HER-2/neu-Specific Monoclonal Antibodies Collaborate with HER-2/neu-Targeted Granulocyte Macrophage Colony-Stimulating Factor Secreting Whole Cell Vaccination to Augment CD8+ T Cell Effector Function and Tumor-Free Survival in Her-2/neu-Transgenic Mice

• Published in: The Journal of immunology (1950) 2003-08, Vol.171 (4), p.2161-2169
• Main Authors: Wolpoe, Matthew E, Lutz, Eric R, Ercolini, Anne M, Murata, Satoshi, Ivie, Susan E, Garrett, Elizabeth S, Emens, Leisha A, Jaffee, Elizabeth M, Reilly, R. Todd
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Adjuvants, Immunologic - administration & dosage; Adjuvants, Immunologic - therapeutic use; Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cancer Vaccines - administration & dosage; Cancer Vaccines - genetics; Cancer Vaccines - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Line; Cytotoxicity, Immunologic - genetics; Cytotoxicity, Immunologic - immunology; Epitopes, T-Lymphocyte - biosynthesis; Epitopes, T-Lymphocyte - genetics; Epitopes, T-Lymphocyte - immunology; Female; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Immunization Schedule; Injections, Subcutaneous; Lymphocyte Count; Mammary Neoplasms, Experimental - immunology; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - mortality; Mammary Neoplasms, Experimental - prevention & control; Mice; Mice, Transgenic; Rats; Receptor, ErbB-2 - biosynthesis; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - immunology; Receptor, ErbB-2 - metabolism; Survival Analysis; Ubiquitins - metabolism; Up-Regulation - genetics; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.171.4.2161

HER-2/neu is overexpressed in several cancers including 30% of breast carcinomas, and correlates with a poor outcome. HER-2/neu-transgenic (neu-N) mice that overexpress the non-transforming rat neu develop spontaneous mammary carcinomas and demonstrate immunotolerance to the neu protein similar to that observed in patients with neu-expressing cancers. In neu-N mice, neu-targeted vaccination induces weak T cell and negligible Ab responses sufficient to delay but not eradicate transplanted neu-expressing tumor. Here we demonstrate that passive infusion of neu-specific mAbs in sequence with whole cell vaccination significantly improves tumor-free survival over either modality alone. Importantly, treatment of neu-N mice with vaccine in combination with two distinct neu-specific Abs is particularly efficacious, preventing tumor in 70% and eradicating established tumor in 30% of neu-N mice. In vivo lymphocyte subpopulation depletion experiments demonstrate that the efficacy of Ab, alone or combined with vaccine, is dependent on both CD4(+) and CD8(+) T cells. Furthermore, the in vivo antitumor effects of vaccine and Ab are associated with a significant increase in the number and function of neu-specific CD8(+) T cells. Collectively, these observations suggest that similarly increased efficacy could be obtained by combining neu-targeted vaccination and neu-specific Abs such as trastuzumab (Herceptin) in patients with neu-expressing cancers.