Role of B-cell mediated anti-tumor antibodies in responses to radiation and immunotherapy in HNSCC

B 细胞介导的抗肿瘤抗体在 HNSCC 放疗和免疫治疗反应中的作用

• 批准号: 10372922
• 负责人: Andrew B. Sharabi
• 金额: $ 36.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372922
• 关键词: Adaptive Immune System; Antibodies; Antibody Response; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Antitumor Response; Antiviral Agents; B cell clonality; B-Cell Antigen Receptor; B-Cell Development; B-Lymphocytes; Binding; Cells; Clinical Trials; Clonality; Data; Development; Dose; Goals; Head and Neck Squamous Cell Carcinoma; Human Papillomavirus; Immune response; Immunoglobulin G; Immunologics; Immunosuppression; Immunotherapeutic agent; Immunotherapy; MHC Class I Genes; Mediating; Modeling; Patients; Play; Proteins; Public Health; Radiation; Radiation therapy; Recurrence; Research; Resistance; Rimantadine; Role; T cell response; T-Lymphocyte; Testing; Translating; Tumor Antibodies; Tumor Antigens; Tumor Immunity; Virus Diseases; adaptive immune response; anti-IgG; anti-tumor immune response; antigen processing; antitumor effect; arm; cell mediated immune response; combinatorial; draining lymph node; efficacy evaluation; immune checkpoint blockade; improved; improved outcome; inhibitor; insight; neoplastic cell; novel; novel anticancer drug; novel marker; objective response rate; radiation effect; radiation response; resistance mechanism; response; trafficking; tumor; Adaptive Immune System; Antibodies; Antibody Response; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Antitumor Response; Antiviral Agents; B cell clonality; B-Cell Antigen Receptor; B-Cell Development; B-Lymphocytes; Binding; Cells; Clinical Trials; Clonality; Data; Development; Dose; Goals; Head and Neck Squamous Cell Carcinoma; Human Papillomavirus; Immune response; Immunoglobulin G; Immunologics; Immunosuppression; Immunotherapeutic agent; Immunotherapy; MHC Class I Genes; Mediating; Modeling; Patients; Play; Proteins; Public Health; Radiation; Radiation therapy; Recurrence; Research; Resistance; Rimantadine; Role; T cell response; T-Lymphocyte; Testing; Translating; Tumor Antibodies; Tumor Antigens; Tumor Immunity; Virus Diseases; adaptive immune response; anti-IgG; anti-tumor immune response; antigen processing; antitumor effect; arm; cell mediated immune response; combinatorial; draining lymph node; efficacy evaluation; immune checkpoint blockade; improved; improved outcome; inhibitor; insight; neoplastic cell; novel; novel anticancer drug; novel marker; objective response rate; radiation effect; radiation response; resistance mechanism; response; trafficking; tumor

