Immune activation by cetuximab in head and neck cancer patients

西妥昔单抗对头颈癌患者的免疫激活作用

• 批准号: 8499285
• 负责人: Robert L. Ferris
• 金额: $ 36万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8499285
• 关键词: Activated Natural Killer Cell; Animal Model; Antigens; Apoptosis; Applications Grants; Binding; Biological; Biological Markers; Biological Models; Cancer Patient; Cell Maturation; Cells; Cellular Immunity; Cetuximab; Clinical; Clinical Trials; Codon Nucleotides; Colorectal Cancer; Cross Presentation; Cytolysis; Cytotoxic T-Lymphocytes; Data; Defect; Dendritic Cells; Development; Disease; Down-Regulation; Effector Cell; Enrollment; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Equilibrium; Fc Receptor; Fc domain; Generations; Genetic Polymorphism; Genotype; HLA G antigen; Head and Neck Squamous Cell Carcinoma; Histocompatibility Antigens Class I; Immune; Immune Cell Activation; Immune system; Immunotherapy; In Vitro; Individual; Infiltration; Interferons; Investigation; Link; Literature; Lymphocyte; Mediating; Modeling; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Natural Killer Cells; Outcome; Patient Selection; Patients; Peripheral Blood Mononuclear Cell; Phase; Play; Proteins; Publishing; Role; Signal Pathway; Small Inducible Cytokine A3; Source; Specimen; Staging; T cell response; T-Cell Activation; T-Lymphocyte; TNF gene; Testing; Tumor Antibodies; Tumor Antigens; Universities; antibody-dependent cell cytotoxicity; antigen processing; arm; base; chemokine; chemoradiation; clinical efficacy; clinically relevant; cytokine; effective therapy; head and neck cancer patient; immune activation; in vivo; interest; monocyte; mouse model; neoplastic cell; pre-clinical; public health relevance; receptor; receptor expression; resistance mechanism; response; tumor; uptake

DESCRIPTION (provided by applicant): There is convincing clinical evidence that the epidermal growth factor receptor (EGFR)-specific monoclonal antibody (mAb), cetuximab, is effective therapy only for a subset of advanced head and neck squamous cell carcinoma (HNC). Thus, there is a need to understand why clinical responses vary between individuals. In contrast to EGFR tyrosine kinase inhibitors, the use of a mAb raises the potential that the immune system might play a role in this clinical activity. Also, since treatment of HNC cells with cetuximab does not induce significant apoptosis in vitro, anti-tumor effects in vivo may be due in part to additional factors, such as immune cell activation through antibody dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells and monocytes, through the constant fragment (Fc) domain of the mAb binding to polymorphic Fc? receptors (Fc?R). However, little is known about whether T cells contribute to mAb therapies or whether polymorphic Fc?Rs influence the induction of T cell responses. The frequent downregulation of HLA class I antigen processing machinery (APM) and expression of NK inhibitory molecules by HNC cells, may provide a mechanism of resistance to NK cell- and tumor antigen specific T cell lysis of HNC cells. Thus, we hypothesize that the cellular arm of the immune system plays an important role in mediating the anti-tumor effects of cetuximab. We have evidence that Fc?R polymorphisms at Fc?RIIa131R/H and FcRIII158V/F influence ADCC activity in PBMC of healthy donors and HNC patients, and these codons also correlate with outcome of colorectal cancer patients treated with single agent cetuximab. In addition, we have identified that TNF-a, IFN-?, MIP-1a, and MIP-1¿, are consistently expressed in vitro in the supernatant of ADCC responding PBMC. Released from activated NK cells, these cytokines and chemokines are chemotactic for T cells and dendritic cells (DC) cells, suggesting a potential link between cetuximab-induced NK lysis and induction of TA-specific T cell induction. Understanding immune mediated mechanisms of these mAb is important: (i) to select the most appropriate patients for cetuximab therapy with greatest ability to mount immune activation, (ii) to enhance anti-tumor ADCC and T cell activity in order to increase responses in cetuximab-treated patients and (ii) to identify predictive immune biomarkers of biological and clinical responsiveness, such as Fc?R polymorphisms, cellular immunity and immune escape mechanisms. A HNC murine model with different levels of EGFR expression and lymphocytes, characterized by Fc?R genotype from HNC patients of different disease stage and in the presence or absence of chemoradiotherapy or NK inhibitory molecules expressed by the tumor, will be used to test the hypothesis that PBMC expressing certain Fc?R genotypes or from advanced HNC patients influences antitumor activity. In addition we will determine whether cetuximab enhances antigen specific T cell induction by DC maturation and cross-presentation, which is influenced by Fc?R polymorphisms, cetuximab and NK cells. Lastly we propose to determine the effect of cetuximab responsiveness in HNC patients on NK and T cell activation, tumor infiltration, and defects in APM expression in HNC specimens from a phase II, single agent cetuximab clinical trial (08-013) at the University of Pittsburgh.

