ANTIGEN SPECIFIC T CELL ACTIVATION, APPLICATION TO VACCINES FOR CANCER AND AIDS

抗原特异性 T 细胞激活，在癌症和艾滋病疫苗中的应用

• 批准号: 2456830
• 负责人: J A BERZOFSKY
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2456830
• 关键词: AIDS therapy; AIDS vaccines; HIV envelope protein gp160; MHC class I antigen; T cell receptor; cellular immunity; clinical research; clinical trial phase I; cytotoxic T lymphocyte; drug design /synthesis /production; epitope mapping; human subject; human therapy evaluation; immunotherapy; interleukin 2; laboratory mouse; leukocyte activation /transformation; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; neutralizing antibody; synthetic vaccines; vaccine development; virus infection mechanism

We studied the mechanisms for T cell recognition of antigens in association with major histocompatibility complex (MHC)-encoded molecules, and applications to the design of synthetic vaccines for AIDS and cancer. We developed synthetic vaccines for HIV using broadly reactive HIV helper, cytotoxic T lymphocyte (CTL) and neutralizing antibody epitopes, and showed the importance of an intrinsic or covalently linked helper epitope for induction of CTL. We developed ways to steer responses with cytokines. Using an adjuvant that we found allowed induction of CTL, TH1 help, and neutralizing antibodies, we commenced a human phase I immunotherapy trial with these vaccine constructs. Initial results show induction of a new HIV peptide-specific CTL response in one patient not present prior to vaccination, the first induction of CTL with a peptide vaccine in humans. We found in murine studies that peptide vaccines for HIV can be made more potent or more broadly effective by selective introduction of mutations that improve binding to MHC or T-cell receptors ("epitope enhancement") and demonstrated proof of principle with second generation synthetic vaccine constructs in mice. To apply these approaches to human vaccines we studied the binding of HIV envelope and reverse transcriptase peptides to human HLA molecules, raised HIV peptide-specific human CTL, and mapped the residues involved in binding to HLA-A2 and to the T-cell receptor (TCR). We showed that avidity of CTL can be selected and plays a profound role in efficacy for adoptive immunotherapy of viral infection. However, high concentrations of antigen can induce apoptosis of high avidity CTL by a TNF-dependent, fas-independent mechanism. We showed that free peptide inhibits CTL, by a self-veto-like mechanism involving dual engagement of MHC and TCR on the TCR. We showed the profound effect of cytokine imbalance on CTL activity and identified cells that suppress the CTL response. We identified several CTL epitopes in proteins of the hepatitis C virus that causes liver cancer using a novel approach, and developed model vaccine constructs. We showed an inverse correlation between IL-2 response to human papillomavirus peptides and stage of cervical neoplastic disease, the first specific T-cell response correlated with progression of human neoplasia. We developed peptide cancer vaccines inducing CTL immunity to mutant p53 expressed in cancer cells. We induced murine CTL against fusion proteins from chromosomal translocations in pediatric tumors, that protect mice. 23 patients have been entered in a phase I/II clinical trial of the mutant p53/ras peptide vaccine.

我们研究了T细胞识别抗原的机制 与主要的组织相容性复合物（MHC）编码的分子相关， 以及用于设计艾滋病和癌症的合成疫苗的应用。 我们使用广泛反应性的HIV助手开发了用于HIV的合成疫苗， 细胞毒性T淋巴细胞（CTL）和中和抗体表位和 显示了固有或共价连接的辅助表位的重要性 用于诱导CTL。我们开发了用细胞因子引导反应的方法。 使用我们发现允许CTL，TH1帮助和 中和抗体，我们开始了人类I期免疫疗法试验 使用这些疫苗构建体。初始结果表明诱导了新的艾滋病毒 一名不存在之前的患者的肽特异性CTL反应 疫苗接种，是人类中用肽疫苗的首次诱导CTL。 我们在鼠研究中发现，可以使HIV肽疫苗更多 通过选择性引入突变，有效或更广泛地有效 改善了与MHC或T细胞受体的结合（“表位增强”） 并证明了第二代合成的原理证明 小鼠的疫苗构建体。将这些方法应用于人类疫苗 研究了HIV包膜和逆转录酶肽与 人HLA分子，提高HIV肽特异性人CTL，并映射 与HLA-A2结合和与T细胞受体（TCR）结合的残基。 我们表明，可以选择CTL的亲和力，并在 病毒感染免疫疗法的功效。但是，高 抗原的浓度会诱导A的高潮CTL凋亡 TNF依赖性，独立于FAS的机制。我们证明了游离肽 通过涉及双重参与的自veto样机制来抑制CTL MHC和TCR上的TCR。我们展示了细胞因子的深刻作用 CTL活性的不平衡和识别抑制CTL的细胞 回复。我们确定了肝炎蛋白质中的几个CTL表位 C病毒使用一种新方法引起肝癌，并开发 模型疫苗构建体。我们显示IL-2之间的反相关性 对人乳头瘤病毒肽的反应和宫颈肿瘤的阶段 疾病，第一个特定的T细胞响应与 人类肿瘤。我们开发了诱导CTL的肽癌疫苗 对在癌细胞中表达的突变体p53的免疫力。 我们诱导了鼠CTL 针对小儿染色体易位的融合蛋白 肿瘤，保护小鼠。 23例患者已进入I/II期 突变体P53/RAS肽疫苗的临床试验。