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筛查和手术切除已大大降低了宫颈癌的发生率，但检测缺乏精确度，而切除这些癌前病变的LEEP/锥切术与宫颈功能不全和早产有关。最近，联合检测高危HPVDNA，特别是细胞学样本中的HPV16，已被广泛实施，以提高筛查的准确性，特别是对于可疑的细胞学诊断，以及在30岁或30岁以上的女性中的联合检测。由于一半的持续性HPV16感染进展为CIN2，根据ASCCP指南，细胞学正常(上皮内病变和恶性肿瘤阴性，NILM)的HPV16+妇女在一年内接受重复联合检测。如果HPV16+NILM再次出现，这些妇女将接受阴道镜检查。这项筛查确定了大量30岁及以上持续感染HPV16的妇女，她们最终可能会进展，需要手术治疗，有可能继续传播或在宫颈和其他肛门生殖部位发生肿瘤，并遭受相当大的心理社会压力。我们的总体目标是开发一种方案，以安全和有效地诱导持续的宫颈HPV16感染的免疫清除，用于宫颈癌的二级预防，这是一个重要的未得到满足的医疗需求。单独肌肉注射HPV16E6E7L2融合蛋白(称为TA-CIN)对HPV16+高级别疾病几乎没有影响。最近的研究表明，佐剂GPI-0100有效地增强了TA-CIN疫苗接种后的细胞免疫反应，它们针对疾病部位的重要性，以及咪喹莫特在清除疾病过程中对局部微环境的影响。我们推测，有效的生殖道免疫需要局部炎症和相关引流淋巴结的抗原传递。因此，我们建议将GPI-0100佐剂配制的TA-CIN用于持续HPV16感染但细胞学正常的妇女的宫颈，以将HPV特异性免疫细胞招募到生殖道，无论是否启动局部微环境，在接种疫苗后立即在宫颈局部给药咪喹莫特。

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.