IMMUNIZATION AGAINST TUMOR CELL ANTIGENS

该项目的总体目标是检验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的假设。 工作集中在两种类型的抗原。 第一种类型的抗原，以GD 3神经节苷脂为代表，是分化抗原-细胞表达的正常分子，作为分化程序的一部分。 我们已经开发了两种可以在患者中诱导抗GD 3抗体的疫苗构建体：BEC 2抗独特型单克隆抗体与BCG佐剂组合，以及GD 3-内酯-KLH与QS 21佐剂组合。 GD 3系统的具体目的是：a）确定BEC 2/BCG疫苗在一系列BEC 2剂量下的相对免疫原性; B）确定延长BEC 2免疫是否增强抗GD 3抗体应答; c）评估BEC 2/BCG初免是否增强由GD 3-内酯- KLH/QS 21免疫诱导的抗GD 3抗体应答; d）评估用GD 3-内酯-KLH/QS 21引发是否会增强由BEC 2/BCG免疫诱导的抗GD 3抗体应答; e）在局限性疾病小细胞肺癌中，确定初始放化疗后用BEC 2/BCG免疫是否会提高总存活率。 第二类抗原--突变的癌基因--代表了绝对的肿瘤特异性靶点。 作为这种类型的抗原靶点的模型，我们正在进行疫苗研究，以免疫胰腺癌中突变的K-ras蛋白。 K-ras系统的具体目的：a）检验针对患者肿瘤中存在的K-ras突变的免疫接种可诱导针对K-ras突变的特异性T细胞应答的假设; B）观察皮肤试验反应性或HLA类型是否与抗K-ras T细胞应答的诱导相关; 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。 本补助金提案的另一个目标是提供一个机会，培训开始临床研究人员。 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目前的教学模式。 该补助金将为PI提供更多的时间来进行临床试验，并指导其他开始的临床研究者。

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.