Retrovirally transduced murine T lymphocytes expressing FasL mediate effective killing of prostate cancer cells. Cancer Gene Ther 2009 May;16(5):439-52
Date
12/20/2008Pubmed ID
19096446Pubmed Central ID
PMC2857530DOI
10.1038/cgt.2008.96Scopus ID
2-s2.0-65049090448 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
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-2(b) 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.
Author List
Symes JC, Siatskas C, Fowler DH, Medin JAAuthor
Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntineoplastic Agents
Cell Line
Cell Line, Tumor
Cells, Cultured
Fas Ligand Protein
Gene Expression Regulation
Humans
Immunotherapy
Male
Mice
Mice, Inbred C57BL
Mitoxantrone
Phenotype
Prostatic Neoplasms
Retroviridae
T-Lymphocytes
Taxoids
Transduction, Genetic
