Lentiviral engineered T cell immunotherapy in tumors overexpressing mesothelin

描述（由申请人提供）：项目摘要/摘要：本提案的总体目标是评估使用表达嵌合受体和信号传导模块的慢病毒工程化T细胞是否会提高针对间皮素的癌症免疫疗法的疗效的新概念。间皮素是一种肿瘤相关抗原，是间皮瘤、卵巢癌、头颈部鳞状细胞癌、宫颈癌、食管癌、胰腺癌和许多非小细胞肺癌（NSCLC）的有希望的靶点。在这项提案中，我们将测试基本假设，即可以创建对表达间皮素的癌症具有重定向特异性的人类T细胞，并可以提供临床相关和成功的治疗方法。最终目标是开发一种新的和改进的治疗方法，用于治疗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（LV）已在HIV/AIDS患者的I期临床试验中得到成功评估，为应用该技术治疗癌症提供了可能性。Lentigen的合作者Carl June博士帮助开创了过继免疫疗法，作为血液恶性肿瘤的潜在治疗方法。他最近发现，人类CD 8细胞的最佳生长需要来自CD 137（4-1BB）的信号。因此，在该提议的目的1中，我们将开发表达嵌合抗间皮素单链抗体的自失活（SIN）LV，所述嵌合抗间皮素单链抗体使用CD 8 α铰链和跨膜结构域与4-1BB（CD 137）或CD 28胞内共刺激结构域串联连接至T细胞受体（TCR）ζ链的胞内结构域。在目的2中，我们将测试T细胞中的抗间皮素LV载体的安全性和功能性。在与June和Grupp博士合作的Aim 3中，我们将确定载体构建体是否是杀死体内致瘤细胞并实现有效植入和增殖的最佳载体构建体。总之，Lentigen公司，June博士的实验室具有独特的优势，能够首次对重定向T细胞方法进行全面评估，以在癌症患者中产生抗肿瘤作用，并将其应用于未来常见和危及生命的恶性肿瘤患者的临床试验。项目叙述：该提案的最终目标是开发一种新的和改进的治疗方法，用于目前的治疗方法不能提供令人满意的结果的肿瘤。这种疗法是基于免疫细胞的激活，这些细胞将在实验室中进行操作，并放回患者体内以对抗癌细胞。由于其为其他治疗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全球的癌症患者和医疗保健提供者具有重要意义。

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.