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: 8705630
• 负责人: Robert L. Ferris
• 金额: $ 17.81万
• 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/8705630
• 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; 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(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)特异性单抗(MAb)西妥昔单抗仅对部分晚期头颈部鳞状细胞癌(HNC)有效。因此，有必要了解为什么不同个体的临床反应不同。与EGFR酪氨酸激酶抑制剂相比，单抗的使用提高了免疫系统可能在这一临床活动中发挥作用的可能性。此外，由于西妥昔单抗在体外不能诱导HNC细胞明显的凋亡，体内的抗肿瘤作用可能部分是由于额外的因素，例如通过自然杀伤(NK)细胞和单核细胞介导的抗体依赖的细胞毒(ADCC)激活免疫细胞，通过mAb的恒定片段(Fc)区域与多态的Fc？受体(Fc？R)。然而，关于T细胞是否有助于单抗治疗，或者Fc？Rs基因多态是否影响T细胞反应的诱导，我们知之甚少。HNC细胞频繁下调HLAI类抗原处理机制(APM)和NK抑制分子的表达，可能是HNC细胞抵抗NK细胞和肿瘤抗原特异性T细胞杀伤的机制之一。因此，我们假设免疫系统的细胞臂在西妥昔单抗的抗肿瘤作用中起重要作用。我们有证据表明，Fc？RIIa131R/H和FcRIII158V/F的Fc？R多态影响健康供者和HNC患者PBMC中ADCC的活性，并且这些密码子还与单药西妥昔单抗治疗的结直肠癌患者的预后相关。此外，我们还发现，在体外培养的ADCC反应的PBMC上清液中，肿瘤坏死因子-α、干扰素-α、MIP-1α和MIP-1β的表达是一致的。这些细胞因子和趋化因子从激活的NK细胞中释放出来，对T细胞和树突状细胞(DC)具有趋化作用，这表明西妥昔单抗诱导的NK溶解和TA特异性T细胞的诱导之间存在潜在的联系。了解这些单抗的免疫介导机制很重要：(I)选择最合适的患者进行西妥昔单抗治疗，使其具有最大的免疫激活能力；(Ii)增强抗肿瘤ADCC和T细胞的活性，以增加西妥昔单抗治疗患者的应答；(Ii)寻找生物学和临床反应性的预测性免疫标志物，如Fc？R基因多态性、细胞免疫和免疫逃逸机制。以不同疾病阶段的HNC患者的Fc？R基因型为特征，在有无肿瘤表达的放化疗或NK抑制分子的情况下，建立具有不同水平的EGFR表达和淋巴细胞的HNC小鼠模型，以验证表达某些Fc？R基因的PBMC或来自晚期HNC患者的PBMC影响抗肿瘤活性的假设。此外，我们还将确定西妥昔单抗是否通过DC成熟和交叉提呈来增强抗原特异性T细胞的诱导，这受Fc？R基因、西妥昔单抗和NK细胞的影响。最后，我们建议从匹兹堡大学的II期单药西妥昔单抗临床试验(08-013)中确定西妥昔单抗对HNC患者NK和T细胞激活、肿瘤侵袭和APM表达缺陷的影响。