Oncolytic viruses and their application to cancer immunotherapy.
Oncolytic viruses and their application to cancer immunotherapy.
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DOI：
10.1158/2326-6066.cir-14-0015
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发表时间：
2014-04
影响因子：
10.1
通讯作者：
Rabkin SD
中科院分区：
文献类型：
--
作者：
Chiocca EA;Rabkin SD
溶瘤病毒（OV）选择性地在癌细胞中复制并杀死癌细胞，并在肿瘤内扩散，同时不伤害正常组织。除了这种直接的溶瘤活性之外，OV还非常有效地诱导对自身和感染的肿瘤细胞的免疫应答。OV涵盖了广泛多样的DNA和RNA病毒，这些病毒具有天然的癌症选择性或可以进行基因工程改造。OV为免疫疗法提供了一个多样化的平台;它们作为原位疫苗，可以与免疫调节转基因或与其他免疫疗法相结合。然而，OV与免疫系统的相互作用可能以相反的方式影响治疗结果：通过限制病毒复制和/或传播产生负面影响，或通过诱导抗肿瘤免疫应答产生正面影响。OV-肿瘤/宿主相互作用的许多方面对于描述治疗的有效性很重要;它们包括：（i）先天性免疫应答和诱导的炎症程度，（ii）病毒诱导的细胞死亡类型，（iii）固有的肿瘤生理学，例如浸润和驻留免疫细胞、血管分布/缺氧、血管生成和基质结构，和（iv）肿瘤细胞表型，包括IFN信号传导、致癌途径、细胞表面免疫标志物（MHC、共刺激、NK受体）和免疫抑制因子表达的改变。最近用各种OV，特别是表达GM-CSF的OV进行的临床试验已经证明了在没有显著毒性的情况下的抗肿瘤免疫应答的功效和诱导。操纵抗病毒和抗肿瘤反应之间的平衡，通常涉及重叠的免疫途径，将是OV临床成功的关键。
Oncolytic viruses (OVs) selectively replicate in and kill cancer cells, and spread within the tumor, while not harming normal tissue. In addition to this direct oncolytic activity, OVs are also very effective at inducing immune responses to themselves and to the infected tumor cells. OVs encompass a broad diversity of DNA and RNA viruses that are naturally cancer-selective or can be genetically-engineered. OVs provide a diverse platform for immunotherapy; they act as in situ vaccines, and can be armed with immune modulatory transgenes or combined with other immunotherapies. However, the interactions of OVs with the immune system may affect therapeutic outcomes in opposing fashions: negatively by limiting virus replication and/or spread, or positively by inducing antitumor immune responses. Many aspects of the OV-tumor/host interaction are important in delineating the effectiveness of therapy; they include: (i) innate immune responses and the degree of inflammation induced, (ii) types of virus-induced cell death, (iii) inherent tumor physiology, such as infiltrating and resident immune cells, vascularity/hypoxia, lymphatics, and stromal architecture, and (iv) tumor cell phenotype, including alterations in IFN signaling, oncogenic pathways, cell surface immune markers (MHC, co-stimulatory, NK receptors), and the expression of immunosuppressive factors. Recent clinical trials with a variety of OVs, especially those expressing GM-CSF, have demonstrated efficacy and induction of antitumor immune responses in the absence of significant toxicity. Manipulating the balance between anti-virus and antitumor responses, often involving overlapping immune pathways, will be critical to the clinical success of OVs.