Treatment of Cancer Patients With a Serotype 5/3 Chimeric Oncolytic Adenovirus Expressing GMCSF
Treatment of Cancer Patients With a Serotype 5/3 Chimeric Oncolytic Adenovirus Expressing GMCSF
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DOI：
10.1038/mt.2010.161
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发表时间：
2010-10-01
影响因子：
12.4
通讯作者：
Hemminki, Akseli
中科院分区：
文献类型：
--
作者：
Koski, Anniina;Kangasniemi, Lotta;Hemminki, Akseli
增强抗肿瘤免疫力是增强溶瘤腺病毒治疗效力的一种有前途的方法。粒细胞巨噬细胞集落刺激因子 (GMCSF) 可通过招募自然杀伤细胞和诱导肿瘤特异性 CD8(+) 细胞毒性 T 淋巴细胞来介导抗肿瘤作用。血清型 5 腺病毒 (Ad5) 常用于癌症基因治疗。然而，柯萨奇腺病毒受体的表达在许多晚期肿瘤中是可变的，临床前数据已经证明用 Ad3 旋钮替代 Ad5 旋钮具有优势。在这里，编码 GMCSF 的 5/3 衣壳嵌合和 p16-Rb 途径选择性溶瘤腺病毒被设计并进行了临床前测试。随后，共有 21 名标准疗法难治的晚期实体瘤患者接受了 Ad5/3-D24-GMCSF 的瘤内和静脉注射治疗，并结合低剂量节拍环磷酰胺以减少调节性 T 细胞。没有发生严重不良事件。对恶性胸水和腹水预处理样本的分析证实了 Ad5/3-D24-GMCSF 在转导和细胞杀伤方面的功效。在 13/21 名患者中发现了病毒的生物活性证据，8/12 名患者显示出客观的临床益处，这是通过放射学按照实体瘤反应评估标准 (RECIST) 标准进行评估的。治疗后引发抗腺病毒和抗肿瘤免疫反应。因此，Ad5/3-D24-GMCSF 在治疗癌症患者方面似乎是安全的，并且看到了有希望的疗效迹象。
Augmenting antitumor immunity is a promising way to enhance the potency of oncolytic adenoviral therapy. Granulocyte-macrophage colony-stimulating factor (GMCSF) can mediate antitumor effects by recruiting natural killer cells and by induction of tumor-specific CD8(+) cytotoxic T-lymphocytes. Serotype 5 adenoviruses (Ad5) are commonly used in cancer gene therapy. However, expression of the coxsackie-adenovirus receptor is variable in many advanced tumors and preclinical data have demonstrated an advantage for replacing the Ad5 knob with the Ad3 knob. Here, a 5/3 capsid chimeric and p16-Rb pathway selective oncolytic adenovirus coding for GMCSF was engineered and tested preclinically. A total of 21 patients with advanced solid tumors refractory to standard therapies were then treated intra-tumorally and intravenously with Ad5/3-D24-GMCSF, which was combined with low-dose metronomic cyclophosphamide to reduce regulatory T cells. No severe adverse events occurred. Analysis of pretreatment samples of malignant pleural effusion and ascites confirmed the efficacy of Ad5/3-D24-GMCSF in transduction and cell killing. Evidence of biological activity of the virus was seen in 13/21 patients and 8/12 showed objective clinical benefit as evaluated by radiology with Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Antiadenoviral and antitumoral immune responses were elicited after treatment. Thus, Ad5/3-D24-GMCSF seems safe in treating cancer patients and promising signs of efficacy were seen.