Lu Liangjian, Yan Haixi, Shyam-Sundar Vijay, Janowitz Tobias
School of Clinical Medicine, University of Cambridge, Cambridge, UK.
Cancer Research UK, Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.
Drug Des Devel Ther. 2014 Sep 27;8:1539-53. doi: 10.2147/DDDT.S65963. eCollection 2014.
Cancer vaccination has been researched as a means of treating and preventing cancer, but successful translational efforts yielding clinical therapeutics have been limited. Numerous reasons have been offered in explanation, pertaining both to the vaccine formulation, and the clinical trial methodology used. This study aims to characterize the tumor vaccine clinical trial landscape quantitatively, and explore the possible validity of the offered explanations including the translational obstacles posed by the current common endpoints.
We performed a detailed cross-sectional and longitudinal analysis of tumor vaccine trials (n=955) registered in the US Clinical Trials database.
The number of tumor vaccine trials initiated per annum has declined 30% since a peak in 2008. In terms of vaccine formulation, 25% of trials use tumor cell/lysate preparations; whereas, 73% of trials vaccinate subjects against defined protein/peptide antigens. Also, 68% of trials do not use vectors for antigen delivery. Both these characteristics of tumor vaccines have remained unchanged since 1996. The top five types of cancer studied are: melanoma (22.6%); cervical cancer (13.0%); breast cancer (11.3%); lung cancer (9.5%); and prostate cancer (9.4%). In addition, 86% of the trials are performed where there is established disease rather than prophylactically, of which 67% are performed exclusively in the adjuvant setting. Also, 42% of Phase II trials do not measure any survival-related endpoint, and only 23% of Phase III trials assess the immune response to vaccination.
The clinical trial effort in tumor vaccination is declining, necessitating a greater urgency in identifying and removing the obstacles to clinical translation. These obstacles may include: 1) vaccination against a small range of antigens; 2) naked delivery of antigen; 3) investigation of less immunogenic cancer types; and 4) investigation in the setting of established disease. In addition, the prevalence of late phase failure may be due to inadequate assessment of survival-related endpoints in Phase II trials. The clinical trial development of tumor vaccines should include mechanism-based translational endpoints, as well as the discovery of immune biomarkers with which to stratify, monitor, and prognosticate patients.
癌症疫苗接种已作为一种治疗和预防癌症的手段进行了研究，但成功转化为临床治疗方法的努力一直有限。对此有诸多原因，涉及疫苗配方和所使用的临床试验方法。本研究旨在定量描述肿瘤疫苗临床试验的情况，并探讨所提出解释的可能有效性，包括当前常用终点所带来的转化障碍。
我们对在美国临床试验数据库中注册的肿瘤疫苗试验（n = 955）进行了详细的横断面和纵向分析。
自2008年达到峰值以来，每年启动的肿瘤疫苗试验数量下降了30%。在疫苗配方方面，25%的试验使用肿瘤细胞/裂解物制剂；而73%的试验针对特定蛋白质/肽抗原对受试者进行接种。此外，68%的试验不使用载体进行抗原递送。自1996年以来，肿瘤疫苗的这两个特征一直未变。研究的前五种癌症类型为：黑色素瘤（22.6%）；宫颈癌（13.0%）；乳腺癌（11.3%）；肺癌（9.5%）；前列腺癌（9.4%）。此外，86%的试验是在已有疾病的情况下进行，而非预防性试验，其中67%仅在辅助治疗环境中进行。另外，42%的II期试验未测量任何与生存相关的终点，只有23%的III期试验评估了对疫苗接种的免疫反应。
肿瘤疫苗接种的临床试验工作正在减少，因此更迫切需要识别并消除临床转化的障碍。这些障碍可能包括：1）针对少数抗原进行接种；2）裸抗原递送；3）对免疫原性较低的癌症类型进行研究；4）在已有疾病的情况下进行研究。此外，晚期失败的普遍性可能是由于II期试验中对与生存相关终点评估不足所致。肿瘤疫苗的临床试验开发应包括基于机制的转化终点，以及发现用于对患者进行分层、监测和预后判断的免疫生物标志物。
