Delivery of interferon-alpha transfected dendritic cells into central nervous system tumors enhances the antitumor efficacy of peripheral peptide-based vaccines.

Abstract

We evaluated the effects, on immunity and survival, of injection of interferon (IFN)-alpha-transfected dendritic cells (DC-IFN-alpha) 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-alpha promotes the activation and survival of both DCs and T cells, we evaluated the combinational antitumor effects of injecting adenoviral (Ad)-IFN-alpha-engineered DCs into intracranial M05 tumors in preimmunized mice. Delivery of DC-IFN-alpha 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-alpha appeared to persist longer than mock-transfected DCs within the intracranial tumor microenvironment, and DC-IFN-alpha-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-alpha by DCs within the intracranial tumor site may enhance the clinical efficacy of peripheral vaccine approaches for brain tumors.

• Authors: Hideho Okada, Takahiko Tsugawa, Hidemitsu Sato, Naruo Kuwashima, Andrea Gambotto, Kaori Okada, Jill E Dusak, Wendy K Fellows-Mayle, Glenn D Papworth, Simon C Watkins, William H Chambers, Douglas M Potter, Walter J Storkus, Ian F Pollack
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 16 Pg. 5830-8 (Aug 15 2004) ISSN: 0008-5472 [Print] United States
• PMID: 15313927 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cancer Vaccines
• Epitopes, T-Lymphocyte
• Interferon-alpha
• Ovalbumin

Topics

• Amino Acid Sequence
• Animals
• Brain Neoplasms (immunology, prevention & control, therapy)
• Cancer Vaccines (immunology, pharmacology)
• Dendritic Cells (immunology)
• Epitopes, T-Lymphocyte (immunology)
• Female
• Immunotherapy, Adoptive (methods)
• Interferon-alpha (genetics, immunology)
• Melanoma, Experimental (immunology, prevention & control, therapy)
• Mice
• Mice, Inbred C57BL
• Molecular Sequence Data
• Ovalbumin (immunology, pharmacology)
• T-Lymphocytes, Cytotoxic (immunology)
• T-Lymphocytes, Helper-Inducer (immunology)
• Transfection