IMMUNIZATION AGAINST TUMOR CELL ANTIGENS

针对肿瘤细胞抗原的免疫接种

• 批准号: 6513542
• 负责人: PAUL B CHAPMAN
• 金额: $ 10.66万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-21 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6513542
• 关键词: Bacillus Calmette Guerin vaccine; antibody formation; antiidiotype antibody; clinical research; clinical trials; differentiation antigens; gangliosides; gene mutation; human subject; human therapy evaluation; immunization; immunoconjugates; monoclonal antibody; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; oncogenes; pancreas neoplasms; small cell lung cancer; tumor antigens; vaccine development

The overall goal of this project is to test the hypothesis that immunization against antigens expressed by tumor cells can result in meaningful anti-tumor effects in patients. Work is focussed on two types of antigens. The first type of antigen, represented by GD3 ganglioside, is a differentiation antigen - a normal molecule expressed by cells as part of the differentiation program. We have developed 2 vaccine constructs that can induce anti-GD3 antibodies in patients: BEC2 anti-idiotypic monoclonal antibody combined with BCG adjuvant, and GD3-lactone-KLH combined with QS21 adjuvant. The specific aims for the GD3 system are: a) To determine the relative immunogenicity of BEC2/BCG vaccine at a range of BEC2 doses; b) To determine whether prolonged immunization with BEC2 boosts the anti-GD3 antibody response; c) To assess whether priming with BEC2/BCG will enhance the anti-GD3 antibody response induced by immunization with GD3-lactone- KLH/QS21; d) To assess whether priming with GD3-lactone-KLH/QS21 will enhance the anti-GD3 antibody response induced by immunization with BEC2/BCG; e) In limited disease small-cell lung cancer, determine whether immunization with BEC2/BCG following initial chemoradiotherapy will enhance overall survival. The second type of antigen -- mutated oncogenes -- represent absolutely tumor-specific targets. As a model for this type of antigenic target, we are carrying out vaccine studies to immunize against mutated K-ras protein in pancreatic carcinoma. Specific aims for the K-ras system: a) To test the hypothesis that immunization against the K-ras mutation present in a patient's tumor can induce a specific T cell response against the K-ras mutation; b) To observe whether skin test reactivity or HLA type correlates with the induction of anti-K-ras T cell response; c) To observe any anti-tumor effects. To accomplish these specific aims, we propose a series of 4 clinical trials. The other objective of this grant proposal is to provide an opportunity to train beginning clinical investigators. This will be accomplished by having Medical Oncology fellows participate in every aspect of performing the trials, analyzing the data, and presenting the results. This close mentoring relationship reflects our current teaching paradigm. The grant award will provide the PI with more time to conduct the clinical trials and to mentor additional beginning clinical investigators.

该项目的总体目标是检验以下假设：针对肿瘤细胞表达的抗原的免疫可以在患者中产生有意义的抗肿瘤作用。 工作重点是两种类型的抗原。 第一种类型的抗原，以 GD3 神经节苷脂为代表，是一种分化抗原 - 作为分化程序的一部分由细胞表达的正常分子。 我们开发了2种可以在患者体内诱导抗GD3抗体的疫苗结构：BEC2抗独特型单克隆抗体与BCG佐剂联合，以及GD3-内酯-KLH与QS21佐剂联合。 GD3 系统的具体目标是： a) 确定 BEC2/BCG 疫苗在一定 BEC2 剂量范围内的相对免疫原性； b) 确定长期使用 BEC2 免疫是否会增强抗 GD3 抗体反应； c) 评估用 BEC2/BCG 引发是否会增强用 GD3-内酯-KLH/QS21 免疫诱导的抗 GD3 抗体应答； d) 评估用GD3-内酯-KLH/QS21引发是否会增强由BEC2/BCG免疫诱导的抗GD3抗体应答； e) 在局限性疾病小细胞肺癌中，确定初始放化疗后使用 BEC2/BCG 免疫是否会提高总体生存率。 第二种类型的抗原——突变的癌基因——代表绝对的肿瘤特异性靶标。 作为此类抗原靶标的模型，我们正在进行疫苗研究，以针对胰腺癌中突变的 K-ras 蛋白进行免疫。 K-ras 系统的具体目标： a) 检验针对患者肿瘤中存在的 K-ras 突变的免疫可以诱导针对 K-ras 突变的特异性 T 细胞反应的假设； b) 观察皮试反应性或HLA类型是否与抗K-ras T细胞反应的诱导相关； c) 观察任何抗肿瘤作用。 为了实现这些具体目标，我们提出了一系列 4 项临床试验。 该拨款提案的另一个目标是提供培训初级临床研究人员的机会。 这将通过让肿瘤内科研究员参与试验、分析数据和展示结果的各个方面来实现。 这种密切的指导关系反映了我们当前的教学模式。 资助金将为 PI 提供更多时间来进行临床试验并指导更多的初级临床研究人员。