B7-H3 in prognosis and immunotherapy of pancreatic cancer

B7-H3 在胰腺癌的预后和免疫治疗中的作用

• 批准号: 7877983
• 负责人: Xinhui Wang
• 金额: $ 4.59万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7877983
• 关键词: Address; Adjuvant Chemotherapy; Adjuvant Therapy; American Cancer Society; Antibodies; Attention; Biological Assay; Biological Markers; Biological Models; Cell Line; Cells; Cessation of life; Clinical; Clinical Course of Disease; Codon Nucleotides; Common Neoplasm; Cytolysis; Data; Development; Diagnosis; Disease; Ductal Epithelial Cell; ERBB2 gene; Effector Cell; Epidermal Growth Factor Receptor; Excision; Exocrine pancreas; Family; Fc Receptor; Frequencies; Funding; Future; Generations; Genetic Polymorphism; Human; Hypopharyngeal Carcinoma; Immune; Immune system; Immunotherapeutic agent; Immunotherapy; In Vitro; Laboratories; Lesion; Literature; Lung; Lymphoma; MS4A1 gene; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mediating; Monoclonal Antibodies; Natural Killer Cells; Normal tissue morphology; Operative Surgical Procedures; Pancreatic Adenocarcinoma; Pancreatic carcinoma; Patients; Phase I Clinical Trials; Prostate; Prostate carcinoma; Reagent; Recombinants; Renal Cell Carcinoma; Role; Solid Neoplasm; Staging; Testing; Therapeutic; Translations; Tumor Antigens; Veins; Work; advanced disease; antibody-dependent cell cytotoxicity; base; cancer cell; chemotherapy; clinical efficacy; clinically relevant; clinically significant; combinatorial; cytotoxicity; design; gemcitabine; improved; in vivo; innovation; kidney cell; lung Carcinoma; member; mouse model; neoplastic cell; novel; novel therapeutics; outcome forecast; pancreatic neoplasm; prognostic; public health relevance; receptor; response; stem; tumor

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.

描述（由申请人提供）：胰腺腺癌是最致命的胰腺肿瘤。目前，手术切除是唯一可以提供5年生存的疗法。但是，不到15％的被诊断为胰腺腺癌的患者将很幸运地接受手术切除。即使完成手术切除和辅助化疗，实际的5年生存率也只有12％。这些临床发现凸显了生物标志物以确定这一小部分患者并发展替代性和创新性治疗策略。为了满足这些需求，该提案将检验以下假设：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疗法的临床反应有关，而肿瘤限制性的b7-H3的临床反应代表了对抗体基于此类疾病的适当靶标。 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恶性人肿瘤细胞的频率，包括胰腺癌细胞系和外科手术去除胰腺癌病变，但在正常组织中的分布非常限制，iii）mAb 376.96介导了细胞依赖性细胞毒性细胞的细胞毒性细胞的细胞毒性依赖性细胞介导的依赖性细胞介导的细胞毒性（ADCCCCCCCCCCCCCCCCCCCCCCCCCCC）。为此，我们将在原发性胰腺癌病变中测量B7-H3表达水平，并具有明确的临床信息，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，我们将检验以下假设：裂解程度和由MAB 376.96介导的抗肿瘤作用，例如由其他肿瘤抗原特异性MAB介导的，例如CD20- EGFR-和HER2-特异性mAb，受到FC的多态性的影响？受体FC？riiia，由NK细胞表达。后者是主要效应细胞。这些研究产生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，ii）ii）ii）代表了设计基于抗体的免疫治疗策略的有用背景，以在I期试验中在胰腺腺癌患者中进行I期试验。公共卫生相关性：不仅需要有效的治疗策略来改善胰腺腺癌患者的生存，而且还需要生物标志物来鉴定可能从外科手术和辅助化学疗法结合中受益的患者。为了满足这些需求，该提案将检验以下假设：B7免疫共刺激分子家族的成员B7-H3代表了一种新型的预后生物标志物，并且是对胰腺腺癌患者应用基于抗体的免疫疗法的有效靶标。