Vidal Laura, Pandha Hardev S, Yap Timothy A, White Christine L, Twigger Katie, Vile Richard G, Melcher Alan, Coffey Matt, Harrington Kevin J, DeBono Johann S
The Royal Marsden NHS Foundation Trust, London and Sutton, United Kingdom.
Clin Cancer Res. 2008 Nov 1;14(21):7127-37. doi: 10.1158/1078-0432.CCR-08-0524.
To determine the safety and feasibility of daily i.v. administration of wild-type oncolytic reovirus (type 3 Dearing) to patients with advanced cancer, assess viral excretion kinetics and antiviral immune responses, identify tumor localization and replication, and describe antitumor activity.
Patients received escalating doses of reovirus up to 3 x 10(10) TCID(50) for 5 consecutive days every 4 weeks. Viral excretion was assessed by reverse transcription-PCR and antibody response by cytotoxicity neutralization assay. Pretreatment and post-treatment tumor biopsies were obtained to measure viral uptake and replication.
Thirty-three patients received 76 courses of reovirus from 1 x 10(8) for 1 day up to 3 x 10(10) TCID(50) for 5 days, repeated every four weeks. Dose-limiting toxicity was not seen. Common grade 1 to 2 toxicities included fever, fatigue, and headache, which were dose and cycle independent. Viral excretion at day 15 was not detected by reverse transcription-PCR at 25 cycles and only in 5 patients at 35 cycles. Neutralizing antibodies were detected in all patients and peaked at 4 weeks. Viral localization and replication in tumor biopsies were confirmed in 3 patients. Antitumor activity was seen by radiologic and tumor marker (carcinoembryonic antigen, CA19.9, and prostate-specific antigen) evaluation.
Oncolytic reovirus can be safely and repeatedly administered by i.v. injection at doses up to 3 x 10(10) TCID(50) for 5 days every 4 weeks without evidence of severe toxicities. Productive reoviral infection of metastatic tumor deposits was confirmed. Reovirus is a safe agent that warrants further evaluation in phase II studies.
确定对晚期癌症患者每日静脉注射野生型溶瘤呼肠孤病毒（3型迪林株）的安全性和可行性，评估病毒排泄动力学和抗病毒免疫反应，确定肿瘤定位和复制情况，并描述抗肿瘤活性。
患者每4周连续5天接受递增剂量的呼肠孤病毒，最高剂量达3×10¹⁰半数组织培养感染剂量（TCID₅₀）。通过逆转录聚合酶链反应评估病毒排泄情况，通过细胞毒性中和试验评估抗体反应。获取治疗前和治疗后的肿瘤活检样本以测量病毒摄取和复制情况。
33例患者接受了76个疗程的呼肠孤病毒治疗，剂量从1×10⁸持续1天至3×10¹⁰ TCID₅₀持续5天，每四周重复一次。未观察到剂量限制性毒性。常见的1至2级毒性包括发热、疲劳和头痛，这些与剂量和疗程无关。在25个循环时逆转录聚合酶链反应未检测到第15天的病毒排泄，仅在35个循环时在5例患者中检测到。所有患者均检测到中和抗体，在4周时达到峰值。在3例患者中证实了肿瘤活检样本中的病毒定位和复制。通过影像学和肿瘤标志物（癌胚抗原、CA19.9和前列腺特异性抗原）评估观察到抗肿瘤活性。
溶瘤呼肠孤病毒可以通过静脉注射安全且重复给药，剂量高达3×10¹⁰ TCID₅₀，每4周持续5天，未出现严重毒性的证据。证实了转移性肿瘤沉积物中呼肠孤病毒的有效感染。呼肠孤病毒是一种安全的药物，值得在II期研究中进一步评估。
