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Delivery of Dendritic Cells Engineered to Secrete IFN- into Central Nervous System Tumors Enhances the Efficacy of Peripheral Tumor Cell Vaccines: Dependence on Apoptotic Pathways¹

Naruo Kuwashima^2,*, Fumihiko Nishimura^2,*, Junichi Eguchi^*, Hidemitsu Sato^*, Manabu Hatano, Takahiko Tsugawa^*, Tsukasa Sakaida^*, Jill E. Dusak^*, Wendy K. Fellows-Mayle^*, Glenn D. Papworth, Simon C. Watkins, Andrea Gambotto, Ian F. Pollack^*,¶, Walter J. Storkus and Hideho Okada^3,*,,¶

^* Department of Neurological Surgery, Department of Surgery, Department of Dermatology, and Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and ^¶ Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213

We tested whether modulation of the CNS-tumor microenvironment by delivery of IFN--transduced dendritic cells (DCs: DC-IFN-) would enhance the therapeutic efficacy of peripheral vaccinations with cytokine-gene transduced tumor cells. Mice bearing intracranial GL261 glioma or MCA205 sarcoma received peripheral immunizations with corresponding irradiated tumor cells engineered to express IL-4 or GM-CSFs, respectively, as well as intratumoral delivery of DC-IFN-. This regimen prolonged survival of the animals and induced tumor-specific CTLs that expressed TRAIL, which in concert with perforin and Fas ligand (FasL) was involved in the tumor-specific CTL activity of these cells. The in vivo antitumor activity associated with this approach was abrogated by administration of neutralizing mAbs against TRAIL or FasL and was not observed in perforin^–/–, IFN-^–/–, or FasL^–/– mice. Transduction of the tumor cells with antiapoptotic protein cellular FLIP rendered the gene-modified cells resistant to TRAIL- or FasL-mediated apoptosis and to CTL killing activity in vitro. Furthermore, the combination therapeutic regimen was ineffective in an intracranial cellular FLIP-transduced MCA205 brain tumor model. These results suggest that the combination of intratumoral delivery of DC-IFN- and peripheral immunization with cytokine-gene transduced tumor cells may be an effective therapy for brain tumors that are sensitive to apoptotic signaling pathways.

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