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

• Published in: Clinical cancer research Vol. 14; no. 21; pp. 6933 - 6943
• Main Authors: SLOOTS, Arjen, MASTINI, Cristina, ROHRBACH, Florian, WETH, Robert, CURCIO, Claudia, BURKHARDT, Ute, JÄGER, Elke, FORNI, Guido, CAVALLO, Federica, WELS, Winfried S
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-11-2008
• Subjects: Animals; Antigen-Presenting Cells - immunology; Antigens, CD - immunology; Antineoplastic agents; B7-1 Antigen - immunology; BALB-neuT; Biological and medical sciences; CTLA-4; CTLA-4 Antigen; DNA vaccine; ErbB2; Female; Gynecology. Andrology. Obstetrics; HER-2; Mammary gland diseases; Mammary Neoplasms, Experimental - immunology; Mammary Neoplasms, Experimental - therapy; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Transgenic; Neu; NY-ESO-1; Pharmacology. Drug treatments; Receptor, ErbB-2 - immunology; Tumors; Vaccines, DNA - administration & dosage; Vaccines, DNA - therapeutic use; Vaccines, Synthetic - therapeutic use; Antineoplastic agent; Immunoprotection; Breast disease; Tumor associated antigen; Targeting; erbB2 Gene; Accessory cell; Breast cancer; Malignant tumor; Genetic vaccine; Costimulatory molecule; Mammary gland diseases; Breast carcinoma; Target; Treatment; Age of onset; Antigen presenting cell; C-Onc gene; Immunotherapy; B7 molecule; Protooncogene; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-1257

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-ErbB2 222 plasmid DNA markedly improved tumor-free survival on challenge with ErbB2-expressing Renca cells in comparison with untargeted
ErbB2 222 , 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-Neu 224 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.