ERB 2NEU DNA VACCINES FOR BREAST CANCER IMMUNOTHERAPY

描述(改编自《调查者摘要》)：本项目 评估erb B-2/neu免疫治疗肿瘤疾病的潜力 DNA疫苗在转基因未激活大鼠神经细胞中的应用 致癌基因。这些小鼠都会出现高表达的乳腺肿瘤。 Neu水平，因此可以作为癌症患者的模型 过度表达人类neu同源基因erb B-2。调查人员已经做出了 编码erb B-2(PERB B-2)或大鼠Neu(Pneu)的质粒载体可诱导 肌肉或真皮注射erb B-2或neu的免疫反应 (ID)。研究人员发现，pneu可以诱导保护性免疫。 在FVB/N非TG小鼠中过继转移其他同基因neu-1 表达FVB/N neu-TG小鼠来源的乳腺肿瘤。然而，他们 还发现FVB/N小鼠具有与不良相关的H-2单倍型 PErbB-2/neu DNA疫苗的免疫应答潜力，可以说是有限的 它们在FVB/N neu-TG小鼠中打破对neu的自我耐受的能力。他们 已经将neu转基因基因培育到了具有高反应性的小鼠品系上 对PERB B-2和Pneu的潜力(例如BALB/c)。初步研究表明 在带有H-2d的neu-TG小鼠中，对neu的自我耐受可以被打破 通过ID注射pErbB-2进行单倍型。在此基础上并行完成的工作 该项目已经开发出了诱导所需免疫的改进策略 对DNA疫苗编码的抗原的反应。调查人员 发现编码嵌合抗原的质粒是快速反应的目标 依赖蛋白酶体的降解显著更有效地 诱导特异性细胞毒性T淋巴细胞(CTL)反应优于常规 DNA疫苗。此外，他们还发现，联合注射DNA 编码CD40配体(CD154)的疫苗可显著 提高对转基因抗原的免疫反应。他们将测试是否 这些策略增强了他们打破对Neu和Neu的自我容忍的能力 诱导对从头感染或过继转移的保护性免疫 Neu-tg小鼠中neu表达的乳腺肿瘤。此外，他们还将比较 这类DNA疫苗策略与使用的相对有效性 ErbB-2/neu多肽冲击的抗原提呈细胞诱导CTL抗 高表达erb B-2/neu原癌基因的同基因细胞。

DESCRIPTION (Adapted from the Investigator's Abstract): This project evaluates the potential of erb B-2/neu immunotherapy for neoplastic disease using DNA vaccines in mice transgenic for the non-activated rat neu oncogene. These mice uniformly develop mammary tumors that express high levels of neu, and thus serve as a model for patients with cancers that overexpress erb B-2, the human neu homologue. The investigators have made plasmid vectors encoding erb B-2 (pErb B-2) or rat neu (Pneu) that induce immune responses to erb B-2 or neu when injected into muscle (IM) or dermis (ID). The investigators have found that pNeu can induce protective immunity in FVB/N non-Tg mice from the adoptive transfer of otherwise syngeneic neu- expressing mammary tumors derived from FVB/N neu-Tg mice. However, they also find that FVB/N mice have an H-2 haplotype associated with a poor immune response potential to pErbB-2/neu DNA vaccines, arguably limiting their capacity to break self-tolerance to neu in FVB/N neu-Tg mice. They have bred the neu transgene onto strains of mice that have a high response potential to pErb B-2 and pNeu (e.g. BALB/c). Preliminary studies indicate that self-tolerance to neu can be broken in neu-Tg mice with the H-2d haplotype by ID injections of pErbB-2. Work done in parallel on this project has developed improved strategies for inducing desired immune responses against the antigens encoded by DNA vaccines. The investigators find that plasmids that encode chimeric antigens that are targeted for rapid proteasome-dependent degradation are significantly more efficient in inducing specific cytotoxic T lymphocyte ( CTL) responses than conventional DNA vaccines. In addition they have found that co-injection of a DNA vaccine with the plasmid encoding the CD40-ligand (CD154) can significantly improve the immune response to a transgene antigen. They will test whether these strategies enhance their ability to break self-tolerance to neu and induce protective immunity against de novo or adoptively transferred neu-expressing mammary tumors in neu-Tg mice. In addition they will compare the relative efficacy of such DNA vaccines strategies with that of using erbB-2/neu peptide-pulsed antigen presenting cells to induce CTL against syngeneic cells expressing high levels of the erb B-2/neu proto-oncogene.