[Frontiers in Bioscience 13, 2578-2587, January 1, 2008]

Cancer therapy with local oncolysis and topical cytokine secretion

Masatoshi Tagawa1,5, Kiyoko Kawamura1, Taro Ueyama2, Makoto Nakamura2, Yuji Tada2, Guangyu Ma1,3,5, Quanhai Li1,5, Nobuo Suzuki3, Hideaki Shimada4,5 Takayuki Kuriyama2, Tekenori Ochiai4,5

1Division of Pathology, Chiba Cancer Center Research Institute, Chiba, Japan,2Department of Respirology, Graduate School of Medicine, Chiba University, Japan, 3Department of Environmental Biochemistry, Graduate School of Medicine, Chiba University, Japan, 4Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Japan, 5Center of Excellence (COE) Program in the 21st Century, Graduate School of Medicine, Chiba University, Japan


2. Introduction
3. Anti-tumor effects produced by replication-competent Ad
4. Improved cytotoxic activity of fiber-modified Ad
5. Efficient antigen-loading in DCs
6. Augmentation of cell-mediated immunity by cytokines released from activated DCs
7. Prospect
8. Acknowledgements
9. References


Direct destruction of targeted tumors and subsequent induction of systemic immunity is not pertinent to gene therapy but gene therapy is probably the most suitable therapeutic modality to achieve the local and systemic anti-tumor effects. Current strategies for cancer gene therapy in fact consist of direct inhibition of tumor growth and activation of systemic host defense mechanisms. We have been working on development of oncolytic adenoviruses and cytokine-mediated activation of host immune systems to produce better therapeutic effects. The adenoviruses in which the E1A expression is controlled by an exogenous regulatory region are preferentially cytotoxic to target tumor cells depending on the specificity of the regulatory region and cytokines that differentiate naïve T cells into T helper type 1 cells can amplify immune responses generated. Combination of the two strategies has an advantage. Tumor destruction by oncolytic viruses does not impair immune systems in contract to chemotherapy and radiotherapy but enable to produce anti-tumor responses against putative tumor antigens that are subsequently released from the destroyed tumor. In this process, dendritic cells play a pivotal role since they act as professional antigen presenting cells and are involved in an initial phase of immune responses, either activation of immunity or induction of immune tolerance. Antigen loading with subsequent appropriate activation of dendritic cells is thereby crucial for activated anti-tumor responses, which possibly eliminate even distant metastatic foci. Combinatory gene therapy with oncolytic viruses and activation of host immune system thereby can evoke immune responses against all the tumor antigens expressed by the process of "antigen-spreading" mechanisms.