IMPROVING T CELL THERAPY OF NASOPHARYNGEAL CANCER

改善鼻咽癌的 T 细胞治疗

• 批准号: 8378617
• 负责人: Stephen Gottschalk
• 金额: $ 25.92万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8378617
• 关键词: Acute; Antigen Receptors; Antiviral Agents; Area; Autologous; Binding; Biological Assay; Bulky Disease; CD45 Antigens; CD70 antigen; Cell Line; Cell Survival; Cell physiology; Cells; Clinical Research; Clinical Trials; Complement; Cytotoxic T-Lymphocytes; Data; Deposition; Disease; Disease-Free Survival; Distant Metastasis; Dose; Down-Regulation; Effectiveness; Elements; Engineering; Ensure; Environment; Epithelial Cells; Epstein-Barr Virus Infections; Exposure to; Frequencies; Functional disorder; Gene Family; Goals; Human Herpesvirus 4; Hypoxia; Hypoxia Inducible Factor; Hypoxia-Responsive Elements; IL2 gene; Image; Immune; Immunity; Immunotherapy; Implant; In complete remission; Incidence; Infusion procedures; Intensity-Modulated Radiotherapy; Interleukin-15; LMP1; Long-Term Survivors; Lymphocyte; MHC Class I Genes; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of nasopharynx; Measures; Methods; Modification; Monoclonal Antibodies; Mus; Nasopharynx; Nasopharynx Carcinoma; Outcome; Oxygen measurement, partial pressure, arterial; PTPRC gene; Pathway interactions; Patients; Phase I Clinical Trials; Plasma; Population; Proliferating; Receptor Signaling; Refractory; Regulatory T-Lymphocyte; Relapse; Research; Resistance; Risk; Safety; Signal Transduction; Site; Staging; Staining method; Stains; Structure; T cell therapy; T-Lymphocyte; Testing; Treatment outcome; Undifferentiated; Viral Antigens; Viral Proteins; Xenograft Model; cancer cell; cytokine; improved; in vivo; killer T cell; killings; neoplastic cell; novel; outcome forecast; overexpression; peripheral blood; programs; radiation effect; response; therapeutic effectiveness; trafficking; tumor; viral DNA

Latent Epstein-Barr virus (EBV) infection is associated with nasopharyngeal carcinoma (NPC), which expresses the EBV antigens LMP1 and LMP2, both potential targets for immunotherapy. Clinical studies with EBV-specific cytotoxicT cells (EBV-CTLs) in NPC have already yielded promising results, including some complete responses, but their efficacy is limited because the EBV-CTL generated by standard methods are 1) dominated by T-cell clones not reactive to the EBV proteins LMP1 and LMP2 expressed in NPC, 2) cannot expand significantly after infusion, 3) are sensitive to immune evasion strategies employed by NPCs such as downregulation of MHC class I expression and the presence of regulatory T cells (Tregs) in the tumor environment, and 4) are dysfunctional in areas of hypoxia within NPC deposits. Our central hypothesis is that overcoming these limitations will enhance the antitumor activity of infused CTLs and improve treatment outcome. Thus, we will prepare EBV-LMP1 and LMP2-specific CTLs (LMP-CTLs) and evaluate three strategies to enhance their activity using a clinical trial or a xenograft model. Aim 1 extends our current Phase I clinical trials in NPC by combining LMP-CTL with lymphodepleting CD45 monoclonal antibodies to augment CTL expansion in vivo and improve disease response rates. In Aim 2, we will express a chimeric antigen receptor (CAR) specific for CD70 in LMP-CTLs. CD70 is overexpressed in EBV-positive NPCs, and the modified CTLs should thus be able to kill NPC cells through both MHC class l-restricted and unrestricted pathways, increasing their therapeutic effectiveness in our xenograft model. Moreover, we will incorporate signaling endodomains from costimulatory molecules in the CAR and test whether these modifications make the CAR-LMP-CTL resistant to Tregs present in NPC. In Aim 3, we will exploit our previous observations showing that expression of the IL-2 gene regulated by the hypoxia inducible factor (HIF-IL2) can render CTL resistant to hypoxia. We will measure cellular persistence, proliferation and function of HIF-IL2 expressing LMP-CTL in hypoxic areas within NPC tumors, and determine, if they produce enhanced antitumor activity. These aims complement but do not overlap with those in projects 1-3, such that advances emerging from our research could be rapidly assimilated into strategies being tested in other tumors within this program and vice versa. Lav Summary: The body's immune defenses against cancers often fail because the malignancies do not induce or actively inhibit immunity. We will try to counteract these limitations by engineering killer T cells to recognize structures on cancer cells (LMP1 and LMP2) and to resist the defenses imposed by the tumor cell environment. The effects of the T cells will then be tested in patients with nasopharyngeal carcinoma (NPC).

