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

项目总结 据估计，在美国，人类乳头瘤病毒(HPV)每年导致42,700例癌症， 它导致了90%以上的肛门癌和宫颈癌，以及大约70%的口咽癌、阴道癌和外阴癌。 癌症。在美国，与HPV相关的肛门癌和口咽癌的发病率增加了 值得注意的是，宫颈癌是全球女性最常见的第四大癌症。这是第二次 R01的竞争性更新，其长期目标是开发HPV治疗性疫苗。这 意义重大，因为目前可用的预防性疫苗仅对预防HPV感染有效， 但不是为了一旦它们建立起来就消除它们。感染HPV的估计寿命可能是 男性占91.3%，女性占84.6%。我们开发并正在测试PepCan，一种治疗性疫苗， 由四种覆盖HPV型E6蛋白的“当前良好制造级”合成多肽组成 16(HPV16)，以及假丝酵母菌皮试试剂作为一种新的疫苗佐剂。我们的剂量递增单次- PepCan治疗宫颈高度鳞状上皮内病变的现场I期临床试验 (HSIL)最近完成。它证明了安全性，显著降低了HPV16型病毒载量，并 免疫后外周血中T辅助细胞数量显著增加。一个随机的(到两个治疗臂)， 双盲、二期临床试验即将完成招募。此外，在双盲法中， 安慰剂对照(3：1比例)I/II期临床试验，PepCan正在测试以减少鳞状细胞癌的复发 头颈部细胞癌是指经治疗后达到“无疾病证据”状态的患者。 以下目标将检验我们的假设，即PepCan诱导HPV特异性免疫反应，导致 减少头颈癌(HNC)的复发和增加HSIL的消退 (即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 和颈椎HSIL回归 目的2：检测影响PepCan反应的免疫因素和疫苗机制 目标3：检查肠道和病变部位(宫颈和口腔)的微生物群如何有助于 疫苗效力 拟议的调查结果可能导致FDA批准两种与HPV相关的治疗性疫苗 对癌症的研究以及对免疫治疗机制的更好理解。

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.