ADMINISTRATION OF HER2 CHIMERIC RECEPTOR AND TGFBETA DOMINANT NEGATIVE RECEPTOR

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 复发性/转移性肺癌患者的结局在过去20年中没有改变，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一需求。 身体对癌症的免疫防御通常失败，因为癌症不会诱导或主动抑制免疫力。我们将通过i）设计杀伤T细胞或识别肺癌细胞上的结构以及ii）抵抗癌细胞环境施加的防御来抵消这些限制。利用基因转移技术，有可能利用杀伤性T细胞的肿瘤杀伤能力，并使它们对肿瘤细胞分泌的抑制因子产生抗性。我们建议提取患者自身的T细胞，并将两个基因植入其中。第一个基因是一个人工结构（受体），将直接T细胞的肿瘤和第二个基因是显性负性受体（DNR），这使得T细胞对肺癌细胞分泌的主要抑制因子之一的抗性。 我们将把这两个基因放入T细胞中，这些T细胞是预先选择的，因为它们有能力识别大多数人长期存在的爱泼斯坦巴尔病毒。由于这些EBV特异性T细胞与病毒阳性细胞以及肿瘤细胞相遇，因此它们受到额外的刺激。我们将使用改良的病毒（Moloney逆转录病毒载体）将人工受体和DNR的基因放入患者的EBV特异性T细胞中。然后，这些经过修饰的T细胞将通过中心静脉或静脉直接进入患者的血流。患者将在诊所接受治疗，并在输注后数小时内密切监测。我们将定期从外周血中采集血液样本。我们将寻找我们植入患者体内的细胞的安全性、持久性和功能。最终，我们希望得到证据，证明这些修饰的T细胞在对抗癌症方面是有效的。

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.