Institute of Cancer Research, 237 Fulham Road, London, United Kingdom.
Clin Cancer Res. 2010 Aug 1;16(15):4005-15. doi: 10.1158/1078-0432.CCR-10-0196.
This study sought to define the recommended dose of JS1/34.5-/47-/GM-CSF, an oncolytic herpes simplex type-1 virus (HSV-1) encoding human granulocyte-macrophage colony-stimulating factor (GM-CSF), for future studies in combination with chemoradiotherapy in patients with squamous cell cancer of the head and neck (SCCHN).
Patients with stage III/IVA/IVB SCCHN received chemoradiotherapy (70 Gy/35 fractions with concomitant cisplatin 100 mg/m(2) on days 1, 22, and 43) and dose-escalating (10(6), 10(6), 10(6), 10(6) pfu/mL for cohort 1; 10(6), 10(7), 10(7), 10(7) for cohort 2; 10(6), 10(8), 10(8), 10(8) for cohort 3) JS1/34.5-/47-/GM-CSF by intratumoral injection on days 1, 22, 43, and 64. Patients underwent neck dissection 6 to 10 weeks later. Primary end points were safety and recommended dose/schedule for future study. Secondary end points included antitumor activity (radiologic, pathologic). Relapse rates and survival were also monitored.
Seventeen patients were treated without delays to chemoradiotherapy or dose-limiting toxicity. Fourteen patients (82.3%) showed tumor response by Response Evaluation Criteria in Solid Tumors, and pathologic complete remission was confirmed in 93% of patients at neck dissection. HSV was detected in injected and adjacent uninjected tumors at levels higher than the input dose, indicating viral replication. All patients were seropositive at the end of treatment. No patient developed locoregional recurrence, and disease-specific survival was 82.4% at a median follow-up of 29 months (range, 19-40 months).
JS1/34.5-/47-/GM-CSF combined with cisplatin-based chemoradiotherapy is well tolerated in patients with SCCHN. The recommended phase II dose is 10(6), 10(8), 10(8), 10(8). Locoregional control was achieved in all patients, with a 76.5% relapse-free rate so far. Further study of this approach is warranted in locally advanced SCCHN.
本研究旨在确定 JS1/34.5-/47-/GM-CSF 的推荐剂量，这是一种复制型单纯疱疹病毒 1 型（HSV-1），可编码人粒细胞-巨噬细胞集落刺激因子（GM-CSF），用于未来在头颈部鳞状细胞癌（SCCHN）患者中联合放化疗的研究。
III/IVA/IVB 期 SCCHN 患者接受放化疗（70 Gy/35 次分割，同时给予顺铂 100mg/m2 于第 1、22 和 43 天）和剂量递增（10(6)、10(6)、10(6)、10(6) pfu/mL 用于队列 1；10(6)、10(7)、10(7)、10(7) 用于队列 2；10(6)、10(8)、10(8)、10(8) 用于队列 3）JS1/34.5-/47-/GM-CSF 瘤内注射，分别于第 1、22、43 和 64 天进行。6 至 10 周后患者接受颈淋巴结清扫术。主要终点是安全性和未来研究的推荐剂量/方案。次要终点包括抗肿瘤活性（影像学、病理学）。复发率和生存率也进行了监测。
17 例患者未延迟放化疗或发生剂量限制性毒性。14 例患者（82.3%）根据实体瘤反应评价标准（RECIST）显示肿瘤有反应，93%的患者在颈淋巴结清扫术时病理完全缓解得到证实。在注射部位和相邻未注射肿瘤中检测到高于输入剂量的 HSV，表明病毒复制。所有患者在治疗结束时均呈血清阳性。无局部区域复发，中位随访 29 个月（19-40 个月）时疾病特异性生存率为 82.4%。
JS1/34.5-/47-/GM-CSF 联合顺铂放化疗在 SCCHN 患者中耐受性良好。推荐的 II 期剂量为 10(6)、10(8)、10(8)、10(8)。所有患者均获得局部区域控制，无复发生存率为 76.5%。在局部晚期 SCCHN 中进一步研究该方法是合理的。
