Tumor reactive, TGF-Beta insensitive T cells

描述（由申请人提供）：本探索性提案是根据PA-01-020提交的。它描述了一种新的基因治疗方案来根除转移性癌细胞。我们将采用原位前列腺癌模型作为检测系统。转移是癌症患者死亡的主要原因，因为局部局限的疾病可以通过许多现有的方式加以控制。转移性肿瘤的治疗需要全身性的方法。然而，尽管取得了重大进展，目前的方法只对少数几种类型的癌症有效。转移性癌症患者迫切需要新的有效的治疗方法。在我们之前的研究中，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小鼠转移性癌细胞的免疫。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了广泛的炎症，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，我们修改了这种方法，目的是在不发生广泛炎症的情况下根除转移性癌细胞。

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.