ADMINISTRATION OF HER2 CHIMERIC RECEPTOR AND TGFBETA DOMINANT NEGATIVE RECEPTOR

HER2嵌合受体和TGFβ显性阴性受体的施用

• 批准号: 8166774
• 负责人: Stephen Gottschalk
• 金额: $ 0.23万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166774
• 关键词: Blood; Blood specimen; Cell physiology; Cells; Clinic; Computer Retrieval of Information on Scientific Projects Database; Disease; Dominant Negative Receptor; Engineering; Environment; Funding; Gene Transfer; Genes; Grant; Hour; Human Herpesvirus 4; Immune; Immunity; Immunotherapy; Infusion procedures; Institution; Malignant Neoplasms; Malignant neoplasm of lung; Metastatic/Recurrent; Moloney Leukemia Virus; Monitor; Outcome; Patients; Research; Research Personnel; Resistance; Resources; Retroviral Vector; Safety; Source; Stream; Structure; Synthetic Genes; T-Lymphocyte; Technology; Transforming Growth Factor beta; United States National Institutes of Health; Veins; Virus; cancer cell; cancer therapy; fighting; killer T cell; killings; meetings; neoplastic cell; peripheral blood; receptor; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The outcome for patients with recurrent/metastatic lung cancer has not changed over the last 2 decades and most patients die of their disease. New anti-lung cancer therapies are needed and immunotherapy holds the promise to fulfill this need. The body's immune defense against cancers often fails because cancers either do not induce or actively inhibit immunity. We will counteract these limitations by i) engineering killer T cells or recognize structures on lung cancer cells and ii) to resist the defenses imposed by the cancer cell environment. Using gene transfer technology, it may be possible to take advantage of the tumor killing ability of killer T cells and render them resistant to inhibitory factors secreted by tumor cells. We propose taking the patients own T cells and putting into them two genes. The first gene is for an artificial structure (receptor) that will direct the T cells to the tumor and the second gene is for a dominant negative receptor (DNR), which renders T cells resistant against one of the major inhibitory factors secreted by lung cancer cells. We will place the two genes into T cells that are pre-selected for their ability to recognize the Epstein Barr virus which is chronically present in most people. Because these EBV-specific T cells meet the virus positive cells as well as tumor cells, they receive extra stimulation. We will put the genes for the artificial receptor and the DNR into patients EBV-specific T cells using a modified virus (Moloney retroviral vector). These modified T-cells will then be given directly into the patient s blood stream through a central line or a vein. Patients will be treated in the clinic and will be monitored closely for several hours after infusion. We will collect samples of blood from peripheral blood at regular intervals. We will look for the safety, the persistence and the function of the cells we put into the patients. Ultimately we hope to get evidence that these modified T cells are effective at fighting the cancer.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 在过去的20年中，复发/转移性肺癌的患者的结果没有改变，大多数患者死于疾病。需要新的抗肺癌疗法，免疫疗法有望满足这种需求。 人体针对癌症的免疫防御常常失败，因为癌症不会诱导或积极抑制免疫力。我们将通过i）工程杀手T细胞来抵消这些局限性，或识别肺癌细胞上的结构，ii）抵抗癌细胞环境施加的防御能力。使用基因转移技术，有可能利用杀伤剂T细胞的肿瘤杀伤能力，并使其对肿瘤细胞分泌的抑制因子具有抗性。我们提议将患者自己的T细胞带入两个基因。第一个基因是用于人工结构（受体），该结构将将T细胞引导到肿瘤，第二个基因用于显性阴性受体（DNR），该基因使T细胞具有抵抗由肺癌细胞分泌的主要抑制因子之一。 我们将将两个基因放入T细胞中，以识别大多数人长期存在的爱泼斯坦Barr病毒的能力。由于这些EBV特异性T细胞符合病毒阳性细胞以及肿瘤细胞，因此它们会受到额外的刺激。我们将使用修饰的病毒（Moloney逆转录病毒载体）将人工受体和DNR的基因和DNR的基因放入患者中。然后，这些修饰的T细胞将直接通过中央线或静脉直接给予患者的血液。患者将在诊所接受治疗，并在输注后几个小时对患者进行治疗。我们将定期从外周血中收集血液样本。我们将寻找我们投入患者细胞的安全性，持久性和功能。最终，我们希望获得证据表明这些修饰的T细胞有效地与癌症作斗争。