潜伏性 Epstein-Barr 病毒 (EBV) 感染与鼻咽癌 (NPC) 相关， 表达 EBV 抗原 LMP1 和 LMP2，两者都是免疫治疗的潜在靶点。临床研究 鼻咽癌中的 EBV 特异性细胞毒性 T 细胞 (EBV-CTL) 已经取得了有希望的结果，包括一些 完全缓解，但其功效有限，因为标准方法生成的 EBV-CTL 是 1) 以对 NPC 中表达的 EBV 蛋白 LMP1 和 LMP2 不发生反应的 T 细胞克隆为主，2) 输注后不能显着扩增，3) 对 NPC 采用的免疫逃避策略敏感 例如 MHC I 类表达的下调以及调节性 T 细胞 (Treg) 的存在 肿瘤环境，4) 在 NPC 沉积物内的缺氧区域功能失调。我们的中心假设 克服这些限制将增强输注 CTL 的抗肿瘤活性并改善 治疗结果。因此，我们将制备 EBV-LMP1 和 LMP2 特异性 CTL (LMP-CTL) 并评估 使用临床试验或异种移植模型增强其活性的三种策略。目标 1 扩展我们目前的 通过将 LMP-CTL 与淋巴细胞清除 CD45 单克隆抗体相结合来治疗鼻咽癌的 I 期临床试验 增强 CTL 在体内的扩增并提高疾病反应率。在目标 2 中，我们将表达一个嵌合体 LMP-CTL 中 CD70 特异性抗原受体 (CAR)。 CD70 在 EBV 阳性 NPC 中过度表达，并且 因此，修饰后的 CTL 应该能够通过 MHC I 类限制性和非限制性杀死 NPC 细胞 途径，提高其在我们的异种移植模型中的治疗效果。此外，我们将纳入 CAR 中共刺激分子的信号传导内域，并测试这些修饰是否使 CAR-LMP-CTL 对 NPC 中存在的 Tregs 具有抗性。在目标 3 中，我们将利用之前的观察结果 表明受缺氧诱导因子（HIF-IL2）调节的IL-2基因的表达可以导致CTL 耐缺氧。我们将测量 HIF-IL2 表达的细胞持久性、增殖和功能 LMP-CTL 位于 NPC 肿瘤内的缺氧区域，并确定它们是否产生增强的抗肿瘤活性。 这些目标与项目 1-3 中的目标相补充但不重叠，因此我们的进展 研究可以迅速融入到该计划中正在其他肿瘤中测试的策略中，并且 反之亦然。 Lav 摘要：人体针对癌症的免疫防御经常失败，因为 恶性肿瘤不会诱导或主动抑制免疫力。我们将尝试通过以下方式抵消这些限制 改造杀伤 T 细胞以识别癌细胞（LMP1 和 LMP2）上的结构并抵抗 肿瘤细胞环境施加的防御。然后将在患有以下疾病的患者中测试 T 细胞的效果 鼻咽癌（NPC）。