Understanding and Enhancing T-Cell Responses to High Risk Human Papillomaviruses-Renewal

项目摘要 据估计，人乳头瘤病毒（HPV）是负责42,700癌症在美国每年， 它引起了超过90%的肛门癌和宫颈癌，以及约70%的口咽癌、阴道癌和外阴癌。 癌的在美国，HPV相关肛门癌和口咽癌的发病率增加， 值得注意的是，宫颈癌是全球妇女第四大常见癌症。这是第二 R 01的竞争性更新，其长期目标是开发HPV的治疗性疫苗。这 是重要的，因为目前可用的预防性疫苗仅对预防HPV感染有效， 而不是在它们建立后就将其消除。估计感染HPV的寿命可能是 男性91.3%，女性84.6%。我们开发并正在测试PepCan，一种治疗性疫苗， 由四种“当前良好的制造级”合成肽组成，其覆盖HPV类型的E6蛋白 16（HPV 16），沿着念珠菌皮试试剂作为一种新的疫苗佐剂。我们的剂量递增单- PepCan治疗宫颈高度鳞状上皮内病变妇女的I期临床试验 （HSILs）最近完成。它证明了安全性，HPV 16病毒载量显着下降， 接种后循环T辅助1型细胞显著增加。随机（分为两个治疗组）， 一项双盲、II期临床试验即将完成招募。此外，在双盲试验中， 安慰剂对照（3：1比例）I/II期临床试验，PepCan正在测试减少鳞状细胞癌复发 头颈部细胞癌患者在治愈治疗后达到“无疾病证据”状态。 以下目的将检验我们的假设，即PepCan诱导HPV特异性免疫应答，导致 减少头颈癌（HNC）的复发，增加HSIL的消退， (i.e., T细胞）到达疾病部位。 目的1：评估我们的HPV治疗性疫苗减少HNC复发的有效性和安全性 和宫颈HSIL消退 目的2：检查影响PepCan反应和疫苗机制的免疫因素 目的3：检查肠道和疾病部位（宫颈和口腔）的微生物组如何有助于 疫苗效力 拟议的研究结果可能导致FDA批准治疗两种HPV相关疾病的疫苗。 癌症和提高对免疫治疗机制的理解。

PROJECT SUMMARY It is estimated that human papillomavirus (HPV) is responsible for 42,700 cancers in the US each year and that it caused more than 90% of anal and cervical cancers and about 70% of oropharyngeal, vaginal, and vulvar cancers. The increases in incidences of HPV-associated anal and oropharyngeal cancers in the US are notable, and cervical cancer is the fourth most common cancer among women globally. This is the second competitive renewal of this R01, which has the long-term goal of developing therapeutic vaccines for HPV. This is significant because currently available prophylactic vaccines are effective only for preventing HPV infections, but not for eliminating them once they are established. The estimated lifetime probably of acquiring HPV is 91.3% for men and 84.6% for women. We developed and are testing PepCan, a therapeutic vaccine that consists of four “current good manufacturing grade” synthetic peptides that cover the E6 protein of HPV type 16 (HPV 16), along with a Candida skin-test reagent as a novel vaccine adjuvant. Our dose-escalation single- site Phase I clinical trial of PepCan to treat women with cervical high-grade squamous intraepithelial lesions (HSILs) was recently completed. It demonstrated safety, a significant decrease in HPV 16 viral load, and a significant increase in circulating T-helper type 1 cells after vaccination. A randomized (to two treatment arms), double-blind, Phase II clinical trial is on track to complete recruitment soon. Furthermore, in a double-blind, placebo-controlled (3:1 ratio) Phase I/II clinical trial, PepCan is being tested to reduce recurrence of squamous cell carcinoma of head and neck in patients who reach “no evidence of disease” status after curative treatment. The following aims will test our hypothesis that PepCan induces HPV-specific immune responses, resulting in reduced recurrence of head and neck cancer (HNC) and increased regression of HSILs when the effector cells (i.e., T-cells) reach the disease sites. Aim 1: Assess efficacy and safety of our HPV therapeutic vaccine for HNC recurrence reduction and cervical HSIL regression Aim 2: Examine immune factors that influence PepCan response and vaccine mechanisms Aim 3: Examine how microbiomes of gut and of disease sites (cervix and mouth) contribute to vaccine efficacy Results of the proposed investigations may lead to FDA approval of a therapeutic vaccine for two HPV-related cancers and to an improved understanding of immunotherapy mechanisms.