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Delivery of Interferon- Transfected Dendritic Cells into Central Nervous System Tumors Enhances the Antitumor Efficacy of Peripheral Peptide-Based Vaccines

Departments of ¹ Neurological Surgery, ² Surgery, ³ Pathology, and the ⁴ Center for Biologic Imaging, Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine; ⁵ Biostatistics Department, University of Pittsburgh Graduate School of Public Health; and ⁶ Biostatistics Facility and ⁷ Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania

We evaluated the effects, on immunity and survival, of injection of interferon (IFN)--transfected dendritic cells (DC-IFN-) into intracranial tumors in mice immunized previously with syngeneic dendritic cells (DCs) pulsed either with ovalbumin-derived CTL or T helper epitopes. These immunizations protected animals from s.c. challenge with ovalbumin-expressing M05 melanoma (class I⁺ and class II-negative). Notably, antiovalbumin CTL responses were observed in animals vaccinated with an ovalbumin-derived T helper epitope but only after the mice were challenged with M05 cells. This cross-priming of CTL was dependent on both CD4⁺ and CD8⁺ T cells. Because we observed that s.c., but not intracranial, tumors were infiltrated with CD11c⁺ DCs, and because IFN- promotes the activation and survival of both DCs and T cells, we evaluated the combinational antitumor effects of injecting adenoviral (Ad)-IFN--engineered DCs into intracranial M05 tumors in preimmunized mice. Delivery of DC-IFN- prolonged survival. This was most notable for animals prevaccinated with both the CTL and T helper ovalbumin epitopes, with 60% (6 of 10) of mice (versus 0 of 10 of control animals) surviving for >80 days after tumor challenge. DC-IFN- appeared to persist longer than mock-transfected DCs within the intracranial tumor microenvironment, and DC-IFN--treated mice exhibited enhanced levels of ovalbumin-specific CTL in draining cervical lymph nodes. On the basis of these results, we believe that local expression of IFN- by DCs within the intracranial tumor site may enhance the clinical efficacy of peripheral vaccine approaches for brain tumors.

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