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

宫颈上皮内瘤样病变（CIN 2/3）的巴氏筛查和手术切除大大降低了宫颈癌的发病率，但测试缺乏准确性，LEEP/锥切术切除这些癌前病变与宫颈机能不全和早产有关。最近，细胞学样本中高危HPV DNA，特别是HPV 16的联合检测已被广泛实施，以提高筛查的准确性，特别是对于不明确的细胞学诊断，以及对30岁或以上女性的联合检测。由于所有持续性HPV 16感染中有一半进展为CIN 2，细胞学正常的HPV 16+女性（上皮内病变和恶性肿瘤阴性，NILM）根据ASCCP指南在一年内进行重复联合检测。如果HPV 16 + NILM再次，这些妇女进行阴道镜检查。这种筛查确定了大量30岁及以上的妇女持续HPV 16感染，这些妇女最终可能会进展并需要手术干预，在宫颈和其他肛门生殖器部位继续传播或发展肿瘤的可能性，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，安全有效地诱导持续性宫颈HPV 16感染的免疫清除，用于宫颈癌的二级预防，这是一个重要的未满足的医疗需求。单独肌内施用HPV 16 E6 E7 L2融合蛋白（称为TA-CIN）对HPV 16+高级别疾病几乎没有影响。最近的研究表明，佐剂GPI-0100有效地增强了对TA-CIN疫苗接种的细胞免疫应答、它们靶向疾病部位的重要性以及咪喹莫特在疾病清除中对局部微环境的影响。我们推测，局部炎症和相关引流淋巴结的抗原递送是有效的生殖道免疫所必需的。因此，我们建议在患有持续性HPV 16感染但细胞学正常的女性宫颈中给予与GPI-0100佐剂配制的TA-CIN，以将HPV特异性免疫细胞募集到生殖道，无论是否通过局部给予咪喹莫特来启动局部微环境接种疫苗后立即在宫颈上。

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.