ENHANCED IMMUNOGENICITY OF NEUROBLASTOMA CELLS BY GENETIC ENGINEERING

通过基因工程增强神经母细胞瘤细胞的免疫原性

• 批准号: 6102903
• 负责人: Joseph David Rosenblatt
• 金额: --
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 1998-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6102903
• 关键词: MHC class I antigen; Retroviridae; child (0-11); clinical trials; clone cells; cytokine; cytotoxic T lymphocyte; gene therapy; genetic transduction; human subject; human therapy evaluation; minimal residual disease; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neuroblastoma; pediatric neoplasm /cancer

Neuroblastoma is the most common extracranial solid tumor in children. Despite the ability to achieve minimal residual disease (MRD) with myeloablative therapy and autologous bone marrow transplantation (ABMT), over 50% of high risk patients develop recurrent fatal disease. We wish to determine whether active specific immunotherapy with neuroblastoma cells engineered to evoke an immune response can play a role in eradication of MRD and improve prognosis for high risk patients. We shall introduce cytokine genes, specifically interferon-gamma (IFN-gamma) and GM-CSF genes, into autologous and HLA single locus matched allogeneic neuroblastoma cells, assay levels of cytokine expression, and determine phenotypic changes. A panel of cytokine transduced tumor cells that stably express common HLA A or B antigens will be derived. The ability of neuroblastoma cells to process and present specific peptide antigens derived from HTLV-1 tax and MAGE-1 as targets for cytolytic T-cells (CTL) will be assayed. The ability of cytokine expressing autologous and MHC class I matched allogeneic neuroblastoma cells to elicit CTL will be assessed following administration of genetically engineered tumor cells to patients. Preliminary results using retroviral IFN-gamma producing vectors are sufficiently encouraging to warrant a phase 1/lb clinical trial. Future clinical trials employing GM-CSF transduced neuroblastoma cells are envisioned. Neuroblastoma offers a unique setting in which to test immunotherapeutic gene transfer strategies due to availability of cell lines, the predictable relapse rate despite achievement of MRD status, and the strong correlation of cell line outgrowth with poor survival.

神经母细胞瘤是儿童最常见的颅外实体瘤。 尽管能够实现最小残留病（MRD）， 清髓性治疗和自体骨髓移植（ABMT）， 超过50%的高危病人会出现复发性致命疾病。 我们希望 确定是否主动特异性免疫治疗与神经母细胞瘤细胞 工程化以引起免疫反应可以在根除 MRD和改善高危患者的预后。 我们将介绍 细胞因子基因，特别是干扰素-γ（IFN-γ）和GM-CSF基因， 自体和HLA单位点匹配的同种异体神经母细胞瘤 细胞，测定细胞因子表达水平，并确定表型 变化 一组细胞因子转导的肿瘤细胞， 将衍生常见的HLA A或B抗原。 神经母细胞瘤 细胞加工和呈递来自HTLV-1的特异性肽抗原 将测定Tax和法师-1作为细胞溶解性T细胞（CTL）靶。 的 自体细胞因子表达能力与MHC I类匹配 将在以下条件下评估同种异体神经母细胞瘤细胞引发CTL 向患者施用基因工程改造的肿瘤细胞。 使用产生IFN-γ的逆转录病毒载体的初步结果如下： 足以令人鼓舞地保证I期/Ib临床试验。 未来 使用GM-CSF转导的神经母细胞瘤细胞的临床试验， 预想的 神经母细胞瘤提供了一个独特的环境， 由于细胞可用性，免疫抑制基因转移策略 行，尽管达到MRD状态，但可预测的复发率，以及 细胞系生长与存活率差的强相关性。