A Therapeutic Vaccine for HPV 16-Positive Head and Neck Cancer

描述（由申请方提供）：合理靶向治疗的重点是识别维持恶性表型所必需的肿瘤细胞特异性分子遗传学改变。人乳头瘤病毒（HPV）的病毒癌蛋白E6和E7是HPV相关恶性肿瘤的靶点。病毒癌蛋白E6和E7在HPV相关癌症中一致表达，是维持恶性表型所必需的，并且与人类蛋白质没有已知的同源性。因此，E6和E7癌蛋白是免疫调节疗法的理想靶点，该疗法旨在增强对肿瘤特异性抗原的细胞免疫应答。我们小组开发了一种治疗性裸DMA疫苗（pNGVL 4a-HPV 16 Sig/E7（排毒）/HSP 70），旨在增强对HPV 16阳性肿瘤表达的E7蛋白的细胞免疫反应。该疫苗在临床前模型系统中对已建立的表达E7的鼠肿瘤表现出显著的效力，并且在临床前毒理学研究中表现出最小的毒性。最近，HPV 16已被确定为头颈部鳞状细胞癌（HNSCC）的一个独特的子集的病因学的作用，从而提供了一个新的治疗目标，这种恶性肿瘤。我们假设，在未来的III期试验中，对诊断为HPV 16阳性的HNSCC患者施用pNGVL 4a-HPV 16 Sig/E7（detox）/HSP 70疫苗将增强对E7蛋白的细胞免疫应答，根除微小残留疾病，并改善疾病特异性生存。本提案的总体目标是通过对III期和IV期HPV 16阳性HNSCC癌症患者进行四次肌内疫苗接种的I期开放标签剂量递增试验，评估pNGVL 4a-HPV 16 Sig/E7（detox）/HSP 70的可行性、安全性和免疫原性。临床级pNGVL 4a-HPV 16 Sig/E7（detox）/HSP 70已在快速获得干预开发（RAID）计划的支持下生产，研究性新药申请（BB-IND 11713）已获得美国食品药品监督管理局的批准。本申请旨在请求为临床试验提供财务支持，包括研究护士支持、数据管理支持、临床试验合规性和稽查服务以及临床标本处理和储存。

DESCRIPTION (provided by applicant): The focus of rationally targeted therapies is to identify molecular-genetic alterations specific to tumor cells that are necessary for maintenance of the malignant phenotype. The viral oncoproteins of human papillomavirus (HPV), E6 and E7, are such targets for HPV-associated malignancies. The viral oncoproteins E6 and E7 are consistently expressed in HPV-associated cancers, are necessary for maintenance of the malignant phenotype, and have no known homology to human proteins. E6 and E7 oncoproteins are therefore ideal targets for immunomodulatory therapies designed to augment the cellular immune response to a tumor-specific antigen. Our group has developed a therapeutic, naked DMA vaccine (pNGVL4a-HPV16 Sig/E7(detox)/HSP70) designed to enhance the cellular immune response to the E7 protein expressed by HPV16-positive tumors. This vaccine has demonstrated significant potency in preclinical model systems against established E7-expressing murine tumors and minimal toxicity in preclinical toxicology studies. Recently, HPV16 has been determined to play an etiologic role for a distinct subset of head and neck squamous cell carcinomas (HNSCC), thus providing a new therapeutic target for this malignancy. We hypothesize that administration of pNGVL4a-HPV16 Sig/E7(detox)/HSP70 vaccine to patients with a diagnosis of HPV16-positive HNSCC will augment the cellular immune response to E7 protein, eradicate minimal residual disease, and improve disease-specific survival in future phase III trials. The overall objective of this proposal is to evaluate the feasibility, safety and immunogenicity of pNGVL4a-HPV16 Sig/E7(detox)/HSP70 by performing a phase I open-label dose escalation trial of four intramuscular vaccinations administered in the adjuvant setting to patients with Stage III and IV HPV16-positive HNSCC cancer. Clinical grade pNGVL4a-HPV16 Sig/E7(detox)/HSP70 has been produced with support from the Rapid Access to Intervention Development (RAID) program and The Investigational New Drug Application (BB-IND 11713) has been approved by the Food and Drug Administration. This application is written to request financial support for the clinical trial, including research nurse support, data management support, clinical trails compliance and auditing services, and clinical specimen processing and storage.