Overcoming Tumor Evasion in EBV+ve Lymphomas

克服 EBV 和淋巴瘤的肿瘤逃逸

• 批准号: 10247740
• 负责人: CLIONA M ROONEY
• 金额: $ 25.97万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 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/10247740
• 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' 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

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.

项目摘要 /摘要 项目3的广泛目标是制定和实施有效，低毒性EBV特异性的新颖策略 T细胞治疗EBV阳性淋巴瘤，约占所有人类淋巴瘤的40％。 在输液时，这种免疫疗法的最新临床试验在具有高风险活性疾病的患者中 在EBV特异性T细胞（EBVST）中，我们发现有利的肿瘤反应与数量增加相关 在识别非病毒肿瘤抗原（TAS）的EBVST和T细胞中，这是抗原扩散的一个例子。 但是，在大多数患者中，两种类型的T细胞的增加仅是短暂的，这表明诱导 肿瘤微环境中有效的免疫抑制机制的T细胞消极。那延长了 在这种敌对环境中的细胞扩展和功能，我们正在测试人工共刺激是否通过 共刺激嵌合抗原受体（可可）将增强T细胞增殖并维持EBVST 面对抑制分子的激活。这种方法，与古典汽车一样，将 抗体的抗原结合结构域具有共刺激性内分域触发宿主T的增殖 细胞，但缺乏启动细胞毒性所需的TCR的Zeta链。因此，Cocar允许 任何同源靶细胞都会诱导T细胞共刺激，而无需造成损害本身。选择了CD19 作为COCAR靶抗原，因为B细胞在淋巴组织中普遍存在，并且经常被发现 淋巴瘤部位；此外，它们作为专业抗原的细胞的功能应使他们能够 增强COCAR信号传导。该策略的总体假设 - 适当的 EBV抗原和CD19的刺激将使表达Cocar的EBVST对肿瘤衍生 抑制分子，促进其输注后其膨胀和持久性，从而更大的抗原 扩散和更好的肿瘤反应 - 将在以下特定目的中进行测试。 AIM 1：在临床前模型中优化CD19特异性COCAR用于人EBV特异性T细胞。 AIM 2：评估使用CD19定向椰油修饰的EBVST的可行性和安全性 患有EBV相关的霍奇金淋巴瘤或非霍奇金淋巴瘤的患者。 AIM 3：评估Cocar修饰的EBVST和TA-的膨胀，持久性和抗肿瘤活性 特定的T细胞基于定量PCR测量，ELISPOT测定结果和成像研究。 对该策略的验证可能导致其在治疗EBV阳性淋巴瘤治疗中的共同使用。