Tumor reactive, TGF-Beta insensitive T cells

肿瘤反应性、TGF-β 不敏感 T 细胞

• 批准号: 6767870
• 负责人: CHUNG LEE
• 金额: $ 9.81万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6767870
• 关键词: T lymphocyte; athymic mouse; bone marrow transplantation; flow cytometry; gene therapy; growth factor receptors; histology; immune response; immune tolerance /unresponsiveness; inflammation; interleukin 2; laboratory mouse; metastasis; neoplastic cell; passive immunization; terminal nick end labeling; tetracyclines; therapy design /development; transforming growth factors

DESCRIPTION (provided by applicant): This exploratory proposal is submitted in response to PA-01-020. It describes a novel gene therapy program to eradicate metastatic cancer cells. We will use the autochthonous TRAMP prostate cancer model as the test system. Metastasis is the major cause of death in cancer patients, as locally confined diseases are manageable by many available modalities. Treatment of metastatic tumors requires a systemic approach. However, despite significant advances, current approaches are only effective to selected few types of cancer. New and effective approaches are urgently needed for patients with metastatic cancer. In our previous studies, we have developed an approach to enhance host immune system against metastatic cancer cells in mice by rendering host immune cells insensitive to transforming growth factor beta (TGF-beta). Those results were encouraging. However, this approach, although eliminated metastatic tumor cells, caused the development of a widespread inflammation in host animals, leading to eventual death of the host. This is an undesirable side effect and must be corrected. In the present exploratory proposal, we have modified this approach with the objective to eradicate metastatic cancer cells without the development of the widespread inflammation. Specific Aim 1: We propose to develop an adoptive therapy in which specific tumor reactive, TGF-beta insensitive T cells will be transferred into advanced staged TRAMP mice. Basically, we will transfer tumor reactive, TGF-beta insensitive T cells into recipient mice in order to eliminate metastatic tumor cells without the development of the widespread inflammatory syndrome. Specific Aim 2: We propose to develop a bone marrow transplant program in which TGF-beta insensitivity will be regulated under a tetracycline inducible system. In this manner, we will be able to control the timing of onset of TGF-beta insensitivity. When metastatic tumor cells are eliminated, we will turn off the TGF-beta insensitivity so that the widespread inflammation can be avoided in recipient animals. If any one of these exploratory studies proves successful, we will be able to pursue clinical trials as well as to search for molecular and cellular mechanisms to elucidate the role of TGF-beta insensitive immune cells in tumor eradication.

描述（由申请人提供）：本探索性提案是根据PA-01-020提交的。它描述了一种根除转移性癌细胞的新型基因治疗计划。我们将使用本地TRAMP前列腺癌模型作为测试系统。转移是癌症患者死亡的主要原因，因为局限于局部的疾病可以通过许多可用的方式来管理。转移性肿瘤的治疗需要系统方法。然而，尽管取得了重大进展，但目前的方法仅对选定的少数几种癌症有效。转移性癌症患者迫切需要新的有效方法。在我们以前的研究中，我们已经开发了一种方法，通过使宿主免疫细胞对转化生长因子β（TGF-β）不敏感来增强宿主免疫系统对抗小鼠中的转移性癌细胞。这些结果令人鼓舞。然而，这种方法虽然消除了转移性肿瘤细胞，但在宿主动物中引起广泛炎症的发展，导致宿主最终死亡。这是一种不良的副作用，必须加以纠正。在目前的探索性建议中，我们已经修改了这种方法，目的是根除转移性癌细胞，而不发展广泛的炎症。 具体目标1：我们建议开发一种过继疗法，其中将特异性肿瘤反应性、TGF-β不敏感的T细胞转移到晚期TRAMP小鼠中。基本上，我们将肿瘤反应性，TGF-β不敏感的T细胞转移到受体小鼠中，以消除转移性肿瘤细胞，而不发展广泛的炎症综合征。具体目标二：我们建议开发一种骨髓移植计划，其中TGF-β不敏感性将在四环素诱导系统下进行调节。通过这种方式，我们将能够控制TGF-β不敏感性发作的时间。当转移性肿瘤细胞被消除时，我们将关闭TGF-β不敏感性，从而可以避免受体动物中的广泛炎症。如果这些探索性研究中的任何一项被证明是成功的，我们将能够进行临床试验，并寻找分子和细胞机制，以阐明TGF-β不敏感的免疫细胞在肿瘤根除中的作用。