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DNA Vaccines Targeting Tumor Antigens to B7 Molecules on Antigen-Presenting Cells Induce Protective Antitumor Immunity and Delay Onset of HER-2/Neu-Driven Mammary Carcinoma

Authors' Affiliations: ¹ Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Frankfurt am Main, Germany; ² Molecular Biotechnology Center, Department of Clinical and Biological Sciences, University of Turin, Turin, Italy; and ³ Krankenhaus Nordwest, II, Medizinische Klinik, Onkologie/Hämatologie, Frankfurt am Main, Germany

Requests for reprints: Winfried S. Wels, Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Paul-Ehrlich-Straβe 42-44, D-60596 Frankfurt am Main, Germany. Phone: 49-69-63395-188; Fax: 49-69-63395-189; E-mail: wels{at}em.uni-frankfurt.de.

Purpose: Presentation of tumor antigens by professional antigen-presenting cells (APC) is critical for the induction of tumor-specific T-cell responses. To facilitate targeted delivery of tumor antigens to APC, we generated DNA vaccines that encode secreted fusion proteins consisting of the extracellular domain of CTLA-4 for binding to costimulatory B7 molecules on APC, fused to residues 1 to 222 of human ErbB2 (HER-2) or a corresponding 224 residues fragment of its rat homologue Neu.

Experimental Design: Induction of humoral and cellular immune responses and antitumoral activity of the DNA vaccines were tested in murine tumor models with transfected renal carcinoma cells expressing the respective antigens and in transgenic BALB-neuT mice developing spontaneous Neu-driven mammary carcinomas.

Results: Vaccination of BALB/c mice with CTLA-4-ErbB2₂₂₂ plasmid DNA markedly improved tumor-free survival on challenge with ErbB2-expressing Renca cells in comparison with untargeted ErbB2₂₂₂, accompanied by induction of stronger ErbB2-specific antibody and CTL responses. Likewise, a CTLA-4 vaccine carrying the unrelated NY-ESO-1 cancer-germline antigen was more effective than untargeted NY-ESO-1 in the protection of mice from challenge with NY-ESO-1-expressing tumor cells. Importantly, antitumoral activity of such a CTLA-4 fusion vaccine could be reproduced in immunotolerant BALB-neuT mice, where a corresponding CTLA-4-Neu₂₂₄ DNA vaccine markedly delayed the onset of spontaneous Neu-driven mammary carcinomas.

Conclusions: Our results show that plasmid DNA vaccines for in vivo expression of tumor antigens targeted to APC induce potent immune responses and antitumoral activities, providing a rationale for further development of this approach for specific cancer immunotherapy.