IMPROVING T CELL THERAPY OF NASOPHARYNGEAL CANCER

改善鼻咽癌的 T 细胞治疗

基本信息

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
项目类别：
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

项目摘要

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).

潜在的爱泼斯坦 - 巴尔病毒（EBV）感染与鼻咽癌（NPC）有关表达EBV抗原LMP1和LMP2，这都是免疫疗法的潜在靶标。与临床研究 NPC中的EBV特异性细胞毒细胞（EBV-CTL）已经产生了令人鼓舞的结果，其中包括一些完全响应，但是它们的功效受到限制，因为标准方法生成的EBV-CTL是 1）由T细胞克隆独立于NPC中表达的EBV蛋白LMP1和LMP2，2）输注后不能显着扩展，3）对NPC采用的免疫逃避策略敏感例如MHC I类表达的下调以及在 NPC沉积物内缺氧区域的肿瘤环境和4）功能失调。我们的中心假设是克服这些局限性将增强注入CTL的抗肿瘤活性并改善治疗结果。因此，我们将准备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来增强其活性的三种策略。目标1扩展了我们的当前通过将LMP-CTL与淋巴结的CD45单克隆抗体结合到NPC中的I期临床试验增加体内CTL扩张并提高疾病反应率。在AIM 2中，我们将表达一个嵌合 LMP-CTL中CD70的抗原受体（CAR）。 CD70在EBV阳性NPC中过表达，并且因此，修改的CTL应该能够通过MHC类L限制和不受限制地杀死NPC细胞途径，在我们的异种移植模型中提高其治疗效果。而且，我们将合并来自汽车中共刺激分子的信号内分域，并测试这些修饰是否使得对NPC中存在的Treg的CAR-LMP-CTL抗性。在AIM 3中，我们将利用我们以前的观察结果表明由缺氧诱导因子（HIF-IL2）调节的IL-2基因的表达可以使CTL 对缺氧有抵抗力。我们将测量表达HIF-IL2的细胞持久性，增殖和功能 NPC肿瘤内缺氧区域的LMP-CTL，并确定它们是否产生增强的抗肿瘤活性。这些目的是补充，但与项目1-3中的目标没有重叠，以至于从我们的研究可以迅速吸收到该计划中的其他肿瘤中测试的策略，并且反之亦然。 LAV摘要：人体对癌症的免疫防御措施常常失败，因为恶性肿瘤不会诱导或积极抑制免疫力。我们将尝试通过工程杀手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，T细胞的影响将在患有鼻咽癌（NPC）。