IMMUNIZATION AGAINST TUMOR CELL ANTIGENS

该项目的总体目标是验证针对肿瘤细胞表达的抗原免疫可以在患者身上产生有意义的抗肿瘤效果的假设。这项工作主要集中在两种抗原上。第一类抗原，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，由细胞表达的一种正常分子。我们已经开发了两种疫苗载体，可以在患者体内诱导抗GD3抗体：BEC2抗独特型单抗与卡介苗佐剂结合，GD3-内酯-KLH与QS21佐剂结合。GD3系统的具体目标是：a)确定BEC2/BCG疫苗在一定剂量范围内的相对免疫原性；b)确定BEC2的延长免疫是否会增强抗GD3抗体应答；c)评估BEC2/BCG预免疫是否会增强GD3-内酯-KLH/QS21免疫诱导的抗GD3抗体应答；d)评估GD3-内酯-KLH/QS21预免疫是否会增强BEC2/BCG免疫后诱导的抗GD3抗体应答；e)在有限的疾病小细胞肺癌中，确定初始放、化疗后再用BEC2/BCG免疫是否会提高总体生存率。第二类抗原--突变的癌基因--代表绝对的肿瘤特异性靶点。作为这种抗原靶点的模型，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型是否与诱导抗K-ras T细胞反应相关；c)观察任何抗肿瘤效果。为了实现这些特定的目标，我们提出了一系列的4个临床试验。这项拨款提案的另一个目标是提供一个培训初级临床研究人员的机会。这将通过让医学肿瘤学研究员参与执行试验、分析数据和呈现结果的每个方面来实现。这种密切的指导关系反映了我们目前的教学模式。这项拨款将为PI提供更多的时间进行临床试验，并指导更多的初级临床研究人员。

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.