Gradalis, Inc. Dallas, TX, USA.
Curr Pharm Biotechnol. 2012 Jul;13(9):1750-60. doi: 10.2174/138920112800958913.
Oncolytic virotherapy is an evolving but, as yet, unrealized treatment option for cancer. This approach harnesses the cancer-restricted replicative activity of engineered viruses to achieve tumor cell kill. Tumors that are resistant to chemotherapy or radiotherapy can be susceptible to viral oncolysis because of distinct cell kill mechanisms. There is now compelling evidence that collateral induction of anti-tumor immune responses contributes substantially to viral antitumor activities. In addition to the expected anti-viral immune clearance, the "danger" signal created by virus-infected cells can generate immune co-stimulation known to override immune suppression and reverse tolerance within the tumor microenvironment. Our recent findings indicate that immune activation augments the clinical outcomes of oncolytic virotherapy. Strikingly similar and robust clinical response rates ( > 25%) were observed among advanced cancer patients following intratumoral treatments with adenoviral (AdΔ24) and herpes simplex (JS1/34.5-/47) constructs armed with an integrated granulocyte-macrophage colony-stimulating factor (GMCSF) payload. Both agents produced regressions in injected as well as distant, uninjected lesions, demonstrating systemic effectiveness. We discuss the innate and adaptive immune activating events that may contribute to these clinical outcomes, and examine systemic delivery strategies to tilt the immunological balance from viral clearance to tumor elimination.
溶瘤病毒治疗是一种不断发展但尚未实现的癌症治疗选择。这种方法利用工程病毒的肿瘤限制性复制活性来实现肿瘤细胞杀伤。由于独特的细胞杀伤机制，对化疗或放疗耐药的肿瘤可能容易受到病毒溶瘤作用的影响。现在有令人信服的证据表明，抗肿瘤免疫反应的继发诱导对病毒抗肿瘤活性有很大贡献。除了预期的抗病毒免疫清除外，病毒感染细胞产生的“危险”信号可以产生免疫共刺激，已知这种刺激可以克服肿瘤微环境中的免疫抑制和逆转耐受。我们最近的发现表明，免疫激活增强了溶瘤病毒治疗的临床疗效。在对晚期癌症患者进行瘤内治疗后，观察到腺病毒（AdΔ24）和单纯疱疹病毒（JS1/34.5-/47）构建体的类似且强大的临床反应率（>25%），这些构建体携带整合的粒细胞-巨噬细胞集落刺激因子（GMCSF）有效载荷。两种药物都能使注射部位和远处未注射部位的病变消退，显示出系统有效性。我们讨论了可能导致这些临床结果的固有和适应性免疫激活事件，并研究了全身性递送策略，以从病毒清除转变为肿瘤消除来改变免疫平衡。
