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The Use of Filamentous Bacteriophage fd to Deliver MAGE-A10 or MAGE-A3 HLA-A2-Restricted Peptides and to Induce Strong Antitumor CTL Responses¹

Rossella Sartorius^*, Paola Pisu^,, Luciana D’Apice^*, Luciano Pizzella^*, Chiara Romano^,, Giancarlo Cortese^,, Angela Giorgini, Angela Santoni^,, Francesca Velotti^2,,¶ and Piergiuseppe De Berardinis^2,3,*

^* Institute of Protein Biochemistry, Consiglio Nazionale delle Ricerche, Naples; Centro Ricerca Sperimentale and Stabilimento Allevatore Fornitore Utilizzatore Department, Regina Elena Cancer Institute, Rome; Department of Experimental Medicine and Pathology, "La Sapienza" University, Rome; and ^¶ Department of Ecology and Economic Sustainable Development, Tuscia University, Largo dell’Università, Viterbo, Italy

Delivery of tumor-associated Ag-derived peptides in a high immunogenic form represents one of the key issues for effective peptide-based cancer vaccine development. We report herein the ability of nonpathogenic filamentous bacteriophage fd virions to deliver HLA-A2-restricted MAGE-A10_254–262- or MAGE-A3_271–279-derived peptides and to elicit potent specific CTL responses in vitro and in vivo. Interestingly, human anti-MAGE-A3_271–279-specific CTLs were able to kill human MAGE-A3⁺ tumor cells, even if these cells naturally express a low amount of MAGE-A3_271–279 peptide-HLA epitope surface complexes and are usually not recognized by CTLs generated by conventional stimulation procedures. MAGE-A3_271–279-specific/CD8⁺ CTL clones were isolated from in vitro cultures, and their high avidity for Ag recognition was assessed. Moreover, in vivo tumor protection assay showed that vaccination of humanized HHD (HLA-A2.1⁺/H2-D^b+) transgenic mice with phage particles expressing MAGE-A3_271–279-derived peptides hampered tumor growth. Overall, these data indicate that engineered filamentous bacteriophage virions increase substantially the immunogenicity of delivered tumor-associated Ag-derived peptides, thus representing a novel powerful system for the development of effective peptide-based cancer vaccines.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by European Community (QLK3-CT-1999-00064), Italian Ministry of University and Research and Tuscia University, and "Fondo per gli Investimenti della Ricerca di Base" (RBLA033WJX).

² F.V. and P.D.B. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Piergiuseppe De Berardinis, Institute of Protein Biochemistry, Consiglio Nazionale delle Ricerche, Via P. Castellino 111, Naples 80131, Italy. E-mail address: p.deberardinis{at}ibp.cnr.it

⁴ Abbreviations used in this paper: TAA, tumor-associated Ag; C_T, comparative cycle threshold; TCC, transitional-cell carcinoma.