B7-H3 in prognosis and immunotherapy of pancreatic cancer

描述（由申请方提供）：胰腺癌是最致命的胰腺肿瘤。目前手术切除是唯一能提供5年生存率的治疗方法。然而，只有不到15%的胰腺癌患者能够幸运地接受手术切除。即使完全手术切除和辅助化疗，实际5年生存率也只有12%。这些临床发现强调了生物标志物的需要，以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，本提案将检验以下假设：在原发性胰腺癌病变中共刺激分子B7-H3的表达水平与对组合手术和辅助治疗的临床反应相关，并且B7-H3的肿瘤限制性决定簇代表了对该疾病应用基于抗体的免疫疗法的适当靶点。这一假设源于文献中的以下证据和我们自己的结果：i）下咽癌、非小肺癌、肾细胞癌和前列腺癌中B7-H3的表达水平与疾病的临床过程相关，ii）在我们的实验室中产生的B7-H3特异性mAb 376.96，识别在恶性人肿瘤细胞（包括胰腺癌细胞系和手术切除的胰腺癌病变）上以高频率表达但在正常组织中具有非常有限的分布的决定子，和iii）在抗体依赖性细胞介导的细胞毒性（ADCC）测定中，mAb 376.96介导人恶性肿瘤细胞的细胞依赖性细胞毒性。为此，我们将测量具有明确临床信息的原发性胰腺癌病变中的B7-H3表达水平，并将该免疫组织化学分析的结果与临床反应相关联。此外，我们将测试的假设，溶解的程度和单克隆抗体376.96介导的抗肿瘤作用，如其他肿瘤抗原特异性单克隆抗体，如CD 20- EGFR-和HER 2-特异性单克隆抗体介导的，是由Fc？受体，Fc？RIIIa，由NK细胞表达。后者是主要的效应细胞。从这些研究中得到的信息将i）有助于确定原发性胰腺癌病变中B7-H3表达水平的临床意义，和ii）代表设计基于抗体的免疫策略的有用背景，以在胰腺癌患者的I期试验中进行测试。

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.