This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Efferson, C. L. Articles by Ioannides, C. G. Search for Related Content PubMed PubMed Citation Articles by Efferson, C. L. Articles by Ioannides, C. G. Pubmed/NCBI databases Substance via MeSH

 Previous Article  |  Next Article 

Journal of Virology, July 2003, p. 7411-7424, Vol. 77, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.13.7411-7424.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Activation of Tumor Antigen-Specific Cytotoxic T Lymphocytes (CTLs) by Human Dendritic Cells Infected with an Attenuated Influenza A Virus Expressing a CTL Epitope Derived from the HER-2/neu Proto-Oncogene

Clay L. Efferson,¹ Jeanne Schickli,² Byung Kyum Ko,¹ Kouichiro Kawano,¹ Sara Mouzi,¹ Peter Palese,² Adolfo García-Sastre,^2* and Constantin G. Ioannides^1,3

Departments of Gynecologic Oncology,¹ Immunology, M.D. Anderson Cancer Center, Houston, Texas 77030,³ Department of Microbiology, Mt. Sinai School of Medicine, New York, New York 10029²

Received 1 November 2002/ Accepted 31 March 2003

The development of cancer vaccines requires approaches to induce expansion and functional differentiation of tumor antigen-specific cytotoxic T lymphocyte (CTL) effectors which posses cytolytic capability and produce cytokines. Efficient induction of such cells is hindered by the poor immunogenicity of tumor antigens and by the poor transduction efficiency of dendritic cells (DCs) with current nonreplicating vectors. We have investigated the use of influenza A virus, a potent viral inducer of CTLs, as a vector expressing the immunodominant HER-2 CTL epitope KIF (E75). For this purpose, an attenuated influenza A/PR8/34 virus with a truncated nonstructural (NS1) gene was generated containing the E75 epitope in its neuraminidase protein (KIF-NS virus). Stimulation of peripheral blood mononuclear cells from healthy donors and of tumor-associated lymphocytes from ovarian and breast cancer patients with DCs infected with KIF-NS virus (KIF-NS DC) induced CTLs that specifically recognized the peptide KIF and HER-2-expressing tumors in cytotoxicity assays and secreted gamma interferon (IFN-) and interleukin-2 at recall with peptide. Priming with KIF-NS DCs increased the number of E75⁺ CD45RO⁺ cells by more than 10-fold compared to nonstimulated cells. In addition, KIF-NS virus induced high levels of IFN- in DCs. This is the first report demonstrating induction of human epitope-specific CTLs against a tumor-associated antigen with a live attenuated recombinant influenza virus vector. Such vectors may provide a novel approach for tumor antigen delivery, lymphocyte activation, and differentiation in human cancer vaccine development.

---

* Corresponding author. Mailing address: Department of Microbiology, Box 1124, Mount Sinai School of Medicine, 1 Gustave L. Levy Pl., New York, NY 10029. Phone: (212) 241-7769. Fax: (212) 534-1684. E-mail: adolfo.garcia-sastre{at}mssm.edu.

---

Journal of Virology, July 2003, p. 7411-7424, Vol. 77, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.13.7411-7424.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Tsuda, N., Chang, D. Z., Mine, T., Efferson, C., Garcia-Sastre, A., Wang, X., Ferrone, S., Ioannides, C. G. (2007). Taxol Increases the Amount and T Cell Activating Ability of Self-Immune Stimulatory Multimolecular Complexes Found in Ovarian Cancer Cells. Cancer Res. 67: 8378-8387 [Abstract] [Full Text]  
• Efferson, C. L., Tsuda, N., Kawano, K., Nistal-Villan, E., Sellappan, S., Yu, D., Murray, J. L., Garcia-Sastre, A., Ioannides, C. G. (2006). Prostate Tumor Cells Infected with a Recombinant Influenza Virus Expressing a Truncated NS1 Protein Activate Cytolytic CD8+ Cells To Recognize Noninfected Tumor Cells. J. Virol. 80: 383-394 [Abstract] [Full Text]  
• Moran, T. P., Collier, M., McKinnon, K. P., Davis, N. L., Johnston, R. E., Serody, J. S. (2005). A Novel Viral System for Generating Antigen-Specific T Cells. J. Immunol. 175: 3431-3438 [Abstract] [Full Text]  
• Donelan, N. R., Basler, C. F., Garcia-Sastre, A. (2003). A Recombinant Influenza A Virus Expressing an RNA-Binding-Defective NS1 Protein Induces High Levels of Beta Interferon and Is Attenuated in Mice. J. Virol. 77: 13257-13266 [Abstract] [Full Text]