DESIGN & DEVELOPMENT OF RECOMBINANT VACCINES FOR CANCER IMMUNOTHERAPY

研究涉及新的免疫方法的发展 包括重组疫苗的设计和分析 针对癌基因的基因产物和抗原过表达 在肿瘤中。 疫苗靶点包括人类癌胚抗原 (CEA)点突变ras癌基因，前列腺特异性抗原（PSA）， muc-1乳腺、肺和胰腺相关粘蛋白，以及 c-erbB/2癌基因。 用于诱导宿主的疫苗递送的载体 细胞免疫应答包括重组牛痘（RV）， 复制缺陷型禽痘病毒、DNA质粒、肽和 重组蛋白 最近完成的一期临床试验 研究表明，晚期癌症患者接种了 含有CEA基因的重组痘苗病毒（rV-CEA）可 引发对自身抗原CEA的细胞毒性T细胞（CTL）应答。 的 这些T细胞识别的实际表位被定义并用于 建立CTL细胞系和克隆。 这些和其他CTL的效用 表位特异性T细胞系的过继转移中， 目前正在研究中。使用CEA CTL的疫苗试验 肽、重组CEA和复制缺陷型禽痘病毒 含有单独的CEA和与rV-CEA组合的CEA的重组体， 正在设计中。 正在进行研究，以阐明和分析 鉴定的CEA CTL的激动剂和拮抗剂肽 免疫显性表位。 初步研究表明， 可以被设计成比天然肽更有效， 细胞毒性T细胞系的产生。研究也在进行中， 重组痘苗PSA疫苗及PSA CTL免疫优势表位 最近发现的肽。 一项I期临床试验已经在 反映ras癌基因点突变的肽的研究进展， 将密码子12给予肿瘤已显示 包含个体突变。 这些研究表明， 诱导特异性CD 4+辅助性T细胞和CD 8 + CTL， 突变的ras肽而不是原ras或其它突变。正在进行 研究包括使用多维融合蛋白作为 免疫原和T细胞共刺激分子的开发， 基因治疗和疫苗策略。

Research involves the development of novel immunotherapeutic approaches to cancer, including the design and analyses of recombinant vaccines directed against gene products of oncogenes and antigens overexpressed in tumors. Vaccine targets include human carcinoembryonic antigen (CEA), point mutated ras oncogenes, prostate specific antigen (PSA), the muc-1 breast, lung, and pancreatic associated mucin, and the c-erbB/2 oncogene. Vehicles for vaccine delivery for induction of host cellular immune responses include recombinant vaccinia (rV), replication defective avian pox viruses, DNA plasmids, peptides, and recombinant proteins. A Phase I clinical trial recently completed demonstrated that advanced carcinoma patients vaccinated with a recombinant vaccinia virus containing the CEA gene (rV-CEA) could elicit cytotoxic T-cell (CTL) responses to the self antigen CEA. The actual epitopes recognized by these T-cells were defined and used to establish CTL lines and clones. The utility of these and other CTL lines in the adoptive transfer of epitope specific T-cells lines is currently under investigation.Vaccine trials employing CEA CTL peptides, recombinant CEA, and replication defective avian pox virus recombinants containing CEA, alone and in combination with rV-CEA, are being designed. Studies are ongoing in the elucidation and analyses of agonist and antagonist peptides of the identified CEA CTL immunodominant epitopes. Initial studies have indicated that peptides can be designed that are more efficient than the natural peptide in the generation of cytotoxic T-cell lines. Studies are also ongoing with a recombinant vaccinia PSA vaccine, and PSA CTL immunodominant epitope peptides recently identified. A Phase I clinical trial is now in progress in which peptides reflecting ras oncogene point mutations at codon 12 are administered to patients whose tumors have been shown to contain the individual mutation. These studies have shown the induction of both CD4+ helper T-cells and CD8+ CTL specific for the mutated ras peptide and not proto-ras or other mutations. Ongoing studies include the use of multidimensional fusion proteins as immunogens and the exploitation of T-cell co-stimulatory molecules in both gene therapy and vaccine strategies.