Immunotherapeutic HPV cancer vaccines that target Langerhans cells

针对朗格汉斯细胞的免疫治疗 HPV 癌症疫苗

• 批准号: 7943949
• 负责人: GERARD ZURAWSKI
• 金额: $ 49.96万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943949
• 关键词: Activated Lymphocyte; Animals; Antigen Targeting; Antigens; Attenuated; Autoimmunity; B-Lymphocytes; Beds; Biological Preservation; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cancer Etiology; Cancer Vaccines; Cells; Cellular Immunity; Cellular biology; Clinical; Collaborations; Communicable Diseases; Dendritic Cells; Dendritic cell activation; Development; Dose; Employment; Engineering; Exhibits; FDA approved; Fc Receptor; Grant; HIV; Helper-Inducer T-Lymphocyte; Human; Human Papillomavirus; Human papilloma virus infection; Hypersensitivity; Immune; Immune response; Immune system; Immunity; Immunoglobulins; Immunologist; Immunology; Immunotherapeutic agent; In Vitro; Individual; Infection; Institutes; Langerhans cell; Life; Macaca mulatta; Malignant Neoplasms; Medicine; Modeling; Molecular; National Institute of Allergy and Infectious Disease; Occupations; Oncogene Proteins; Outcome Study; Patients; Peptides; Physicians; Plasma Cells; Prevention; Proteins; Recombinant Vaccines; Research; Safety; Scientist; Sexually Transmitted Diseases; Skin; Software Engineering; Specialist; T-Lymphocyte; Technology; Testing; Therapeutic; Translations; University of Texas M D Anderson Cancer Center; Vaccine Adjuvant; Vaccines; Validation; Work; arm; base; clinical efficacy; cytotoxic; design; immunogenicity; in vivo; interstitial; meetings; mouse model; multidisciplinary; neoplastic cell; nonhuman primate; novel; novel therapeutics; novel vaccines; prophylactic; public health relevance; therapeutic vaccine; uptake; vaccine development; vaccine evaluation; vector

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.

描述（由申请人提供）：人乳头瘤病毒（HPV）是最常见的性传播感染之一。虽然正常人群中HPV感染的通常表现为亚临床，但HPV是一种重要的hiv相关恶性肿瘤，可导致癌症。最近，fda批准的一种HPV预防疫苗在预防HPV感染方面显示出显著的临床疗效，但对感染患者的治疗没有疗效。因此，开发安全有效的针对人乳头瘤病毒相关癌症的免疫治疗疫苗，特别是针对艾滋病毒感染患者，是必要的。免疫治疗性疫苗的一个主要免疫分支是细胞免疫。研究表明，HPV癌蛋白E6和E7在HPV感染细胞和肿瘤细胞中均有组成性表达。因此，已经测试了几种携带E6/7蛋白衍生肽的疫苗模型，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。这一差距需要开发安全有效的针对hpv相关癌症的免疫治疗疫苗。为了开发针对多种癌症和感染的新型有效免疫治疗疫苗，BIIR已经建立了一个平台技术，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引起有效和广泛的免疫反应。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。人类皮肤的lc和间质dc （intdc）在激活淋巴细胞的能力上有所不同。intdc诱导幼稚B细胞分化为分泌免疫球蛋白的浆细胞。相反，lc是细胞毒性CD8+ T淋巴细胞（ctl）的特别有效的诱导剂/激活剂，ctl是对抗癌症的主要免疫臂。因此，针对lccs的疫苗将引发针对hpv相关癌症的强效细胞免疫。诱导免疫的基础是伴随抗原的摄取和dc的激活。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。我们将与德克萨斯大学安德森癌症中心的科学家密切合作，在非人灵长类动物（NHP）模型中测试我们的免疫治疗方法。本研究通过开发针对hiv相关恶性肿瘤的安全有效的免疫治疗疫苗（NIAID RFA-OD-09-0004），实现了GO拨款的前提。这笔拨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。