Ganly I, Kirn D, Eckhardt G, Rodriguez G I, Soutar D S, Otto R, Robertson A G, Park O, Gulley M L, Heise C, Von Hoff D D, Kaye S B
Cancer Research Campaign Department of Medical Oncology, CRC Beatson Laboratories, Glasgow, United Kingdom.
Clin Cancer Res. 2000 Mar;6(3):798-806.
An E1B 55 kDa gene-deleted adenovirus, Onyx-015, which reportedly selectively replicates in and lyses p53-deficient cells, was administered by a single intratumoral injection to a total of 22 patients with recurrent head and neck cancer. The objectives of this Phase I study were to determine the safety, feasibility, and efficacy of this therapy and determine any correlation to p53 status. Six cohorts were investigated with a dose escalation from 10(7)-10(11) plaque-forming units. Toxicity was assessed using NCIC criteria. Tumor response was assessed by clinical and radiological measurement. Blood samples were taken to detect adenovirus DNA and neutralizing antibody to adenovirus. Tumor biopsies were taken to detect adenovirus by in situ hybridization. Treatment was well tolerated, with the main toxicity being grade 1/2 flu-like symptoms. Dose-limiting toxicity was not reached at the highest dose of 10(11) plaque-forming units. Twenty-one of the 22 patients treated showed an increase in neutralizing antibody to adenovirus. In situ hybridization showed viral replication in 4 of 22 patients treated, all of whom had mutant p53 tumors. Using conventional response criteria, no objective responses were observed. However, magnetic resonance imaging scans were suggestive of tumor necrosis at the site of viral injection in five patients, three of whom were classified using nonconventional criteria as partial responders, and two of whom were classified using nonconventional criteria as minor responders. Of these five cases, four had mutant p53 tumors. The response duration for the three partial responders was 4, 8, and 12 weeks. An additional eight patients had stable disease in the injected tumors lasting from 4-8 weeks. These preliminary results show that intratumoral administration of Onyx-015 is feasible, well tolerated, and associated with biological activity. Further investigation of Onyx-015, particularly with a more frequent injection protocol and in combination with systemic chemotherapy, is warranted.
一种E1B 55 kDa基因缺失的腺病毒Onyx-015，据报道可在p53缺陷细胞中选择性复制并裂解这些细胞，通过瘤内单次注射给予了总共22例复发性头颈癌患者。这项I期研究的目的是确定该疗法的安全性、可行性和疗效，并确定与p53状态的任何相关性。研究了六个队列，剂量从10(7)-10(11)空斑形成单位逐步递增。使用NCIC标准评估毒性。通过临床和影像学测量评估肿瘤反应。采集血样以检测腺病毒DNA和腺病毒中和抗体。采集肿瘤活检组织通过原位杂交检测腺病毒。治疗耐受性良好，主要毒性为1/2级流感样症状。在最高剂量10(11)空斑形成单位时未达到剂量限制性毒性。接受治疗的22例患者中有21例显示腺病毒中和抗体增加。原位杂交显示，在接受治疗的22例患者中有4例出现病毒复制，所有这些患者均患有p53突变肿瘤。使用传统反应标准，未观察到客观反应。然而，磁共振成像扫描提示5例患者病毒注射部位有肿瘤坏死，其中3例根据非传统标准分类为部分缓解者，2例根据非传统标准分类为轻度缓解者。在这5例病例中，4例患有p53突变肿瘤。3例部分缓解者的反应持续时间分别为4周、8周和12周。另外8例患者注射部位的肿瘤病情稳定，持续4 - 8周。这些初步结果表明，瘤内注射Onyx-015是可行的，耐受性良好，并具有生物学活性。有必要对Onyx-015进行进一步研究，特别是采用更频繁的注射方案并与全身化疗联合使用。