描述（由申请人提供）：有令人信服的临床证据表明表皮生长因子受体（EGFR）特异性单克隆抗体（mAb）西妥昔单抗仅对部分晚期头颈鳞状细胞癌（HNC）有效。因此，有必要了解为什么个体之间的临床反应有所不同，与 EGFR 酪氨酸激酶抑制剂相比，mAb 的使用增加了免疫系统在这方面发挥作用的可能性。此外，由于用西妥昔单抗抗体处理 HNC 细胞在体外不会诱导显着的细胞凋亡，因此体内抗肿瘤作用可能部分归因于其他因素，例如通过依赖细胞毒性 (ADCC) 介导的免疫细胞激活。自然杀伤 (NK) 细胞和单核细胞，通过 mAb 的恒定片段 (Fc) 结构域与多态性 Fc? 受体 (Fc?R) 结合。 然而，对于 T 细胞是否有助于 mAb 治疗，人们知之甚少。多态性 Fc?R 影响 T 细胞反应的诱导 HNC 细胞 HLA I 类抗原加工机制 (APM) 的频繁下调和 NK 抑制分子的表达，可能提供对 NK 细胞和肿瘤抗原特异性 T 的抵抗机制。因此，我们发现免疫系统的细胞臂在介导西妥昔单抗的抗肿瘤作用中发挥着重要作用。 FcRIIa131R/H 和 FcRIII158V/F 影响健康供体和 HNC 患者的 PBMC 中的 ADCC 活性，这些密码子也与单药西妥昔单抗治疗的结直肠癌患者的结果相关。此外，我们还发现 TNF-a、IFN。 -?、MIP-1a 和 MIP-1¿这些细胞因子和趋化因子在 ADCC 反应的 PBMC 上清液中一致表达，这些细胞因子和趋化因子对 T 细胞和树突状细胞 (DC) 细胞具有趋化作用，表明西妥昔单抗诱导的 NK 裂解与诱导 NK 细胞裂解之间存在潜在联系。了解这些 mAb 的免疫介导机制非常重要：(i) 选择最合适的患者进行西妥昔单抗治疗，并具有最大的免疫激活能力， (ii) 增强抗肿瘤 ADCC 和 T 细胞活性，以增强西妥昔单抗治疗患者的反应；(ii) 鉴定生物和临床反应的预测性免疫生物标志物，例如 Fc?R 多态性、细胞免疫和免疫逃逸具有不同水平 EGFR 表达和淋巴细胞的 HNC 小鼠模型，其特征是来自不同疾病阶段的 HNC 患者的 Fc?R 基因型，并且存在或不存在放化疗或由 HNC 表达的 NK 抑制分子。肿瘤，将用于检验表达某些 Fc?R 基因型或来自晚期 HNC 患者的 PBMC 影响抗肿瘤活性的假设。此外，我们将确定西妥昔单抗是否通过 DC 成熟和交叉呈递增强抗原特异性 T 细胞诱导，从而受到影响。最后，我们建议确定西妥昔单抗对 HNC 患者的反应性对 NK 和 T 细胞活化、肿瘤浸润和肿瘤细胞的影响。匹兹堡大学 II 期单药西妥昔单抗临床试验 (08-013) 的 HNC 标本中 APM 表达缺陷。