Rituximab Elicitation of Tumor Specific T-cell Responses in Lymphoma Patients

利妥昔单抗在淋巴瘤患者中引发肿瘤特异性 T 细胞反应

• 批准号: 7628573
• 负责人: STEVEN H BERNSTEIN
• 金额: $ 31.99万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7628573
• 关键词: Address; Affinity; Aftercare; Antibodies; Antibody Therapy; Antigen Targeting; Antigens; Autologous; Binding; Biological Assay; Biopsy; Biotechnology; Blood; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Center; Cell Death; Cells; Clinical; Complement; Cytolysis; Cytotoxic T-Lymphocytes; Data; Development; Disease; Dose; Dot Immunoblotting; Effectiveness; Environment; Enzyme-Linked Immunosorbent Assay; Epitopes; Follicular Lymphoma; Frequencies; Granulocyte-Macrophage Colony-Stimulating Factor; Immune response; Immune system; Immunoglobulin Variable Region; Immunoglobulins; In Vitro; Indolent; Induction of Apoptosis; Inflammatory; Interleukin 2 Receptor; Intravenous infusion procedures; Knockout Mice; Knowledge; Lead; Light; Lymphocyte; Lymphoma; MHC Class I Genes; MS4A1 gene; Malignant Neoplasms; Mediating; Memory; Modeling; Molecular; Monitor; Monoclonal Antibodies; Monoclonal Antibody CD20; Monoclonal Antibody Therapy; Multicenter Trials; Nature; Newly Diagnosed; Oligonucleotides; Passive Immunotherapy; Patients; Peptides; Peripheral Blood Lymphocyte; Peripheral Blood Mononuclear Cell; Production; Proteins; Protocols documentation; Publishing; Qualifying; Refractory; Relapse; Research; Research Ethics Committees; Research Personnel; Seminal; Serum; Specimen; System; T memory cell; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Tumor Antigens; Western Blotting; Work; abstracting; antibody conjugate; antibody-dependent cell cytotoxicity; base; clinical effect; cytokine; design; in vivo; killings; lymph nodes; neoplastic cell; novel; novel strategies; peripheral blood; precursor cell; response; rituximab; treatment strategy; tumor

DESCRIPTION (provided by applicant): Rituximab, a chimeric monoclonal antibody directed against CD20, has shown significant therapeutic activity in patients with follicular lymphoma (FL), yet it's exact mechanism of action has not been completely defined. Although killing of the CD20+ FL cells, either through complement dependent cytolysis, antibody dependent cellular cytotoxicity or direct induction of apoptosis may contribute to its effectiveness, these mechanisms are unlikely to be the only mechanisms of action as; (a) the clinical and molecular responses to Rituximab may continue for months after the last dose of Rituximab and; (b) the median duration of the second response to Rituximab is longer than that of the first response, clinical findings that cannot be explained solely by the mechanisms described above. Rituximab induced FL cell death is expected to result in the release of tumor antigens, for example antigens derived from the variable regions of the heavy (VH) and light chains (VL) of the FL associated immunoglobulin (Ig), and also as yet undefined tumor antigens, in a pro-inflammatory environment. We hypothesize that the Rituximab induced release of lymphoma-associated antigens will provoke a cell-mediated lymphoma specific immune response. We will test this hypothesis by monitoring newly diagnosed FL patients for the presence of both peripheral blood and tumor infitrating lymphoma specific effector and/or memory CD4+ and CD8+ T-cells, before and after Rituximab treatment using Elispot, Fluorispot, Lysispot and intracellular cytokine flow cytometric assays. We will also test two corollaries of this hypothesis, being that a Rituximab elicited active lymphoma specific cellular response would; (a) result in an increase in the effector functions of both the lymphoma-specific CD4+ and CD8+ T cells; and (b) provide the necessary T- cell help required to generate lymphoma-specific humoral responses. The demonstration that Rituximab generates a lymphoma specific immune response, as well as the knowledge of the target antigens of the response would have profound implications as to how we optimally treat patients with FL. For example, it would suggest that combining Rituximab with agents which would be anticipated to augment the elicitation of a lymphoma specific T-cell response, such as GM-CSF, CpG oligonucleotides, and anti-CTLA-4 monoclonal antibodies, would be of potential clinical benefit. In addition, the results of this study should be applicable to antibody therapy of other malignancies, and as