title: 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.
abstract: 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.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Immunology, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Wolpoe
authors.forename: Eric R
authors.initials: ER
authors.lastname: Lutz
authors.forename: Anne M
authors.initials: AM
authors.lastname: Ercolini
authors.forename: Satoshi
authors.initials: S
authors.lastname: Murata
authors.forename: Susan E
authors.initials: SE
authors.lastname: Ivie
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Garrett
authors.forename: Leisha A
authors.initials: LA
authors.lastname: Emens
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Jaffee
authors.forename: R Todd
authors.initials: RT
authors.lastname: Reilly
mesh_terms: D016475:3T3 Cells; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D007115:Immunization Schedule; D007279:Injections, Subcutaneous; D018655:Lymphocyte Count; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D016019:Survival Analysis; D014452:Ubiquitins / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D018719:Erb-b2 Receptor Tyrosine Kinases; D014452:Ubiquitins