Wu Lan, Huang Tian-gui, Meseck Marcia, Altomonte Jennifer, Ebert Oliver, Shinozaki Katsunori, García-Sastre Adolfo, Fallon John, Mandeli John, Woo Savio L C
Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Hum Gene Ther. 2008 Jun;19(6):635-47. doi: 10.1089/hum.2007.163.
Oncolytic vesicular stomatitis virus (VSV) is being developed as a novel therapeutic agent for cancer treatment, although it is toxic in animals when administered systemically at high doses. Its safety can be substantively improved by an M Delta 51 deletion in the viral genome, and yet VSV(M Delta 51) induces a much greater, robust cellular inflammatory response in the host than wild-type VSV, which severely attenuates its oncolytic potency. We have reported that the oncolytic potency of wild-type VSV can be enhanced by vector-mediated expression of a heterologous viral gene that suppresses cellular inflammatory responses in the lesions. To develop an effective and safe VSV vector for cancer treatment, we tested the hypothesis that the oncolytic potency of VSV(M Delta 51) can be substantively elevated by vector-mediated expression of M3, a broad-spectrum and high-affinity chemokine-binding protein from murine gammaherpesvirus-68. The recombinant vector rVSV(M Delta 51)-M3 was used to treat rats bearing multifocal lesions (1-10 mm in diameter) of hepatocellular carcinoma (HCC) in their liver by hepatic artery infusion. Treatment led to a significant reduction of neutrophil and natural killer cell accumulation in the lesions, a 2-log elevation of intratumoral viral titer, substantively enhanced tumor necrosis, and prolonged animal survival with a 50% cure rate. Importantly, there were no apparent systemic and organ toxicities in the treated animals. These results indicate that the robust cellular inflammatory responses induced by VSV(M Delta 51) in HCC lesions can be overcome by vector-mediated intratumoral M3 expression, and that rVSV(M Delta 51)-M3 can be developed as an effective and safe oncolytic agent to treat advanced HCC patients in the future.
溶瘤性水疱性口炎病毒（VSV）正被开发为一种用于癌症治疗的新型治疗剂，尽管高剂量全身给药时它在动物体内具有毒性。通过病毒基因组中的MΔ51缺失可大幅提高其安全性，然而VSV（MΔ51）在宿主中诱导的细胞炎症反应比野生型VSV强烈得多，这严重削弱了其溶瘤效力。我们曾报道，通过载体介导表达一种抑制病变部位细胞炎症反应的异源病毒基因，可增强野生型VSV的溶瘤效力。为开发一种有效且安全的用于癌症治疗的VSV载体，我们测试了这样一种假设，即通过载体介导表达M3（一种来自鼠γ疱疹病毒-68的广谱高亲和力趋化因子结合蛋白），可大幅提高VSV（MΔ51）的溶瘤效力。重组载体rVSV（MΔ51）-M3通过肝动脉灌注用于治疗肝脏中患有多灶性病变（直径1 - 10毫米）的肝细胞癌（HCC）大鼠。治疗导致病变部位中性粒细胞和自然杀伤细胞积累显著减少，肿瘤内病毒滴度提高2个对数，肿瘤坏死显著增强，动物存活期延长，治愈率达50%。重要的是，治疗动物未出现明显的全身和器官毒性。这些结果表明，VSV（MΔ51）在HCC病变中诱导的强烈细胞炎症反应可通过载体介导的肿瘤内M3表达来克服，并且rVSV（MΔ51）-M3未来可开发成为一种有效且安全的溶瘤剂用于治疗晚期HCC患者。
