Overcoming Tumor Evasion in EBV+ve Lymphomas

克服 EBV 和淋巴瘤的肿瘤逃逸

基本信息

批准号：
10000868
负责人：
CLIONA M ROONEY
金额：
$ 26.78万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10000868
关键词：
Adoptive Transfer Antibodies Antigen Receptors Antigen Targeting Antigen-Presenting Cells Antigens B-Lymphocytes Biological Assay CD19 Antigens CD19 gene Cells Clinical Clinical Protocols Clinical Trials Data Dinoprostone Disease Disease Marker Disease remission EBV specific T-cells Engraftment Ensure Environment Epitope spreading Equilibrium Frequencies Goals Hodgkin Disease Homing Human Human Herpesvirus 4 IL7 gene Image Immune Immune Evasion Immunosuppression Immunotherapy Infusion procedures Interleukin-15 Lead Ligands Link Lymphoid Tissue Lymphoma Lymphoma cell Measurement Measures Monitor Non-Hodgkin&apos s Lymphoma Outcome Patients Peer Review Plasma Pre-Clinical Model Proliferating Property Proteins Receptor Signaling Recurrent disease Refractory Disease Reproducibility Research Resistance Retroviral Vector Safety Signal Transduction Site Source Stable Disease T cell anergy T cell therapy T-Cell Activation T-Cell Immunologic Specificity T-Cell Proliferation T-Lymphocyte Testing Time Toxic effect Transforming Growth Factor beta Transgenes Tumor Antigens Tumor Escape Tumor-Derived Validation Viral Antigens Viral Genome Viral Proteins Writing antigen binding antigen-specific T cells base chimeric antigen receptor curative treatments cytotoxicity design disorder risk exosome experimental study hazard high risk imaging study immunogenic in vivo novel strategies partial response peripheral blood pre-clinical primary endpoint response safety and feasibility standard measure tumor tumor microenvironment tumor-immune system interactions

项目摘要

PROJECT SUMMARY / ABSTRACT The broad goal of Project 3 is to devise and implement novel strategies of effective, low-toxicity EBV-specific T cell therapy for EBV-positive lymphomas, which account for approximately 40% of all human lymphomas. In a recent clinical trial of such immunotherapy in patients with high-risk active disease at the time of infusion of EBV-specific T cells (EBVSTs), we found that favorable tumor responses correlated with increased numbers of both EBVSTs and T cells that recognized nonviral tumor antigens (TAs), an example of antigen spreading. In most patients, however, the increases in both types of T cells were only transient, suggesting induction of T-cell anergy by potent immunosuppressive mechanisms in the tumor microenvironment. Thus, to prolong T cell expansion and function in this hostile setting, we are testing whether artificial costimulation by costimulatory chimeric antigen receptors (CoCARs) will enhance T cell proliferation and sustain EBVST activation in the face of inhibitory molecules. This approach, like that with classical CARs, combines the antigen binding domain of an antibody with costimulatory endodomains that trigger proliferation of the host T cell, but lacks the zeta chain of the TCR that is required to initiate cytotoxicity. The CoCAR therefore allows any cognate target cell to induce T cell costimulation without sustaining damage itself. CD19 was selected as the CoCAR target antigen because B cells are ubiquitous in lymphoid tissues and are often found within lymphoma sites; moreover, their function as professional antigen-presenting cells should enable them to enhance CoCAR signaling appreciably. The overarching hypothesis for this strategy – that appropriate stimulation by EBV antigens and CD19 will render CoCAR-expressing EBVSTs resistant to tumor-derived inhibitory molecules, promoting their expansion and persistence after infusion and thus greater antigen spreading and better tumor responses – will be tested in the following specific aims. AIM 1: Optimize in a preclinical model the CD19-specific CoCAR for use in human EBV-specific T cells . AIM 2: Evaluate the feasibility and safety of using EBVSTs modified with CD19-directed CoCARS to treat patients with EBV-associated Hodgkin lymphoma or non-Hodgkin lymphoma. AIM 3: Evaluate the expansion, persistence and antitumor activity of CoCAR-modified EBVSTs and TA- specific T cells, based on quantitative PCR measurements, ELIspot assay results, and imaging studies. Validation of this strategy may lead to its common use in the treatment of EBV-positive lymphoma.

项目概要/摘要项目 3 的总体目标是设计和实施针对 EBV 的有效、低毒性的新策略 T 细胞疗法治疗 EBV 阳性淋巴瘤，约占所有人类淋巴瘤的 40%。在最近一项针对输注时患有高危活动性疾病的患者进行的此类免疫疗法的临床试验中 EBV 特异性 T 细胞 (EBVST) 的数量，我们发现良好的肿瘤反应与数量增加相关识别非病毒肿瘤抗原 (TA) 的 EBVST 和 T 细胞，这是抗原传播的一个例子。然而，在大多数患者中，两种类型 T 细胞的增加只是短暂的，表明诱导通过肿瘤微环境中有效的免疫抑制机制使 T 细胞无反应，从而延长 T 细胞。在这种敌对环境中细胞的扩张和功能，我们正在测试是否通过人工共刺激共刺激嵌合抗原受体 (CoCAR) 将增强 T 细胞增殖并维持 EBVST 与经典 CAR 一样，这种方法结合了抑制分子的激活。抗体的抗原结合结构域，具有触发宿主 T 增殖的共刺激内结构域细胞，但缺乏启动细胞毒性所需的 TCR zeta 链，因此 CoCAR 允许。选择任何诱导 T 细胞共刺激而不对其自身造成损害的同源靶细胞。作为 CoCAR 靶抗原，因为 B 细胞在淋巴组织中普遍存在，并且经常存在于淋巴瘤位点；此外，它们作为专业抗原呈递细胞的功能应该使它们能够该策略的总体假设是适当的。 EBV 抗原和 CD19 的刺激将使表达 CoCAR 的 EBVST 对肿瘤源性耐药抑制分子，促进其在输注后的扩张和持久性，从而产生更大的抗原扩散和更好的肿瘤反应——将在以下具体目标中进行测试。目标 1：在临床前模型中优化 CD19 特异性 CoCAR，以用于人类 EBV 特异性 T 细胞。目标 2：评估使用 CD19 定向 CoCARS 修饰的 EBVST 治疗的可行性和安全性患有 EBV 相关霍奇金淋巴瘤或非霍奇金淋巴瘤的患者。目标 3：评估 CoCAR 修饰的 EBVST 和 TA- 的扩展、持久性和抗肿瘤活性特定 T 细胞，基于定量 PCR 测量、ELIspot 测定结果和成像研究。该策略的验证可能导致其普遍用于治疗 EBV 阳性淋巴瘤。