Immunotherapeutic HPV cancer vaccines that target Langerhans cells

描述(申请人提供)：人乳头瘤病毒(HPV)是最常见的性传播疾病之一。虽然HPV感染在正常人中的常见表现是亚临床的，但HPV是一种与艾滋病毒相关的重要恶性肿瘤，可导致癌症。最近，FDA批准的HPV预防性疫苗在预防HPV感染方面显示出显著的临床效果，但对感染患者的治疗效果不明显。因此，有必要开发安全有效的针对HPV相关癌症的免疫治疗疫苗，特别是在艾滋病毒感染患者的情况下。免疫治疗疫苗的一个主要免疫臂是细胞免疫。研究表明，HPV癌蛋白E6和E7在HPV感染细胞和肿瘤细胞中有结构性表达。因此，已经测试了几种携带E6/7蛋白多肽的疫苗模型，但这些疫苗在免疫缺陷患者的有效性或安全性方面存在缺陷。这一差距要求开发安全有效的针对HPV相关癌症的免疫治疗疫苗。为了开发针对广泛癌症和感染的新型和有效的免疫治疗疫苗，BIIR建立了一种平台技术，通过抗DC受体抗体载体将抗原直接靶向人类DC亚群。小鼠模型、人体体外和NHP体内研究表明，基于DC靶向的疫苗在低抗原剂量下可诱导强大而广泛的免疫反应。基于DC生物学的最新进展，我们打算开发针对朗格汉斯细胞(LCS)的疫苗。人皮肤中的LC和间质DC(IntDC)激活淋巴细胞的能力不同。IntDC可诱导NAOVE B细胞分化为分泌免疫球蛋白的浆细胞。相比之下，LC是细胞毒性CD8 T淋巴细胞(CTL)的特别有效的诱导者/激活剂，CTL是抗癌的主要免疫手臂。因此，针对LCS的疫苗将诱导对HPV相关癌症的强大细胞免疫。免疫诱导的基础是伴随着DC对抗原的摄取和激活。因此，为了最大限度地发挥疫苗的效力，我们还建议测试疫苗佐剂。在与德克萨斯大学安德森癌症中心科学家的密切合作下，我们将在非人类灵长类动物(NHP)模型中测试我们的免疫治疗方法。这项研究通过开发针对HIV相关恶性肿瘤的安全和有效的免疫治疗疫苗(NIAID RFA-OD-09-0004)来满足GO赠款的前提。这笔赠款将使我们能够保留两名研究助理，并为一名技术人员创造就业机会。 公共卫生相关性：这项研究的最终结果将是开发有效和安全的免疫治疗疫苗，可以为患有HPV相关癌症的患者带来显著的临床益处。这项研究的结果也将对合理设计和开发针对其他癌症和感染的疫苗具有直接影响。重要的是，这项工作将允许保留和创造就业机会。

DESCRIPTION (provided by applicant): Human papillomavirus (HPV) is one of the most common sexually transmitted infections. Although the usual manifestation of HPV infection in normal individuals is subclinical, HPV is an important HIV-related malignancy that causes cancer. Recently, an FDA-approved HPV prophylactic vaccine has shown significant clinical efficacy in prevention of HPV infection, but it exhibits no efficacy in treatment of infected patients. Thus, the development of safe and effective immunotherapeutic vaccines against HPV-associated cancers, particularly in the setting of HIV-infected patients, is necessary. A major immune arm of immunotherapeutic vaccines is cellular immunity. Studies have shown that the HPV oncoproteins, E6 and E7, are constitutively expressed in HPV-infected cells and tumor cells. Thus, several types of vaccine models carrying peptides derived from E6/7 proteins have been tested, but these vaccines have drawbacks either in efficacy or safety in immunodeficient patients. This gap necessitates developing safe and potent immunotherapeutic vaccines against HPV-associated cancer. To develop novel and potent immunotherapeutic vaccines against broad ranges of cancer and infections, BIIR has established a platform technology for targeting antigens directly to human DC subsets via anti-DC receptor antibody vehicles. Mouse model, human in vitro, and NHP in vivo studies show that vaccines based on DC-targeting elicit potent and broad immune responses at low antigen doses. Based upon the recent progresses made in DC biology, we intend to develop vaccines that target Langerhans cells (LCs). LCs and interstitial DCs (intDCs) in human skin differ in their capacity to activate lymphocytes. IntDCs induce the differentiation of naove B cells into immunoglobulin-secreting plasma cells. In contrast, LCs are particularly efficient inducers/activators of cytotoxic CD8+ T lymphocytes (CTLs), the major immune arm against cancer. Thus, vaccines that target LCs will elicit potent cellular immunity against HPV-associated cancer. Fundamental to the induction of immunity is concomitant antigen-uptake and activation by DCs. Thus, to maximize the potency of vaccines, we also propose to test vaccine adjuvants. In a close collaboration with scientists at the University of Texas M. D. Anderson Cancer Center, we will test our immunotherapeutic approach in a non-human primate (NHP) model. This study fulfills the premises of the GO grant by developing safe and potent immunotherapeutic vaccines against HIV-related malignancies (NIAID RFA-OD-09-0004). This grant will allow us to preserve two research assistants and create employment for one technician. PUBLIC HEALTH RELEVANCE: The final outcome of this study will be the development of effective and safe immunotherapeutic vaccines that can bring significant clinical benefit to patients who have HPV-associated cancer. The results of this study will also have immediate implications for the rational design and development of vaccines against other cancers and infections. Importantly, this work will allow preservation and creation of jobs.