溶瘤病毒T-Vec应用于肿瘤治疗的临床研究进展

T-Vec(talimogene laherparepvec)是由Ⅰ型单纯疱疹病毒(HSV-1)改造而来的一种溶瘤病毒,能够选择性地在恶性肿瘤细胞中复制而不伤及其他正常细胞。T-Vec在治疗晚期黑色素瘤患者的Ⅲ期临床试验中显示出良好的安全性和肿瘤治疗效果,已于2015年经美国FDA批准用于治疗晚期黑色素瘤。为了提高T-Vec的疗效,扩大其应用范围,T-Vec联合其他抗肿瘤疗法以及应用于其他肿瘤的临床试验仍在陆续开展。近期,T-Vec联合免疫检查点抑制剂在治疗晚期黑色素瘤的临床试验中取得新进展,临床数据显示T-Vec联合疗法具有更强的抗肿瘤活性。此外,T-Vec在治疗头颈癌、胰腺癌、肝癌等肿瘤的临床研究中也取得了一定进展。本文对近年来T-Vec治疗肿瘤的临床试验的相关研究进展做一综述。分子疫苗学和分子诊断学国家重点实验室资助项目(No.2016ZY005);;厦门大学国家传染病诊断试剂与疫苗工程技术研究中心自主项目(No.XDHT2016494A)~

Naturally acquired HPV antibodies against subsequent homotypic infection: A large-scale prospective cohort study

宫颈癌是全球15-44岁女性中第二常见的癌症，其主要病因是高危型HPV的感染，尤其是HPV 16型和18型的感染，在我国与约84%的宫颈癌有关。早期研究显示因自然免疫获得抗体的女性再次感染同型HPV的风险降低较为有限（约35%），但在这些研究中多依据IgG抗体而非中和抗体作为自然免疫指标进行保护效果分析。我校研究人员利用国产双价HPV疫苗III期临床试验中未接种HPV疫苗且HPV DNA为阴性的3600余名18-45岁健康女性队列，分别采用中和抗体和IgG抗体作为获得自然免疫的指标，分析其在之后5.5年的随访期间再次感染同型HPV的风险。该研究首次在大样本长期随访队列中以中和抗体作为免疫指标评价HPV自然免疫效果，获得了客观准确的HPV自然免疫数据，丰富了HPV自然史研究，为HPV疫苗接种策略的制订提供了重要依据。我校博士生姚星妹、中国医学科学院肿瘤医院陈汶教授和北京大学人民医院赵超教授为该论文共同第一作者。我校吴婷教授、张军教授、夏宁邵教授和中国医学科学院肿瘤医院乔友林教授、赵方辉教授为该论文的共同通讯作者。Background: Although recent studies have suggested that naturally acquired Human papillomavirus (HPV) antibodies are partly protective against subsequent homotypic infection, the extent of protection remains indecisive. Here, we evaluate the protective effect of neutralizing and IgG antibodies simultaneously. Methods: In a cohort of 3634 women aged 18-45 years from the control arm of a phase III trial of the HPV-16/18 bivalent vaccine, participants were tested for neutralizing antibodies by pseudovirion-based neutralization assay (PBNA) and IgG antibodies by enzyme-linked immunosorbent assay (ELISA) at baseline. HPV-16/18 incident and persistent infections were identified using cervical specimens periodically collected during the 5.5 years of follow-up. The protective effects of HPV-16/18 neutralizing and IgG antibodies against homotypic infection were assessed using a Cox proportional hazard model. Findings: For the persistent infection (PI) endpoints of HPV-16/18 lasting for over 6/12 months, a prevalence of type-specific neutralizing antibodies was highly protective (6-month PI: hazard ratio (HR) = 0.16,95% confidence interval (CI): 0.04, 0.65; 12-month PI: HR = 0.23, 95% CI: 0.06, 0.94), whereas a prevalence of IgG antibodies was associated with minor and non-significant protection (6-month PI: HR = 0.66, 95% CI: 0.40, 1.09; 12-month PI: HR = 0.66, 95% CI: 0.36, 1.20). After increasing the cut-off value to the median IgG level, the risk of 6-month PI was significantly lower in seropositive vs seronegative women (HR = 0.38, 95% CI: 0.18, 0.83). Interpretation: Naturally acquired antibodies are associated with a substantially reduced risk of subsequent homotypic infection.We thank all the study participants and research staff of the HPV-003 Study Group for their contributions to the present study. In addition, we also thank Dr. Allan Hildesheim of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, National Institutes of Health for his helpful comments on this study.该研究获得国家自然科学基金、福建省卫生教育联合攻关计划项目、厦门市科技重大专项、中国医学科学院医学科学创新基金和厦门万泰沧海生物技术有限公司的支持。Funding: NSFC; The Fujian Province Health Education Joint Research Project; Xiamen Science and Technology Major Project; CIFMS; and Xiamen Innovax