A Phase I/II Trial of a Therapeutic HPV Vaccine

描述（由申请人提供）：宫颈癌是一种性传播疾病，是全世界妇女癌症死亡的第二大原因。在全球范围内，HPV 16型在一半以上的宫颈癌及其前体病变宫颈上皮内瘤变（CIN）中发现。HPV E7基因产物在功能上需要维持转化状态，并且在CIN和宫颈癌中持续高水平表达，但在正常组织中不表达。因此，它代表了一个令人信服的免疫治疗靶点。我们已经开发了一种DNA疫苗策略，其目标是HPV16E7的解毒形式（E7detox）到MHC I类加工途径。在临床前TC-1小鼠模型中，接种DNA-Sig/E7（排毒）/HSP70疫苗可引起强烈的E7特异性免疫应答，该应答依赖于CD8 T细胞，而不依赖于CD4 T细胞，从而产生显著的抗肿瘤作用。临床级疫苗已通过国家癌症研究所快速获取干预发展（RAID）计划获得。该提案的总体目标是开展一项I/II期临床试验，从安全性、毒性、有效性和对CIN2/3女性的免疫激活等方面评估该疫苗策略。该提案的优势包括：1)一个多学科的研究团队，在HPV疾病的合作研究中有着长期的承诺和记录，带来了肿瘤免疫学、临床试验、妇科病理学、病毒学和CIN女性临床护理方面的专业知识；2)一种具有强大生物学原理和有希望的临床前数据的新型免疫治疗干预；3)NCI RAID生产的GMP级药物。该项目将促进将十年的临床前疫苗开发转化为hpv相关宫颈疾病的潜在有效免疫疗法。发现与治疗结果相关的免疫学参数可作为疫苗效果的预测因子，提供对这些效果机制的深入了解，并为治疗性HPV疫苗的下一代策略提供信息。

DESCRIPTION (provided by applicant): Cervical cancer, a sexually transmitted disease, is the second leading cause of cancer death in women worldwide. Globally, HPV type 16 is found in over half of all cervical cancers as well as in its precursor lesion, cervical intraepithelial neoplasia (CIN). The HPV E7 gene product is functionally required to maintain the transformed state, and is consistently expressed at high levels in CIN and in cervical cancers, but not in normal tissue. Therefore, it represents a compelling immunotherapeutic target. We have developed a DNA vaccine strategy which targets a detoxified form of HPV16E7 (E7detox) to the MHC class I processing pathway. In the preclinical TC-1 murine model, vaccination with DNA-Sig/E7(detox)/HSP70 elicits a potent E7-specific immune response which is dependent on CD8 T cells but not on CD4 T cells, and furthermore results in significant antitumor effect. Clinical grade vaccine has been procured via the National Cancer Institute Rapid Access to Intervention Development (RAID) program. The overall objective of this proposal is to conduct a phase I/II clinical trial to evaluate this vaccine strategy in terms of safety, toxicity, efficacy, and immune activation in women with CIN2/3. Strengths of this proposal include 1) a multidisciplinary team of investigators with a longstanding commitment and track record together in collaborative research in HPV disease, bringing expertise in tumor immunology, clinical trials, gynecologic pathology, virology, and clinical care of women with CIN, 2) a novel immunotherapeutic intervention with strong biologic rationale and promising preclinical data, and 3) GMP grade drug which has been manufactured by NCI RAID. This project will facilitate translation of a decade of preclinical vaccine development into a potentially effective immunotherapy for HPV-associated cervical disease. Immunological parameters found to be relevant to therapeutic outcomes may be used as predictors of vaccine effects, provide insight into the mechanism of these effects, and inform the future generation of strategies for therapeutic HPV vaccines.