IMMUNIZATION AGAINST TUMOR CELL ANTIGENS

该项目的总体目标是验证对肿瘤细胞表达的抗原进行免疫可以在患者中产生有意义的抗肿瘤作用的假设。研究的重点是两种抗原。第一种抗原，以GD3神经节苷脂为代表，是一种分化抗原——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种能诱导患者产生抗gd3抗体的疫苗结构：BEC2抗独特型单克隆抗体联合BCG佐剂和gd3 -内酯- klh联合QS21佐剂。GD3系统的具体目标是：a)确定BEC2/BCG疫苗在BEC2剂量范围内的相对免疫原性；b)确定BEC2长时间免疫是否能增强抗gd3抗体应答；c)评估BEC2/BCG是否会增强gd3 -内酯- KLH/QS21免疫诱导的抗gd3抗体应答；d)评估gd3 -内酯- klh /QS21引物是否会增强BEC2/BCG免疫诱导的抗gd3抗体应答；e)在有限疾病小细胞肺癌中，确定初始放化疗后接种BEC2/BCG是否会提高总生存率。第二种抗原——突变的癌基因——代表绝对的肿瘤特异性靶点。作为这类抗原靶点的模型，我们正在开展疫苗研究，以免疫胰腺癌中突变的K-ras蛋白。K-ras系统的具体目的：a)验证针对患者肿瘤中存在的K-ras突变的免疫接种可以诱导针对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类型是否与诱导抗k -ras T细胞反应相关；c)观察其抗肿瘤作用。为了实现这些具体目标，我们提出了一系列的4项临床试验。这项拨款提案的另一个目的是提供培训初级临床研究者的机会。这将通过医学肿瘤学研究员参与执行试验、分析数据和展示结果的各个方面来完成。这种密切的师徒关系反映了我们目前的教学模式。这笔拨款将为PI提供更多的时间来进行临床试验，并指导更多的初级临床研究者。

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.