Gene therapy for malignant pleural mesothelioma: present and future.

Malignant pleural mesothelioma is relatively rare in frequency but one of the intractable diseases linked with asbestos exposure. Clinical outcomes with the present treatment modalities are unsatisfactory and no effective prevention method has been reported. Growing numbers of the patients in the Western countries with a long latent period need development of a novel therapeutic strategy. Gene therapy is a candidate for mesothelioma treatment because of its easy accessibility of a vector-mediated gene medicine into the intrapleural cavity. Several preclinical studies demonstrated that the gene medicine produced antitumor effects, suggesting the feasibility in clinical settings. In this article, we review the current status of gene therapy and clinical trials targeting mesothelioma and address possible directions to improve the efficacy.

Cancer therapy with local oncolysis and topical cytokine secretion.

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 naive 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.