Nguyen Tien V, Barry Mary E, Turner Mallory A, Crosby Catherine M, Trujillo Miguel A, Morris John C, Barry Michael A
Department of Internal Medicine, Division of Infectious Diseases, Translational Immunovirology and Biodefense Program, Mayo Clinic, Rochester, MN 55902, USA.
Virology and Gene Therapy Graduate Program, Mayo Clinic, Rochester, MN 55902, USA.
Biomedicines. 2017 Aug 10;5(3):46. doi: 10.3390/biomedicines5030046.
Oncolytic viruses would ideally be of use for systemic therapy to treat disseminated cancer. To do this safely, this may require multiple layers of cancer specificity. The pharmacology and specificity of oncolytic adenoviruses can be modified by (1) physical retargeting, (2) physical detargeting, (3) chemical shielding, or (4) by modifying the ability of viral early gene products to selectively activate in cancer versus normal cells. We explored the utility of these approaches with oncolytic adenovirus serotype 5 (Ad5) in immunocompetent Syrian hamsters bearing subcutaneous HaK tumors. After a single intravenous injection to reach the distant tumors, the physically hepatocyte-detargeted virus Ad5-hexon-BAP was more effective than conditionally replicating Ad5-1101/07 with mutations in its E1A protein. When these control or Ad5 treated animals were treated a second time by intratumoral injection, prior exposure to Ad5 did not affect tumor growth, suggesting that anti-Ad immunity neither prevented treatment nor amplified anti-tumor immune responses. Ad5-1101/07 was next chemically shielded with polyethylene glycol (PEG). While 5 kDa of PEG blunted pro-inflammatory IL-6 production induced by Ad5-1101/07, this shielding reduced Ad oncolytic activity.
溶瘤病毒理论上可用于全身治疗以治疗播散性癌症。为了安全地做到这一点，可能需要多层癌症特异性。溶瘤腺病毒的药理学和特异性可以通过以下方式进行修饰：（1）物理重靶向，（2）物理去靶向，（3）化学屏蔽，或（4）通过改变病毒早期基因产物在癌细胞与正常细胞中选择性激活的能力。我们在具有皮下HaK肿瘤的免疫健全叙利亚仓鼠中，探讨了这些方法与5型溶瘤腺病毒（Ad5）的效用。单次静脉注射以到达远处肿瘤后，物理性肝细胞去靶向病毒Ad5-六邻体-BAP比其E1A蛋白发生突变的条件性复制型Ad5-1101/07更有效。当这些对照或Ad5处理的动物通过瘤内注射进行第二次治疗时，先前接触Ad5并不影响肿瘤生长，这表明抗Ad免疫既不能阻止治疗也不能增强抗肿瘤免疫反应。接下来，Ad5-1101/07用聚乙二醇（PEG）进行化学屏蔽。虽然5 kDa的PEG减弱了Ad5-1101/07诱导的促炎细胞因子IL-6的产生，但这种屏蔽降低了Ad的溶瘤活性。