such, we anticipate that these studies will lead to novel treatment strategies designed to enhance the effectiveness of monoclonal antibody therapy for cancer in general. Follicular lymphoma (FL) is an indolent, but essentially incurable disease, however new treatments, including Rituximab therapy, are offering new hope for patients suffering with this disease. Rituximab is an antibody, which is a protein that targets another protein on the lymphoma cell, resulting in lymphoma cell death, however the exact mechanism(s) by which Rituximab destroys lymphoma cells is not yet clearly defined. Our group is determining whether Rituximab induces lymphoma cell death by stimulating the patient's own immune system to eradicate the disease, as a better understanding of how Rituximab works in patients with lymphoma will allow us to develop new approaches to treatment that we anticipate will lead to increased benefit for patients with this disease. PROJECT SUMMARY/ABSTRACT Rituximab, a chimeric monoclonal antibody directed against CD20, has shown significant therapeutic activity in patients with follicular lymphoma (FL), yet it's exact mechanism of action has not been completely defined. Although killing of the CD20+ FL cells, either through complement dependent cytolysis, antibody dependent cellular cytotoxicity or direct induction of apoptosis may contribute to its effectiveness, these mechanisms are unlikely to be the only mechanisms of action as; (a) the clinical and molecular responses to Rituximab may continue for months after the last dose of Rituximab and; (b) the median duration of the second response to Rituximab is longer than that of the first response, clinical findings that cannot be explained solely by the mechanisms described above. Rituximab induced FL cell death is expected to result in the release of tumor antigens, for example antigens derived from the variable regions of the heavy (VH) and light chains (VL) of the FL associated immunoglobulin (Ig), and also as yet undefined tumor antigens, in a pro-inflammatory environment. We hypothesize that the Rituximab induced release of lymphoma-associated antigens will provoke a cell-mediated lymphoma specific immune response. We will test this hypothesis by monitoring newly diagnosed FL patients for the presence of both peripheral blood and tumor infitrating lymphoma specific effector and/or memory CD4+ and CD8+ T-cells, before and after Rituximab treatment using Elispot, Fluorispot, Lysispot and intracellular cytokine flow cytometric assays. We will also test two corollaries of this hypothesis, being that a Rituximab elicited active lymphoma specific cellular response would; (a) result in an increase in the effector functions of both the lymphoma-specific CD4+ and CD8+ T cells; and (b) provide the necessary T- cell help required to generate lymphoma-specific humoral responses. The demonstration that Rituximab generates a lymphoma specific immune response, as well as the knowledge of the target antigens of the response would have profound implications as to how we optimally treat patients with FL. For example, it would suggest that combining Rituximab with agents which would be anticipated to augment the elicitation of a lymphoma specific T-cell response, such as GM-CSF, CpG oligonucleotides, and anti-CTLA-4 monoclonal antibodies, would be of potential clinical benefit. In addition, the results of this study should be applicable to antibody therapy of other malignancies, and as such, we anticipate that these studies will lead to novel treatment strategies designed to enhance the effectiveness of monoclonal antibody therapy for cancer in general.PROJECT NARRATIVE Follicular lymphoma (FL) is an indolent, but essentially incurable disease, however new treatments, including Rituximab therapy, are offering new hope for patients suffering with this disease. Rituximab is an antibody, which is a protein that targets another protein on the lymphoma cell, resulting in lymphoma cell death, however the exact mechanism(s) by which Rituximab destroys lymphoma cells is not yet clearly defined. Our group is determining whether Rituximab induces lymphoma cell death by stimulating the patient's own immune system to eradicate the disease, as a better understanding of how Rituximab works in patients with lymphoma will allow us to develop new approaches to treatment that we anticipate will lead to increased benefit for patients with this disease.

