Targeted Hsp70 expression combined with CIK-activated immune reconstruction synergistically exerts antitumor efficacy in patient-derived hepatocellular carcinoma xenograft mouse models

// Huanzhang Hu 1,2,* , Yinghe Qiu 2,* , Minggao Guo 3,* , Yao Huang 2 , Lin Fang 4 , Zhangxiao Peng 2 , Weidan Ji 2 , Yang Xu 2 , Shuwen Shen 2 , Yan Yan 2 , Xuandong Huang 5 , Junnian Zheng 4 and Changqing Su 2,4 1 Department of Hepatobiliary Surgery, Fuzhou General Hospital of Nanjing Military Area, Fuzhou, China 2 Department of Molecular Oncology & Biliary Tract Surgery, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, China 3 Department of Surgery, Shanghai Sixth People Hospital, Shanghai Jiao-Tong University, Shanghai, China 4 Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical College, Xuzhou, China 5 Department of Oncological Surgery, Second People’s Hospital of Huai’an, Jiangsu Province, China * These authors contributed equally to this work Correspondence: Changqing Su, email: // Junnian Zheng, email: // Keywords : Patient-derived tumor xenograft model; Hepatocellular carcinoma; Onolytic adenovirus; Heat shock protein; Cytokine-induced killer Received : October 23, 2014 Accepted : November 25, 2014 Published : November 26, 2014 Abstract The patient-derived tumor xenograft (PDTX) models can reproduce a similar natural genetic background and similar biological behaviors to tumor cells in patients, which is conducive to the assessment of personalized cancer treatment. In this study, to verify the targeting and effectiveness of the therapeutic strategy using a Survivin promoter-regulated oncolytic adenovirus expressing Hsp70, the PDTX models of hepatocellular carcinoma (HCC) were established in nude mice and the cytokine-induced killer (CIK) cells were intravenously infused into mice to partially reconstruct the mouse immune function. The results demonstrated that, either the immune anti-tumor effect caused by CIK cell infusion or the oncolytic effect generated by oncolytic adenovirus replication was very limited. However, the synergistic tumor inhibitory effect was significantly enhanced after treatments with oncolytic adenovirus expressing Hsp70 combined with CIK cells. Oncolytic adenovirus mediated the specific expression of Hsp70 in cancer tissues allowed the CIK chemotaxis, and induce the infiltration of CD3+ T cells in tumor stroma, thereby exhibiting anti-tumor activity. The anti-tumor effect was more effective for the highly malignant tumor xenografts with highly Survivin expression. This strategy can synergistically activate multiple anti-tumor mechanisms and exert effective anti-tumor activities that have a significant inhibitory effect against the growth of HCC xenografts.