Local TA-CIN/GPI-0100 Vaccination and Imiquimod for Persistent HPV16+/Normal Cytology Patients

宫颈上皮内瘤变（CIN2/3）的Pap筛查和手术切除大大降低了宫颈癌的发病率，但检测缺乏准确性，LEEP/锥形手术切除这些癌前病变与宫颈功能不全和早产有关。最近，为了提高筛查的准确性，特别是对模棱两可的细胞学诊断和30岁以上妇女的筛查准确性，广泛实施了细胞学样本中高危HPV dna的联合检测，特别是HPV16的联合检测。由于一半的持续性HPV16感染进展为CIN2，细胞学正常（上皮内病变和恶性肿瘤阴性，NILM）的HPV16阳性妇女在一年内根据ASCCP指南进行重复联合检测。如果再次出现HPV16+ NILM，这些妇女接受阴道镜检查。这项筛查发现了大量30岁及以上的持续HPV16感染的妇女，这些妇女最终可能会进展并需要手术干预，她们有可能继续传播或在子宫颈和其他肛门生殖器部位发生瘤变，并承受相当大的社会心理压力。我们的总体目标是开发一种安全有效地引发持续宫颈HPV16感染的免疫清除的方案，用于宫颈癌的二级预防，这是一个重要的未满足的医疗需求。肌肉内单独给药HPV16 E6E7L2融合蛋白（称为TA-CIN）对HPV16+高级别疾病影响不大。最近的研究表明，佐剂GPI-0100可以有效地增强细胞对TA-CIN疫苗的免疫应答，以及它们靶向疾病部位的重要性，以及咪喹莫特对疾病清除中局部微环境的影响。我们假设局部炎症和抗原递送到相关的引流淋巴结是有效的生殖道免疫所必需的。因此，我们建议将GPI-0100佐剂配制的TA-CIN用于持续感染HPV16但细胞学正常的妇女的子宫颈，以招募hpv特异性免疫细胞到生殖道，在接种疫苗后立即在子宫颈局部施用咪喹莫特或不启动局部微环境。

Pap screening and surgical removal of cervical intraepithelial neoplasia (CIN2/3) has greatly reduced the incidence of cervical cancer, but testing lacks precision and the LEEP/conization procedure to excise these pre-cancerous lesions is associated with cervical incompetence and premature births. Recently co-testing for high risk HPV DNAs and specifically for HPV16 in cytologic samples has been broadly implemented to improve the accuracy of screening, particularly for equivocal cytologic diagnoses, and co-testing in women of 30 or more years. Since half of all persistent HPV16 infections progress to CIN2, HPV16+ women with normal cytology (negative for intraepithelial lesion and malignancy, NILM) undergo repeat co-testing in one year per ASCCP guidelines. If HPV16+ NILM again, these women undergo colposcopy. This screening identifies large numbers of women 30 years and over with persistent HPV16 infections who are likely to eventually progress and need surgical intervention, with continued potential for transmission or the development of neoplasia at the cervix and other anogenital sites, and suffering considerable psychosocial stress. Our overall goal is to develop a regimen to safely and effectively elicit immune clearance of persistent cervical HPV16 infections for secondary prevention of cervical cancer, an important unmet medical need. Intra-muscular administration of an HPV16 E6E7L2 fusion protein (termed TA-CIN) alone had little impact on HPV16+high grade disease. Recent studies suggest that the adjuvant GPI-0100 potently enhances cellular immune responses to TA-CIN vaccination, the importance of their targeting to the disease site, and the impact of imiquimod on the local microenvironment in disease clearance. We hypothesize that local inflammation and antigen-delivery to relevant draining lymph nodes is required for effective genital tract immunity. Thus we propose to administer TA-CIN formulated with GPI-0100 adjuvant in the cervix of women with persistent HPV16 infections but normal cytology to recruit HPV-specific immune cells to the genital tract, with or without priming the local microenvironment by topical administration of imiquimod on the cervix immediately following vaccination.