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