DESIGN & DEVELOPMENT OF RECOMBINANT VACCINES FOR CANCER IMMUNOTHERAPY

研究涉及开发新的免疫治疗方法 癌症，包括重组疫苗的设计和分析 针对癌基因和抗原过度表达的基因产物 在肿瘤中。疫苗靶标包括人类癌胚抗原 (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-erb B/2癌基因。用于诱导宿主的疫苗递送载体 细胞免疫反应包括重组牛痘(RV)， 复制缺陷的禽痘病毒、DNA质粒、多肽和 重组蛋白。最近完成的一项I期临床试验 证明晚期癌症患者接种A疫苗后 含有CEA基因的重组痘苗病毒(RV-CEA)可以 诱导细胞毒性T细胞(CTL)对自身抗原CEA的反应。这个 定义了这些T细胞识别的实际表位，并将其用于 建立CTL品系和克隆。这些CTL和其他CTL效用 表位特异性T细胞系过继转移的品系为 目前正在调查中。使用CEA CTL的疫苗试验 多肽、重组癌胚抗原和复制缺陷禽痘病毒 含有CEA的重组体，单独和与RV-CEA结合，是 正在设计中。目前正在进行澄清和分析方面的研究。 经鉴定的CEA CTL的激动肽和拮抗肽 免疫优势表位。初步研究表明，多肽 可以设计成比天然多肽更有效的 细胞毒T细胞系的建立。研究也在进行中， 重组牛痘PSA疫苗及其CTL优势表位 最近发现的多肽。一期临床试验目前正在进行中 反映ras癌基因突变的多肽在肿瘤中的研究进展 密码子12被用来治疗那些肿瘤已经显示为 包含个体突变。这些研究表明， CD_4~+辅助性T细胞和CD_8~+CTL的诱导 突变的ras多肽，而不是原ras或其他突变。正在进行中 研究包括使用多维融合蛋白作为 免疫原与T细胞共刺激分子的开发 无论是基因疗法还是疫苗策略。

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.