Combined Therapy with Cytokine-Induced Killer Cells and Oncolytic Adenovirus Expressing IL-12 Induce Enhanced Antitumor Activity in Liver Tumor Model

Zhi Yang,Junjie Shen,Youhong Cui,Feng Xia,Ke Xu,Limei Liu,Xia Zhang,Yanmin Xu,Xiu-Wu Bian,Juanjuan Shan,Cheng Qian,Qianzhen Zhang,Ping Bie,Maciej S Lesniak

doi:10.1371/journal.pone.0044802

Zhi Yang, Junjie Shen + Show 12 more

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https://doi.org/10.1371/journal.pone.0044802

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Journal: PloS one	Publication Date: Sep 18, 2012
Citations: 84	License type: CC BY 4.0

Affiliation: Army Medical University, Southwest Hospital

Abstract

Both adoptive immunotherapy and gene therapy hold a great promise for treatment of malignancies. However, these strategies exhibit limited anti-tumor activity, when they are used alone. In this study, we explore whether combination of cytokine-induced killer (CIK) adoptive immunotherapy with oncolytic adenovirus-mediated transfer of human interleukin-12 (hIL-12) gene induce the enhanced antitumor potency. Our results showed that oncolytic adenovirus carrying hIL-12 (AdCN205-IL12) could produce high levels of hIL-12 in liver cancer cells, as compared with replication-defective adenovirus expressing hIL-12 (Ad-IL12). AdCN205-IL12 could specifically induce cytotoxocity to liver cancer cells. Combination of CIK cells with AdCN205-IL12 could induce higher antitumor activity to liver cancer cells in vitro than that induced by either CIK or AdCN205-IL12 alone, or combination of CIK and control vector AdCN205-GFP. Furthermore, treatment of the established liver tumors with the combined therapy of CIK cells and AdCN205-IL12 resulted in tumor regression and long-term survival. High level expression of hIL-12 in tumor tissues could increase traffic of CIK cells to tumor tissues and enhance their antitumor activities. Our study provides a novel strategy for the therapy of cancer by the combination of CIK adoptive immunotherapy with oncolytic adenovirus-mediated transfer of immune stimulatory molecule hIL-12.

Highlights

As malignant diseases, liver cancer still holds a very high mortality rate despite of progression in the cutting edge medical technology
We explore whether the enhanced antitumor activity can be achieved by the combination of adoptive immunotherapy of cytokine-induced killer (CIK) cells with oncolytic adenovirus expressing human interleukin-12 (hIL-12) (AdCN205IL12)
The Construction of AdCN205-IL12 Virus Previously, we developed a double-controlled oncolytic adenovirus system, AdCN205, in which hTERT promoter was used to control the expression of CR2 deleted E1A region and the 6.7 K/ gp19K of E3 region were substituted by the exogenous genes [25]

Summary

Introduction

Liver cancer still holds a very high mortality rate despite of progression in the cutting edge medical technology. Ex vivo expanded CIK cells with both NK and T cell properties exhibit the most therapeutic effect in different experimental tumor models [6,7,8]. These cells are generated from peripheral blood mononuclear cells (PBMCs) by the sequential addition of interferon-c (IFN-c), anti-CD3 antibody, interleukin-1a and interleukin-2, and represented as heterogeneous cell populations including CD3+CD56+ cells with high antitumor activity [6]. As an adjuvant immunotherapy, CIK cells might prevent recurrence and improve quality of life and progression-free survival rates [9,10]

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