that 100% of participants in both groups appear to have been undelivered at 29 weeks (Figure 2). ![file] ,