背景:溶瘤病毒疗法治疗晚期黑色素瘤的有效性和安全性仍存在争议。有必要在临床前试验报告的基础上进行定量评价。
方法:公开可用的数据库(PubMed,Embase,Medline,WebofScience和Cochrane图书馆。)和登记册(Clinicaltrials.gov)进行搜索,以收集溶瘤病毒疗法的治疗结果(包括1型单纯疱疹病毒(HSV),柯萨奇病毒A21(CVA21),腺病毒,痘病毒和呼肠孤病毒)用于晚期/不可切除的黑色素瘤。治疗反应的比较,不同病毒治疗的不良事件(AE)和生存分析由R软件根据来自符合条件的研究的数据进行.
结果:最后,对34项符合条件的研究进行了分析,HSV病毒疗法的平均完全缓解率最高(CR,24.8%),HSV的平均总反应率(ORR)略高于CVA21(43.8%vs42.6%)。在比较有或没有GM-CSF/ICIs(免疫检查点抑制剂)的talimoogenelaherparepve(T-VEC)与GM-CSF/ICIs单一疗法的汇总结果中,表明病毒疗法在CR亚组中更有效(RR=1.80,95%CI[1.30;2.51],P<0.01),ORR(RR=1.17,95%CI[1.02;1.34],P<0.05),和DCR(RR=1.27,95%CI[1.15;1.40],P<0.01)。在接受T-VEC+ICIs治疗的患者中,2年总生存期(12.1±6.9个月)和无进展生存期(9.9±6.9)明显长于单独使用T-VEC治疗的患者。此外,我们发现,AEs在病毒治疗中经常发生,但在大量入选患者队列中有所下降,其中一些,如腹胀/疼痛,注射部位疼痛和瘙痒,在接受T-VEC单药治疗的患者中,发现与疾病进展呈正相关。
结论:鉴于溶瘤病毒的相对安全性和耐受性,缺乏剂量限制依赖性毒性的报告,未来的评估分析中应增加更多接受T-VEC治疗且有或无ICIs的患者.在将其用作晚期或不可切除的黑色素瘤患者的一线治疗之前,还有很长的路要走。
The efficacy and safety of oncolytic virotherapies in the treatment of advanced melanoma still remains controversal. It is necessary to conduct quantitative evaluation on the basis of preclinical trial reports.
Publicly available databases (PubMed, Embase, Medline, Web of Science and Cochrane Library.) and register (Clinicaltrials.gov) were searched to collect treatment outcomes of oncolytic virotherapies (including herpes simplex virus type 1 (HSV), coxsackievirus A21 (CVA21), adenovirus, poxvirus and reovirus) for advanced/unresectable melanoma. Comparisons of treatment response, adverse events (AEs) and survival analyses for different virotherapies were performed by R software based on the extracted data from eligible studies.
Finally, thirty-four eligible studies were analysed and HSV virotherapy had the highest average complete response (CR, 24.8%) and HSV had a slightly higher average overall response rate (ORR) than CVA21 (43.8% vs 42.6%). In the pooled results of comparing talimogene laherparepve (T-VEC) with or without GM-CSF/ICIs (immune checkpoint inhibitors) to GM-CSF/ICIs monotherapy suggested virotherapy was more efficient in subgroups CR (RR = 1.80, 95% CI [1.30; 2.51], P < 0.01), ORR (RR = 1.17, 95% CI [1.02; 1.34], P < 0.05), and DCR (RR = 1.27, 95% CI [1.15; 1.40], P < 0.01). In patients treated with T-VEC+ICIs, 2-year overall survival (12.1 ± 6.9 months) and progression-free survival (9.9 ± 6.9) were significantly longer than those treated with T-VEC alone. Furthermore, we found that AEs occurred frequently in virotherapy but decreased in a large cohort of enrolled patients, some of which, such as abdominal distension/pain, injection site pain and pruritus, were found to be positively associated with disease progression in patients treated with T-VEC monotherapy.
Given the relative safety and tolerability of oncolytic viruses, and the lack of reports of dose-limiting-dependent toxicities, more patients treated with T-VEC with or without ICIs should be added to future assessment analyses. There is still a long way to go before it can be used as a first-line therapy for patients with advanced or unresectable melanoma.