重组高效抗肿瘤抗病毒蛋白注射液治疗经标准治疗失败的转移性结直肠癌的临床研究

Clinical study of recombinant anti-tumor and anti-virus protein injection compared with placebo in metastatic colorectal cancer after failure of second-line and more than second-line treatment

目的观察重组高效抗肿瘤抗病毒蛋白注射液(乐复能)单药治疗经标准治疗失败的转移性结直肠癌(mCRC)的疗效、不良反应及其对受试者免疫功能的影响,并在此基础上进行剂量效应的探索研究。方法 2011年5月至2012年12月入组105例受试者接受乐复能注射液或安慰剂肌肉注射。根据治疗方式及最终维持治疗剂量的不同,分为安慰剂组15例(生理盐水)、低剂量乐复能治疗组69例(<40μg/次,3次/周)和高剂量乐复能治疗组21例(40μg/次,3次/周)。采用流式细胞术检测57例患者外周血NK细胞和调节性T细胞(Treg细胞)在乐复能治疗前后水平的变化。结果治疗6周后,高剂量乐复能组的疾病控制率为47.4%,优于安慰剂组的21.4%,差异有统计学意义(P<0.05);乐复能的主要不良反应为"流感样"症状、骨髓抑制、肝功能异常、消化道反应等,不良反应程度均较轻,停药或对症处理后均可恢复;与治疗前相比,高剂量乐复能组受试者治疗后NK细胞水平显著升高,Treg细胞水平显著下降(P<0.05)。结论乐复能治疗转移性结直肠癌具有一定疗效,不良反应可耐受,患者免疫抑制状态改善,生活质量提高。

Objective To observe the efficacy, safety and dose-response relationship of novaferon in treatment of metastatic colorectal cancer patients who had received at least two prior palliative regimens, and assess the effects on the immune function of sub- jects. Methods One hundred and five patients were enrolled from May 2011 to December 2012. According to the different treatment modalities and ultimately maintain therapeutic dose, the subjects were divided into three groups： the placebo-group（ 15 cases, saline） , the low-dose treatment group（69 cases, novaferon 〈 40t^g each time, 3 times a week） and the high-dose treatment group（21 cases, novaferon 40p.g each time, 3 times a week）. The proportions of NK and CD4 ~ CD25hish Foxp3 ＋ Treg cells in the peripheral blood sam- ples were detected from 57 subjects by flow eytomet13, before and after treatment. Then, the changes of NK and Treg cells were ana- lyzed. Results After 6 weeks of treatment, disease control rate （DCR） of the high-dose treatment group was 47. 4%, higher than 21.4% of the placebo group. The difference was statistically significant（ P 〈 0. 05 ）. The major adverse reactions of novaferon were ＂flu-like＂ symptoms, bone marrow suppression, abnormal liver function and gastrointestinal discomfort. After treatment, the NK cells in the high-dose treatment group had increased significantly, Treg cells decreased significantly compared with baseline （ P 〈 0. 05 ）. Conclusion Novaferon has moderate efficacy and less adverse reactions in treatment of metastatic eolorectal cancer. Furthermore, it can improve the immune function and life quality of patients.