宫颈癌及癌前病变治疗性疫苗临床研究进展与启示

Clinical research progress and implications of therapeutic vaccines for cervical cancer and precancerous lesions: a qualitative systematic review

目的系统总结并分析宫颈癌及癌前病变治疗性疫苗的临床研究进展。方法系统检索PubMed、Embase、Web of Science、Cochrane Library、Proquest、ClinicalTrails.gov、SinoMed、中国知网、维普网、万方数据知识服务平台,检索日期为建库至2021年2月18日。对纳入的合格研究进行质量评价,并从文献基本信息、研究设计、疫苗信息、研究对象、结局指标等多方面归纳梳理,定性总结临床研究进展。结果共纳入71篇文献,其中随机对照试验14篇,类实验研究15篇,队列研究4篇,病例对照研究1篇,病例系列研究34篇,病例报告3篇。研究对象包括1989—2021年18个国家15~79岁患子宫颈癌或癌前病变的女性。癌前病变治疗性疫苗类文献40篇(n=22867)),涉及疫苗6类21种。研究结果显示,与对照组比较,3种已上市的疫苗[希瑞适(Cervarix)、四价疫苗(Gardasil)、九价疫苗(Gardasil 9)]作为辅助免疫治疗在预防癌前病变复发方面具有显著疗效。特异性治疗性疫苗改良牛痘安卡拉E2重组疫苗相关研究已到临床Ⅲ期,改良牛痘安卡拉E2重组疫苗能完全消除大部分高级别癌前病变。癌前病变治疗性疫苗均显示出良好的安全性。子宫颈癌治疗性疫苗类文献31篇(n=781),涉及疫苗7类19种,均未上市。25篇文献研究为无对照研究,结果显示,疫苗在实体瘤疗效评估、预防宫颈癌复发、延长中位生存时间等方面有效,但由于研究缺少对照组,疫苗疗效无法进行统计学检验。9篇研究显示患者经治疗出现严重不良事件,7篇文献报道患者出现的严重不良事件不能排除是宫颈癌治疗性疫苗导致的结果。结论与宫颈癌治疗性疫苗比较,癌前病变治疗性疫苗的文献证据相对较成熟。已上市的4种疫苗均为宫颈癌癌前病变治疗性疫苗,但一般作为手术辅助免疫治疗或阴道感染治疗,不作特异性治疗使用。其他宫颈癌及癌前病变特异性治疗性疫苗均处于研究初期,以小样本量Ⅰ或Ⅱ期临床试验为主,有效性和安全性数据有限,仍有待进一步研究。

Objective To systematically summarize and analyze the clinical research progress of therapeutic vaccines for cervical cancer or precancerous lesions.Methods English databases(PubMed,Embase,Web of Science,Cochrane library,Proquest,and ClinicalTrails.gov)and Chinese databases(SinoMed,CNKI,WanFang,and VIP Database)were systematically searched to collect literature on therapeutic vaccines for cervical cancer or precancerous lesions from inception to February 18,2021.After screening,we evaluated the risk of bias of included studies,and combed the basic information of the literature,research designs,information of vaccines,study patients,outcome indicators and so on,qualitatively summarized the clinical research progress.Results A total of 71 studies were included in this systematic review,including 14 random controlled trials,15 quasi-random controlled trials,4 cohort studies,1 case-control study,34 case series studies and 3 case reports.The study patients included women aged 15~79 with cervical cancer or precancerous lesions in 18 countries from 1989 to 2021.On the one hand,there were 40 studies on therapeutic vaccines for cervical precancerous lesions(22867 participants),involving 21 kinds of vaccines in 6 categories.Results showed 3 marketed vaccines(Cervarix,Gardasil,Gardasil 9)as adjuvant immunotherapies were significant effective in preventing the recurrence of precancerous lesions compared with the conization only.In addition,MVA E2 vaccine had been in phaseⅢclinical trials as a specific therapeutic vaccine,with relative literature showing it could eliminate most high-grade precancerous lesions.Therapeutic vaccines for precancerous lesions all showed good safety.On the other hand,there were 31 studies on therapeutic vaccines for cervical cancer(781 participants),involving 19 kinds of vaccines in 7categories,with none had been marketed.25 studies were with no control group,showing the vaccines could effectively eliminate solid tumors,prevent recurrence,and prolong the median survival time.However,the vaccines effectiveness couldn′t be statistically calculated due to the lack of a control group.As for the safety of therapeutic vaccines for cervical cancer,9 studies showed that patients experienced serious adverse events after treatments,where 7 studies reported that serious adverse events occurred in patients couldn′t be ruled out as the results of therapeutic vaccines.Conclusions The literature review shows that the literature evidence for the therapeutic vaccines for cervical precancerous lesions is relatively mature compared with the therapeutic vaccines for cervical cancer.The four kinds of vaccines on the market are all therapeutic vaccines for precancerous lesions,but they are generally used as vaginal infection treatments or adjuvant immunotherapies for cervical precancerous lesions,not used for the specific treatments of cervical precancerous lesions.Other specific therapeutic vaccines are in the early stage of clinical trials,mainly phaseⅠ/Ⅱclinical trials with small sample size.The effectiveness and safety data are limited,and further research is still needed.