描述（由申请人提供）：利妥昔单抗是一种针对CD20的嵌合单克隆抗体，在卵泡淋巴瘤（FL）患者中显示出显着的治疗活性，但尚未完全定义其确切的作用机理。尽管杀死CD20+ FL细胞，即通过补体依赖的细胞解，抗体依赖性的细胞毒性或直接诱导凋亡可能有助于其有效性，但这些机制不太可能是作用机制的唯一机制； （a）在最后剂量利妥昔单抗后，对利妥昔单抗的临床和分子反应可能持续数月； （b）对利妥昔单抗的第二个反应的中间持续时间比第一个反应的持续时间更长，临床发现不能仅通过上述机制来解释。利妥昔单抗诱导的FL细胞死亡预计将导致肿瘤抗原的释放，例如源自fl相关免疫球蛋白（Ig）的重（VH）和轻链（VL）的可变区域，以及在促炎环境中尚未确定的肿瘤抗原。我们假设利妥昔单抗诱导的淋巴瘤相关抗原的释放将引起细胞介导的淋巴瘤特异性免疫反应。我们将通过使用ELITUXIMAB治疗前后使用ELISPOT，FluoriSpot，Lysypot，Lysypot和细胞内细胞质的细胞因子流动仪，通过监测新诊断的FL患者的存在，以监测新诊断的FL患者的外周血和肿瘤感染淋巴瘤特异性效应子和/或记忆CD4+和CD8+ T细胞。我们还将检验该假设的两个推论，这是利妥昔单抗引起的活性淋巴瘤特异性细胞反应。 （a）导致淋巴瘤特异性CD4+和CD8+ T细胞的效应函数的增加； （b）提供了产生淋巴瘤特异性体液反应所需的必要T细胞帮助。利妥昔单抗产生淋巴瘤特异性免疫反应的证明以及对反应的靶抗原的了解对我们如何最佳治疗FL患者具有深远的影响。例如，这表明将利妥昔单抗与药物相结合，预计会增加淋巴瘤特异性T细胞反应的诱导，例如GM-CSF，CPG寡核苷酸和抗CTLA-4 -4单克隆抗体，将具有潜在的临床益处。此外，这项研究的结果应适用于其他恶性肿瘤的抗体治疗，因此，我们预计这些研究将导致旨在提高癌症单克隆抗体治疗的有效性的新型治疗策略。卵泡淋巴瘤（FL）是一种懒惰但本质上无法治愈的疾病，但是包括利妥昔单抗治疗在内的新疗法为患有这种疾病的患者提供了新的希望。利妥昔单抗是一种抗体，它是一种靶向淋巴瘤细胞上另一种蛋白质的蛋白质，导致了淋巴瘤细胞死亡，但是rinuximab通过其摧毁淋巴瘤细胞的确切机制尚未明确定义。我们的小组正在确定利妥昔单抗是否通过刺激患者自身的免疫系统消除该疾病来诱导淋巴瘤细胞死亡，以更好地理解利妥昔单抗在淋巴瘤患者中如何发挥作用，使我们能够开发出新的治疗方法，我们预计我们预期的这种疾病患者会增加受益。 针对CD20的嵌合单克隆抗体的项目摘要/摘要利妥昔单抗在卵泡淋巴瘤（FL）患者中显示出显着的治疗活性，但尚未完全定义其确切的作用机理。尽管杀死CD20+ FL细胞，即通过补体依赖的细胞解，抗体依赖性的细胞毒性或直接诱导凋亡可能有助于其有效性，但这些机制不太可能是作用机制的唯一机制； （a）在最后剂量利妥昔单抗后，对利妥昔单抗的临床和分子反应可能持续数月； （b）对利妥昔单抗的第二个反应的中间持续时间比第一个反应的持续时间更长，临床发现不能仅通过上述机制来解释。利妥昔单抗诱导的FL细胞死亡预计将导致肿瘤抗原的释放，例如源自fl相关免疫球蛋白（Ig）的重（VH）和轻链（VL）的可变区域，以及在促炎环境中尚未确定的肿瘤抗原。我们假设利妥昔单抗诱导的淋巴瘤相关抗原的释放将引起细胞介导的淋巴瘤特异性免疫反应。我们将通过使用ELITUXIMAB治疗前后使用ELISPOT，FluoriSpot，Lysypot，Lysypot和细胞内细胞质的细胞因子流动仪，通过监测新诊断的FL患者的存在，以监测新诊断的FL患者的外周血和肿瘤感染淋巴瘤特异性效应子和/或记忆CD4+和CD8+ T细胞。我们还将检验该假设的两个推论，这是利妥昔单抗引起的活性淋巴瘤特异性细胞反应。 （a）导致淋巴瘤特异性CD4+和CD8+ T细胞的效应函数的增加； （b）提供了产生淋巴瘤特异性体液反应所需的必要T细胞帮助。利妥昔单抗产生淋巴瘤特异性免疫反应的证明以及对反应的靶抗原的了解对我们如何最佳治疗FL患者具有深远的影响。例如，这表明将利妥昔单抗与药物相结合，预计会增加淋巴瘤特异性T细胞反应的诱导，例如GM-CSF，CPG寡核苷酸和抗CTLA-4 -4单克隆抗体，将具有潜在的临床益处。此外，这项研究的结果应适用于其他恶性肿瘤的抗体治疗，因此，我们预计这些研究将导致新的治疗策略，旨在增强癌症对癌症对一般癌症的有效性的有效性。这种疾病。利妥昔单抗是一种抗体，它是一种靶向淋巴瘤细胞上另一种蛋白质的蛋白质，导致了淋巴瘤细胞死亡，但是rinuximab通过其摧毁淋巴瘤细胞的确切机制尚未明确定义。我们的小组正在确定利妥昔单抗是否通过刺激患者自身的免疫系统消除该疾病来诱导淋巴瘤细胞死亡，以更好地理解利妥昔单抗在淋巴瘤患者中如何发挥作用，使我们能够开发出新的治疗方法，我们预计我们预期的这种疾病患者会增加受益。