Lentiviral engineered T cell immunotherapy in tumors overexpressing mesothelin

慢病毒工程 T 细胞免疫治疗过度表达间皮素的肿瘤

• 批准号: 7161656
• 负责人: Boro Dropulic
• 金额: $ 23.66万
• 依托单位: LENTIGEN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7161656
• 关键词: immunotherapy; neoplasm /cancer

DESCRIPTION (provided by applicant): Project Summary/Abstract: The overall goal of this proposal is to evaluate the novel concept whether using lentiviral-engineered T cells that express chimeric receptors and signaling modules will improve efficacy for cancer immunotherapy directed against mesothelin. Mesothelin is a tumor associated antigen and a promising target in mesothelioma, ovarian, squamous cell cancers of head and neck, cervical, esophageal, pancreatic and many non-small cell lung cancers (NSCLC). In this proposal, we will test the fundamental hypothesis that human T cells with redirected specificity for carcinomas that express mesothelin can be created and can offer a clinically relevant and successful therapeutic approach. The ultimate goal is the development of a novel and improved therapy in those tumors for which the current therapies do not offer satisfactory results. Lentiviral vectors (LVs) have been successfully evaluated in Phase I clinical trials in patients with HIV/AIDS, offering the possibility to apply this technology for the treatment of cancer. Lentigen's collaborator Dr. Carl June has helped pioneer adoptive immunotherapy as a potential therapeutic approach for hematologic malignancies. He has recently found that optimal growth of human CD8 cells required signals from CD137 (4-1BB). Therefore, in Aim 1 of this proposal, we will develop self inactivating (SIN) LVs expressing the chimeric anti-mesothelin single chain antibody, linked to the intracellular domain of the T cell receptor (TCR) zeta chain in tandem with 4-1BB (CD137) or CD28 intracellular co-stimulatory domains using a CD8 alpha hinge and trans-membrane domain. In Aim 2, we will test the anti-mesothelin LV vectors in T cells for safety and functionality. In Aim 3 in collaboration with Drs. June and Grupp, we will determine whether vector constructs are optimal to kill tumorigenic cells in vivo and to enable efficient engraftment and proliferation. In summary, Lentigen Corp., and Dr. June's laboratory are uniquely positioned to provide the first comprehensive evaluation of the redirected T cell approach to generate anti-tumor effects in cancer patients and to apply this in a future clinical trial for patients with common and life threatening malignancies. Project Narrative: The ultimate goal of this proposal is the development of a novel and improved therapy for those tumors for which the current therapies do not offer satisfactory results. This therapy is based on activation of immune cells that will be manipulated in the laboratory and put back to the patient to fight cancer cells. Because of its great potential to offer a solution for those patients failing other therapies, this therapy will have a significant relevance for cancer patients and health care providers in the United States and worldwide.

描述(由申请人提供)：项目摘要/摘要：这项建议的总体目标是评估使用表达嵌合受体和信号模块的慢病毒工程T细胞是否会提高针对间皮蛋白的癌症免疫治疗的疗效。Mesothelin是一种肿瘤相关抗原，是治疗间皮瘤、卵巢癌、头颈部鳞状细胞癌、宫颈癌、食道癌、胰腺癌和许多非小细胞肺癌(NSCLC)的有前途的靶点。在这项提案中，我们将检验一个基本假设，即可以创造出对肿瘤具有重定向特异性的、表达间硫蛋白的人类T细胞，并能够提供一种临床相关的成功治疗方法。最终的目标是开发一种新的和改进的治疗方法，用于那些目前的治疗方法不能提供令人满意的结果的肿瘤。慢病毒载体已经在HIV/AIDS患者的I期临床试验中成功地进行了评估，这为将这项技术应用于癌症治疗提供了可能性。伦蒂根的合作者卡尔·琼博士帮助开创了过继免疫疗法作为血液系统恶性肿瘤潜在治疗方法的先河。他最近发现，人类CD8细胞的最佳生长需要CD137(4-1BB)的信号。因此，在本提案的目标1中，我们将利用CD8α铰链和跨膜结构域，将表达嵌合的抗间硫蛋白单链抗体的自灭活(SIN)LV与T细胞受体(TCR)Zeta链的胞内域与4-1BB(CD137)或CD28细胞内共刺激结构域连接起来。在目标2中，我们将在T细胞中测试抗间皮蛋白LV载体的安全性和功能性。在目标3中，我们将与琼博士和Grupp博士合作，确定载体构建是否最适合在体内杀死成瘤细胞，并实现有效的植入和增殖。总之，Lentigen公司和琼博士的实验室处于独特的地位，可以提供对重定向T细胞方法的首次全面评估，以产生对癌症患者的抗肿瘤效果，并将其应用于未来对常见和危及生命的恶性肿瘤患者的临床试验。项目简介：这项提议的最终目标是开发一种新的和改进的治疗方法，用于那些目前的治疗方法不能提供满意结果的肿瘤。这种疗法是基于免疫细胞的激活，这些细胞将在实验室中被操纵，并被送回患者体内，以对抗癌细胞。由于其为那些其他疗法失败的患者提供解决方案的巨大潜力，这种疗法将对美国和世界各地的癌症患者和医疗保健提供者具有重要的相关性。