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。疫苗靶标包括人癌胚抗原（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。车辆 用于诱导宿主细胞免疫应答的疫苗递送包括 复制缺陷型重组牛痘病毒 （禽痘）、免疫显性肽和重组蛋白。一期 临床试验已经证明，当晚期癌症 患者接种重组牛痘病毒或重组 含有CEA基因的禽痘病毒，细胞毒性T细胞（CTL）反应是 自身抗原CEA诱导。这些细胞识别的实际表位 T细胞现已被定义并用于建立CEA特异性CTL 线和克隆。这些和其他CTL系在免疫治疗中的效用是显而易见的。 表位特异性T细胞的过继转移目前正在进行 使用CEA CTL肽的疫苗试验， 佐剂或在树突状细胞上脉冲的研究正在进行中。 正在进行的激动剂肽的阐明和分析， 鉴定了CEA CTL免疫显性表位。初步研究表明， 表明肽可以被设计成比 天然肽在产生细胞毒性T细胞系中的作用。临床 在前列腺癌患者中， PSA疫苗。PSA CTL免疫显性表位肽还具有 最近在体外研究中被发现。i期临床试验 现在正在进行中，其中反映ras癌基因点的肽 将密码子12处的突变给予肿瘤具有以下特征的患者： 被证明含有个体突变。这些研究表明 特异性的CD 4+辅助性T细胞和CD 8 + CTL的诱导， 突变的ras肽而不是原ras。正在进行的临床前研究 包括使用多维融合蛋白作为免疫原， 痘病毒载体中T细胞共刺激分子的开发 在基因治疗和疫苗策略中。

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), and the muc-1 breast, lung, and pancreatic associated mucin. Vehicles for vaccine delivery for induction of host cellular immune responses include recombinant vaccinia (rV), replication defective avian pox viruses (avipox), immunodominant peptides, and recombinant proteins. Phase I clinical trials have now demonstrated that when advanced carcinoma patients are vaccinated with recombinant vaccinia virus or recombinant avipox containing the CEA gene, cytotoxic T-cell (CTL) responses are induced to the self antigen CEA. The actual epitopes recognized by these T-cells have now been defined and used to establish CEA-specific CTL lines and clones. The utility of these and other CTL lines in the adoptive transfer of epitope specific T-cells is currently under investigation.Vaccine trials employing CEA CTL peptides, either in adjuvant or pulsed on dendritic cells, are in progress.Studies are ongoing in the elucidation and analyses of agonist 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. Clinical trials are also ongoing in prostate cancer patients with a recombinant vaccinia PSA vaccine. PSA CTL immunodominant epitope peptides have also recently been identified in in vitro studies. 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. Ongoing preclinical studies include the use of multidimensional fusion proteins as immunogens and the exploitation of T-cell co-stimulatory molecules in pox virus vectors in both gene therapy and vaccine strategies.