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.
| Zhang, Qiang; Helfand, Brian T; Jang, Thomas L et al. (2009) Nuclear factor-kappaB-mediated transforming growth factor-beta-induced expression of vimentin is an independent predictor of biochemical recurrence after radical prostatectomy. Clin Cancer Res 15:3557-67 |
| Zhang, Qiang; Yang, Ximing J; Kundu, Shilajit D et al. (2006) Blockade of transforming growth factor-{beta} signaling in tumor-reactive CD8(+) T cells activates the antitumor immune response cycle. Mol Cancer Ther 5:1733-43 |
| Zhang, Qiang; Yang, Ximing; Pins, Michael et al. (2005) Adoptive transfer of tumor-reactive transforming growth factor-beta-insensitive CD8+ T cells: eradication of autologous mouse prostate cancer. Cancer Res 65:1761-9 |
