T Cell Therapy Targeting LMP1 and 2 in EBV+VE Lymphomas

EBV VE 淋巴瘤中靶向 LMP1 和 2 的 T 细胞疗法

• 批准号: 7919498
• 负责人: Stephen Gottschalk
• 金额: $ 30.03万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7919498
• 关键词: Adenovirus Vector; Adopted; Adoptive Transfer; Animal Model; Antigen-Presenting Cells; Antigens; Antitumor Response; Antiviral Agents; Autologous; B-Cell Lymphomas; Biological Assay; Blood specimen; CD45 Antigens; Cell Line; Cell Proliferation; Cell Therapy; Cells; Clinical; Clinical Research; Clinical Trials; Clone Cells; Cytokine Inducible SH2-Containing Protein; Cytotoxic T-Lymphocytes; EBV-associated malignancy; Effectiveness; Ensure; Epstein-Barr Virus Infections; Escape Mutant; Goals; HLA-A2 Antigen; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Home environment; Human Herpesvirus 4; Image; Immune; Immune response; Immune system; Immunity; Immunotherapy; In complete remission; Infusion procedures; Interleukin-12; Interleukin-15; LMP1; Label; Lymphocyte; Lymphoid; Lymphoma; Lymphoproliferative Disorders; Malignant Neoplasms; Marrow; Measures; Methods; Modeling; Monitor; Monoclonal Antibodies; Mus; Myeloid Cells; Non-Hodgkin' s Lymphoma; Outcome; Patients; Phase; Phase I Clinical Trials; Production; Progressive Disease; Recurrent disease; Refractory; Relapse; Reproduction spores; Research; Research Personnel; Resolution; Safety; Signal Transduction; Small Interfering RNA; Staging; Staining method; Stains; Symptoms; T-Cell Activation; T-Cell Lymphoma; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Training; Transgenic Animals; Treatment Protocols; Tumor Tissue; Vaccinated; Vaccination; Vaccines; Viral Antigens; Viral Proteins; Virus; cancer cell; clinically relevant; cytokine; improved; in vivo; neoplastic cell; outcome forecast; peripheral blood; prevent; progenitor; reconstitution; response; tumor; tumor specificity; vaccination strategy; viral DNA

Latent Epstein-Barr (EBV) infection is associated with both Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHL), and EBV antigens expressed in these lymphomas are potential targets for immunotherapy. Although clinical studies with EBV-specific cytotoxic T cells (CTLs) have yielded promising results, their antilymphoma activity is limited by several factors. For example, 1) EBV-specific CTL lines generated by standard methods are dominated by T-cell clones not reactive to the subdominant EBV proteins LMP1 and LMP2 expressed in HD and NHL and 2) infused EBV-specific CTLs do not significantly expand in vivo after adoptive transfer. Our central hypothesis is that by overcoming these limitations, we will enhance the antitumor activity of EBV-specific CTLs and improve clinical outcome in lymphoma patients treated with these cells. To demonstrate the feasibility of this strategy, we propose three specific research aims. AIM 1: We will infuse LMP1- and LMP2-specific CTLs into EBV-positive HD or NHL patients to generate the broadest possible CTL response against the malignant cells, and to ensure that suitable CTL epitopes are available, regardless of the patient's HLA type. AIM 2: We have shown that the infusion of monoclonal antibodies targeting the CD45 antigen results in transient lymphodepletion and enhanced EBV- specific CTL expansion. We will build on these findings and test in an animal model the ability of different vaccines to further enhance the proliferation of adoptively transferred CTLs post lymphodepletion. We hypothesize that the expression of IL-15 or the silencing of SOCS1, in combination with LMP1 and LMP2 expression, will enhance the vaccine-induced proliferation and expansion of LMP1- and LMP2-specific CTLs administered to patients. Finally, in AIM 3, we will test in a second Phase I clinical trial the safety and effects of an optimized vaccine on the expansion, persistence and antitumor effector function of pre-existing or adoptively transferred LMP1- and LMP2-specific CTLs in HD or NHL patients with relapsed disease. Lay summary: The body's immune defenses against cancer are usually not effective because the cancer cells, by themselves, do not attract a strong immune response. Some lymphomas contain parts of the Epstein-Barr virus that do stimulate the immune system. We plan to collect T cells, a component of the immune system, from patients' blood samples and train them to recognize the LMP1 and LMP2 segments of the Epstein-Barr virus. After these cells are returned to the patient, they should attack and destroy the tumors cells that contain LMP1 and LMP2.

潜伏性 Epstein-Barr (EBV) 感染与霍奇金病 (HD) 和非霍奇金病相关 淋巴瘤（NHL）和这些淋巴瘤中表达的 EBV 抗原是潜在的靶标 免疫疗法。尽管 EBV 特异性细胞毒性 T 细胞 (CTL) 的临床研究取得了有希望的结果 结果，它们的抗淋巴瘤活性受到几个因素的限制。例如，1) EBV 特异性 CTL 系 通过标准方法生成的 T 细胞克隆占主导地位，对次优势 EBV 不产生反应 HD 和 NHL 中表达的蛋白质 LMP1 和 LMP2 以及 2) 输注 EBV 特异性 CTL 不会显着影响 过继转移后在体内扩增。我们的中心假设是，通过克服这些限制，我们将 增强 EBV 特异性 CTL 的抗肿瘤活性并改善淋巴瘤患者的临床结果 用这些细胞进行处理。为了证明该策略的可行性，我们提出了三项具体研究 目标。目标 1：我们将向 EBV 阳性 HD 或 NHL 患者输注 LMP1 和 LMP2 特异性 CTL，以 产生针对恶性细胞的最广泛的 CTL 反应，并确保合适的 CTL 无论患者的 HLA 类型如何，都可以获得表位。目标 2：我们已经证明，输注 针对 CD45 抗原的单克隆抗体会导致短暂的淋巴细胞清除并增强 EBV- 特定的 CTL 扩展。我们将在这些发现的基础上，在动物模型中测试不同的能力 疫苗进一步增强淋巴细胞清除后过继转移的 CTL 的增殖。我们 假设 IL-15 的表达或 SOCS1 的沉默与 LMP1 和 LMP2 结合 表达，将增强疫苗诱导的 LMP1 和 LMP2 特异性 CTL 的增殖和扩增 给予患者。最后，在AIM 3中，我们将在第二个I期临床试验中测试安全性和效果 优化疫苗对现有或现有肿瘤的扩展、持久性和抗肿瘤效应功能的研究 在疾病复发的 HD 或 NHL 患者中过继转移 LMP1 和 LMP2 特异性 CTL。 简单总结：身体针对癌症的免疫防御通常无效，因为癌症 细胞本身不会引起强烈的免疫反应。有些淋巴瘤含有部分 爱泼斯坦-巴尔病毒确实会刺激免疫系统。我们计划收集 T 细胞，它是 免疫系统从患者的血液样本中提取数据，并训练他们识别 LMP1 和 LMP2 片段 爱泼斯坦-巴尔病毒。这些细胞被送回患者体内后，它们应该攻击并摧毁 含有 LMP1 和 LMP2 的肿瘤细胞。