IMMUNIZATION AGAINST TUMOR CELL ANTIGENS

针对肿瘤细胞抗原的免疫接种

• 批准号: 6174304
• 负责人: PAUL B CHAPMAN
• 金额: $ 10.51万
• 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/6174304
• 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.

该项目的总体目的是检验以下假设：肿瘤细胞表达的抗原的免疫会导致患者有意义的抗肿瘤作用。 工作集中在两种类型的抗原上。 由GD3神经苷代表的第一类抗原是分化抗原 - 一种由细胞表达的正常分子作为分化程序的一部分。 我们已经开发了2种疫苗构建体，可以诱导患者中的抗GD3抗体：BEC2抗IDiotypic单克隆抗体与BCG辅助抗体结合使用，而GD3-内酮-KLH结合了QS21辅助剂。 GD3系统的具体目的是：a）确定在BEC2剂量范围内BEC2/BCG疫苗的相对免疫原性； b）确定BEC2的长时间免疫是否会增强抗GD3抗体反应； c）评估BEC2/BCG的启动是否会增强用GD3-内酮KLH/QS21免疫引起的抗GD3抗体反应； d）评估使用GD3-六酮-KLH/QS21启动是否会增强对BEC2/BCG免疫诱导的抗GD3抗体反应； e）在有限的疾病小细胞肺癌中，确定初始化学放疗后用BEC2/BCG免疫是否会增强总体生存率。 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。 作为这种类型的抗原靶标的模型，我们正在进行疫苗研究，以对胰腺癌中突变的K-RAS蛋白进行免疫。 K-RAS系统的具体目的：a）检验以下假设：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突变的特定T细胞反应； b）观察皮肤测试反应性或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。 为了实现这些特定目标，我们提出了一系列4项临床试验。 该赠款提案的另一个目的是提供一个机会来培训初学者的临床研究人员。 这将通过让医学肿瘤学研究员参与执行试验，分析数据并提出结果的各个方面来实现。 这种紧密的指导关系反映了我们目前的教学范式。 赠款奖将为PI提供更多的时间来进行临床试验并指导其他临床研究人员。