Project Summary Objective response rates to single agent checkpoint blockade immunotherapy (CBI) in recurrent or metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) are low, in the range of 13-26%. Thus there is a critical need to develop combinatorial strategies to improve response rates and understand mechanisms of resistance. Our group has pioneered combinations of radiation (XRT) and CBI and demonstrated that XRT can enhance development of anti-tumor T-cell responses. However, while most studies have focused on T- cells, the second arm of the adaptive immune system, namely B-cell mediated anti-tumor antibody responses, has remained understudied. Anti-tumor antibodies play crucial roles in identifying and tagging tumor cells for destruction, activating immune responses, as well as limiting spread of viral infections. The primary goals of this project are to establish the role of B-cell mediated antibody responses in HNSCC and exploit mechanisms by which human papilloma virus (HPV) blocks immune responses. In Specific Aim 1 we will characterize the effects of XRT and XRT + CBI on the development and function of B-cell mediated anti- tumor antibody responses in HNSCC. We have identified that XRT and XRT+CBI can enhance development of B-cell IgG antibodies which contribute to tumor control. We will test the hypotheses that B-cell mediated antibody responses are critical for tumor control and that XRT enhances B-cell immune responses via increased antigen trafficking to the draining lymph node. We have discovered a novel HPV mediated resistance mechanism to CBI, whereby HPV E5 inhibits adaptive immune responses by blocking antigen processing and antigen presentation. In specific Aim 2 we will dissect this novel mechanism of HPV E5 mediated immune suppression and determine whether HPV E5 inhibitors enhance B-cell responses to XRT and CBI in HNSCC. Furthermore, we have identified that the antiviral drug and HPV E5 inhibitor Rimantadine has potent and novel anti-tumor effects in HNSCC. We will test the hypothesis that inhibition of HPV E5 improves response rates to CBI and XRT by restoring antigen processing and presentation. Our group is leading multiple clinical trials evaluating the efficacy of XRT and CBI in HNSCC and our preliminary data has identified that patients receiving XRT + CBI develop B-cell responses that correlate with response rates. In specific aim 3 we will establish whether increases in B-cell mediated IgG antibody responses correlate with objective response rates and overall survival in HNSCC patients. Completion of these specific aims will: 1) significantly improve our understanding of the immunological effects of XRT + CBI on B-cell anti-tumor immune responses in HNSCC; 2) elucidate a novel mechanism of HPV E5 mediated resistance to CBI and develop Rimantadine as a novel anti-cancer drug in HNSCC; and 3) establish whether B-Cell mediated IgG responses are a novel biomarker which correlate with responses and survival in HNSCC. Ultimately, these findings can be directly translated to improve outcomes for HNSCC patients.

项目摘要 复发或转移性的单位剂检查点封锁免疫疗法（CBI）的客观响应率 头部和颈部鳞状细胞癌（HNSCC）较低，范围为13-26％。因此有关键 需要制定组合策略以提高响应率并了解 反抗。我们的小组具有辐射（XRT）和CBI的开创性组合，并证明了XRT 可以增强抗肿瘤T细胞反应的发展。但是，尽管大多数研究都集中在T- 细胞是自适应免疫系统的第二组，即B细胞介导的抗肿瘤抗体 回答，依然研究了。抗肿瘤抗体在识别和标记中起着至关重要的作用 肿瘤细胞破坏，激活免疫反应以及限制病毒感染的扩散。这 该项目的主要目标是确定HNSCC和HNSCC中B细胞介导的抗体反应的作用 人类乳头瘤病毒（HPV）阻止免疫反应的利用机制。在特定的目标1中我们 将表征XRT和XRT + CBI对B细胞介导的抗 - 的发展和功能的影响 HNSCC中的肿瘤抗体反应。我们已经确定XRT和XRT+CBI可以增强开发 有助于肿瘤控制的B细胞IgG抗体的。我们将测试B细胞介导的假设 抗体反应对于肿瘤控制至关重要，XRT通过 增加对排水淋巴结的抗原运输。我们发现了一个新颖的HPV介导 CBI的抗性机制，HPV E5通过阻断抗原抑制适应性免疫反应 加工和抗原表现。在特定目标2中，我们将剖析这种新型HPV E5的机制 介导的免疫抑制并确定HPV E5抑制剂是否增强了对XRT的B细胞反应 和HNSCC中的CBI。此外，我们已经确定抗病毒药和HPV E5抑制剂Rimantadine 在HNSCC中具有有效的新型抗肿瘤作用。我们将测试抑制HPV E5的假设 通过恢复抗原处理和表现来提高CBI和XRT的响应率。我们的小组是 领先的多个临床试验评估了XRT和CBI在HNSCC中的功效及我们的初步数据 确定接受XRT + CBI的患者会产生与反应率相关的B细胞反应。在 特定目的3我们将确定B细胞介导的IgG抗体反应的增加是否与 HNSCC患者的客观反应率和总体存活率。这些特定目标的完成将：1） 显着提高了我们对XRT + CBI对B细胞抗肿瘤的免疫学影响的理解 HNSCC的免疫反应； 2）阐明了HPV E5介导的对CBI的抗性的新型机制 在HNSCC中发展为一种新型抗癌药； 3）确定B细胞介导的IgG是否 反应是一种新型的生物标志物，与HNSCC的反应和生存相关。最终，这些 可以将发现直接转化以改善HNSCC患者的预后。