B7-H3 in prognosis and immunotherapy of pancreatic cancer

描述（申请人提供）：胰腺腺癌是最致命的胰腺肿瘤。目前手术切除是唯一能提供5年生存期的治疗方法。然而，只有不到15%的被诊断为胰腺腺癌的患者能够幸运地接受手术切除。即使进行了完全的手术切除和辅助化疗，实际的5年生存率也只有12%。这些临床发现强调了需要生物标志物来识别这一小部分患者，并开发替代和创新的治疗策略。为了满足这些需求，本研究将验证原发性胰腺癌病变中共刺激分子B7-H3的表达水平与联合手术和辅助治疗的临床反应相关的假设，以及B7-H3的肿瘤限制性决定因子代表了应用基于抗体的免疫治疗该疾病的合适靶点。这一假设源于以下文献中的证据和我们自己的结果：i) B7-H3在下咽癌、非小肺癌、肾细胞癌和前列腺癌中的表达水平与疾病的临床病程相关；ii)我们实验室生成的B7-H3特异性mAb 376.96识别了一个在人类恶性肿瘤细胞（包括胰腺癌细胞系和手术切除的胰腺癌病变）上表达频率很高的决定因子，但在正常组织中的分布非常有限。iii) mAb 376.96在抗体依赖细胞介导细胞毒性（ADCC）检测中介导人恶性肿瘤细胞的细胞依赖性细胞毒性。为此，我们将通过明确的临床信息测量原发性胰腺癌病变中B7-H3的表达水平，并将这种免疫组织化学分析的结果与临床反应联系起来。此外，我们将验证mAb 376.96介导的裂解程度和抗肿瘤作用的假设，就像其他肿瘤抗原特异性mAb（如CD20- EGFR-和HER2-特异性mAb）介导的作用一样，受Fc？受体,Fc ?RIIIa，由NK细胞表达。后者是主要的效应细胞。来自这些研究的信息将有助于定义原发性胰腺癌病变中B7-H3表达水平的临床意义，以及ii)为设计基于抗体的免疫治疗策略提供有用的背景，以便在胰腺腺癌患者的i期试验中进行测试。公共卫生相关性：迫切需要的不仅是有效的治疗策略来提高胰腺腺癌患者的生存率，而且还需要生物标志物来识别可能从手术和辅助化疗联合获益的患者。为了满足这些需求，本研究将验证B7- h3作为B7免疫共刺激分子家族的一员，代表了一种新的预后生物标志物和应用基于抗体的免疫治疗胰腺腺癌患者的有效靶点。

DESCRIPTION (provided by applicant): Pancreatic adenocarcinoma is the most lethal pancreatic tumor. Currently surgical resection is the only therapy which can provide a 5 year survival. However, less than 15% of patients diagnosed with pancreatic adenocarcinoma will be fortunate enough to undergo surgical resection. Even with a complete surgical resection and adjuvant chemotherapy the actual 5 year survival is only 12%. These clinical findings highlight the need of biomarkers to identify this small fraction of patients and develop alternative and innovative therapeutic strategies. To address these needs, this proposal will test the hypothesis that the expression level of the costimulatory molecule B7-H3 in primary pancreatic carcinoma lesions correlates with clinical response to combinatorial surgery and adjuvant therapy, and that a tumor-restricted determinant of B7-H3 represents an appropriate target to apply antibody-based immunotherapy for this disease. This hypothesis stems from the following lines of evidence in the literature and our own results: i) the level of B7-H3 expression in hypopharyngeal carcinoma, non-small-lung carcinoma, renal cell carcinoma and prostate carcinoma is associated with the clinical course of the disease, ii) the B7-H3-specific mAb 376.96, generated in our laboratory, recognizes a determinant which is expressed with high frequency on malignant human tumor cells, including pancreatic carcinoma cell lines and surgically removed pancreatic carcinoma lesions, but has a very restricted distribution in normal tissues, and iii) mAb 376.96 mediates cell dependent cytotoxicity of human malignant tumor cells in antibody dependent cell-mediated cytotoxicity (ADCC) assays. To this end, we will measure the B7-H3 expression level in primary pancreatic carcinoma lesions with well- defined clinical information and correlate the results of this immunohistochemical analysis with the clinical responses. Furthermore, we will test the hypothesis that the extent of lysis and the anti-tumor effects mediated by mAb 376.96, like those mediated by other tumor antigen-specific mAb, such as CD20- EGFR- and HER2- specific mAb, are influenced by the polymorphism of the Fc? receptor, Fc?RIIIa, expressed by NK cells. The latter are the main effector cells. The information resulting from these studies will i) contribute to define the clinical significance of B7-H3 expression levels in primary pancreatic carcinoma lesions, and ii) represent a useful background to design antibody-based immunotherapeutic strategies to be tested in phase I trials in patients with pancreatic adenocarcinoma. PUBLIC HEALTH RELEVANCE: There is an urgent need not only for effective therapeutic strategies to improve pancreatic adenocarcinoma patients' survival, but also for biomarkers to identify patients who are likely to benefit from the combination of surgical and adjuvant chemotherapy. To address these needs, this proposal will test the hypothesis that B7-H3, a member of the B7 immune costimulatory molecule family, represents a novel prognostic biomarker and a valid target to apply antibody-based immunotherapy in patients with pancreatic adenocarcinoma.