Retrovirally transduced murine T lymphocytes expressing FasL mediate effective killing of prostate cancer cells

被引:0
作者
J C Symes
C Siatskas
D H Fowler
J A Medin
机构
[1] University of Toronto,Department of Medical Biophysics
[2] Ontario Cancer Institute,Division of Stem Cell and Developmental Biology
[3] Experimental Transplantation and Immunology Branch,undefined
[4] National Cancer Institute,undefined
[5] NIH,undefined
[6] Institute of Medical Sciences,undefined
[7] University of Toronto,undefined
来源
Cancer Gene Therapy | 2009年 / 16卷
关键词
apoptosis; c-FLIP; docetaxel; Fas; gene transfer; mitoxantrone;
D O I
暂无
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学科分类号
摘要
Adoptively transferred T cells possess anticancer activities partially mediated by T-cell FasL engagement of Fas tumor targets. However, antigen-induced T-cell activation and clonal expansion, which stimulates FasL activity, is often inefficient in tumors. As a gene therapy approach to overcome this obstacle, we have created oncoretroviral vectors to overexpress FasL or non-cleavable FasL (ncFasL) on murine T cells of a diverse T-cell receptor repertoire. Expression of c-FLIP was also engineered to prevent apoptosis of transduced cells. Retroviral transduction of murine T lymphocytes has historically been problematic, and we describe optimized T-cell transduction protocols involving CD3/CD28 co-stimulation of T cells, transduction on ice using concentrated oncoretrovirus, and culture with IL-15. Genetically modified T cells home to established prostate cancer tumors in vivo. Co-stimulated T cells expressing FasL, ncFasL and ncFasL/c-FLIP each mediated cytotoxicity in vitro against RM-1 and LNCaP prostate cancer cells. To evaluate the compatibility of this approach with current prostate cancer therapies, we exposed RM-1, LNCaP, and TRAMP-C1 cells to radiation, mitoxantrone, or docetaxel. Fas and H-2b expression were upregulated by these methods. We have developed a novel FasL-based immuno-gene therapy for prostate cancer that warrants further investigation given the apparent constitutive and inducible Fas pathway expression in this malignancy.
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页码:439 / 452
页数:13
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