B7-H3 in prognosis and immunotherapy of pancreatic cancer

描述(申请人提供)：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%的被诊断为胰腺癌的患者会有幸接受手术切除。即使完全手术切除并辅以化疗，实际的5年生存率也只有12%。这些临床发现突出了生物标记物的需要，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，这项提议将检验这样一种假设，即协同刺激分子B7-H3在胰腺癌原发灶中的表达水平与联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治疗的合适靶点。这一假说源于文献中的以下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有关，ii)本实验室制备的B7-H3特异性单抗376.96识别在包括胰腺癌细胞系和手术切除的胰腺癌病变在内的人类恶性肿瘤细胞上高频率表达的决定因素，但在正常组织中的分布非常有限。在抗体依赖细胞介导的细胞毒试验中，单抗376.96介导了人恶性肿瘤细胞的细胞依赖性细胞毒作用。为此，我们将利用明确的临床信息来测量B7-H3在胰腺癌原发灶中的表达水平，并将这种免疫组织化学分析的结果与临床反应相关联。此外，我们还将验证以下假设，即单抗376.96与其他肿瘤抗原特异性单抗如CD20-EGFR-和HER2-特异性单抗一样，其裂解程度和抗肿瘤效应也受到Fc？受体Fc？RIIIa，由NK细胞表达。后者是主要的效应细胞。这些研究产生的信息将有助于确定B7-H3在胰腺癌原发病变中的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，该策略将在胰腺癌患者的I期试验中进行测试。公共卫生相关性：不仅迫切需要有效的治疗策略来提高胰腺癌患者的存活率，而且迫切需要生物标记物来识别哪些患者可能从手术和辅助化疗的组合中受益。为了解决这些需求，这项建议将检验这样的假设，即B7-H3是B7免疫共刺激分子家族的成员，代表着一种新的预后生物标志物和在胰腺癌患者中应用基于抗体的免疫治疗的有效靶点。

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.