HPV VACCINE THERAPY AND CORRELATES OF RESPONSE IN HEAD AND NECK SQUAMOUS CELL

高危型人乳头瘤病毒16型与头颈部肿瘤的关系 和颈部鳞状细胞癌（HNSCC）最近已经确立。鉴于以下因素的因果作用， HPV-16在头颈癌亚群中的作用，包括针对HPV的预防性和治疗性疫苗- 16被认为与HPV-HNSCC的预防和治疗高度相关。HPV病毒 癌蛋白E6和E7在HPV相关的癌症中组成性表达;因此，它们代表了 是开发抗原特异性疫苗的理想靶向肿瘤抗原。在临床前研究中， 发现DMA疫苗包含模型肿瘤抗原（HPV-16 E7），其物理连接到 免疫调节蛋白钙网蛋白（CRT），导致有效的E7特异性CD 8 + T细胞免疫应答 以及对接种疫苗的小鼠中表达E7的肿瘤模型的抗肿瘤作用。该疫苗还 已被证明对表达E7的小鼠肿瘤有效，主要组织相容性下调 复合物（MHC）I类分子;一个重要的发现，考虑到相当大比例的晚期 HNSCC下调MHC I类分子作为免疫逃避的手段。此外，我们发现， CRT/E7 DMA疫苗接种和温和化疗剂表没食子儿茶素-3-没食子酸酯的组合 在绿色茶中发现的化合物表没食子儿茶素没食子酸酯（EGCG）协同作用，增强肿瘤特异性T细胞免疫 反应，以及增强抗肿瘤作用，导致比DNA疫苗接种更高的治愈率 或单独的EGCG。这些发现促使我们研究皮内注射和 CRT/E7基因枪DNA疫苗和口服EGCG是安全的， 在晚期HPV相关头部患者中产生E7特异性CD 8 + T细胞免疫应答， 颈部癌症

The association between the high-risk type-16 of the human papillomavirus (HPV-16) and a subset of head and neck squamous cell carcinomas (HNSCC) has recently been established. Given the causative role of HPV-16 in a subset of head and neck cancers, both prophylactic and therapeutic vaccines targeted to HPV- 16 are accepted as highly relevant for the prevention and treatment of HPV-HNSCC. The HPV viral oncoproteins, E6 and E7, are constitutively expressed in HPV-associated cancers; therefore, they represent ideal target tumor antigens for the development of antigen-specific vaccines. In preclinical studies, we have found that a DMA vaccine comprised of a model tumor antigen (HPV-16 E7) which is physically linked to the immunomodulatory protein calreticulin (CRT), results in potent E7-specific CD8+ T cell immune responses and anti-tumor effects against an E7-expressing tumor model in vaccinated mice. This vaccine has also been proved effective against E7-expressing murine tumors with down-regulated Major Histocompatibility Complex (MHC) class I molecules; an important finding, given a significant proportion of advanced stage HNSCC down-regulate MHC class I molecules as a means of immune evasion. In addition, we found that the combination of CRT/E7 DMAvaccination and a mild chemotherapeutic agent, Epigallocatechin-3-Gallate (EGCG), a compound found in green tea, acted synergistically to enhance tumor-specific T cell immune responses, as well as enhance anti-tumor effects, resulting in a higher cure rate than either DNA vaccination or EGCG alone. These findings have prompted us to investigate whether the combination of intradermal administration of CRT/E7 DNA vaccine via gene gun and oral EGCG administration is safe and able to generate E7-specific CD8+ T cell immune responses in patients with advanced HPV-associated head and neck cancers.