Lentiviral engineered T cell immunotherapy in tumors overexpressing mesothelin

项目摘要/摘要：本项目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素的癌症免疫治疗的疗效。间皮素是一种肿瘤相关抗原，是间皮瘤、卵巢癌、头颈部、宫颈、食管癌、胰腺癌和许多非小细胞肺癌（NSCLC）的一个有希望的靶点。在这个提议中，我们将测试一个基本假设，即表达间皮素的具有癌症重定向特异性的人类T细胞可以被创造出来，并可以提供一种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来治疗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（LVs）已经在HIV/AIDS患者的I期临床试验中成功评估，为将该技术应用于癌症治疗提供了可能性。Lentigen的合作者Carl June博士帮助开拓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CD8细胞的最佳生长需要来自CD137 （4-1BB）的信号。因此，在本提案的目标1中，我们将开发表达嵌合抗间皮素单链抗体的自我失活（SIN） lv，通过CD8 α铰链和跨膜结构域与T细胞受体（TCR） zeta链的胞内结构域与4-1BB （CD137）或CD28胞内共刺激结构域串联。在第二阶段，我们将在T细胞中测试抗间皮素LV载体的安全性和功能性。在Aim 3中，我与dr。June和Grupp，我们将确定载体结构是否最适合在体内杀死致瘤细胞，并实现有效的植入和增殖。总之，Lentigen公司和June博士的实验室具有独特的优势，可以首次全面评估重定向T细胞方法在癌症患者中产生的抗肿瘤作用，并将其应用于未来的常见和危及生命的恶性肿瘤患者的临床试验。项目简介：本提案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，这些免疫细胞将在实验室中被操纵，并被放回病人体内，以对抗癌细胞。由于它有很大的潜力为那些其他疗法失败的患者提供解决方案，这种疗法将对美国和全世界的癌症患者和卫生保健提供者具有重要的相关性。

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.