Cancer therapy with local oncolysis and topical cytokine secretion
Cancer therapy with local oncolysis and topical cytokine secretion
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DOI：
10.2741/2867
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发表时间：
2008-01-01
影响因子：
3.1
通讯作者：
Ochiai, Tekenori
中科院分区：
文献类型：
--
作者：
Tagawa, Masatoshi;Kawamura, Kiyoko;Ochiai, Tekenori
直接破坏靶向肿瘤并随后诱导系统免疫与基因治疗无关，但基因治疗可能是达到局部和系统抗肿瘤效果的最合适的治疗方式。目前癌症基因治疗的策略实际上包括直接抑制肿瘤生长和激活系统宿主防御机制。我们一直致力于开发溶瘤腺病毒和细胞因子介导的宿主免疫系统的激活，以产生更好的治疗效果。由外源调节区控制E1a表达的腺病毒对靶肿瘤细胞具有优先的细胞毒作用，这取决于调节区的特异性，而将初始T细胞分化为辅助性T细胞的细胞因子可以放大产生的免疫反应。这两种战略的结合有一个优势。与化疗和放疗相比，溶瘤病毒对肿瘤的破坏不会损害免疫系统，但能够针对假定的肿瘤抗原产生抗肿瘤反应，这些抗原随后从被破坏的肿瘤中释放出来。在这一过程中，树突状细胞发挥着关键作用，因为它们是专业的抗原提呈细胞，参与免疫反应的初始阶段，无论是激活免疫还是诱导免疫耐受。因此，抗原负载和随后适当激活的树突状细胞对于激活的抗肿瘤反应至关重要，甚至可能消除远处转移灶。与溶瘤病毒联合基因治疗，激活宿主免疫系统，可通过“抗原扩散”机制激发对所有肿瘤抗原表达的免疫应答。
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.