title: A multipeptide vaccine is safe and elicits T-cell responses in participants with advanced stage ovarian cancer.
abstract: Nine participants with epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, who were human leukocyte antigen (HLA)-A1, HLA-A2, or HLA-A3, were eligible to enroll in a phase 1 study designed to assess the safety and immunogenicity of a peptide-based vaccine. Participants received 5 class I major histocompatibility complex-restricted synthetic peptides derived from multiple ovarian cancer-associated proteins plus a class II major histocompatibility complex-restricted synthetic helper peptide derived from tetanus toxoid protein. The vaccines were administered with granulocyte macrophage-colony stimulating factor in Montanide ISA-51 adjuvant over a 7-week period. All vaccine-related toxicities were grade 1 to 2, the most common being injection site reaction (grade 2, 100%), fatigue (grade 1, 78%), and headache (grade 1, 67%). Lymphocytes from the peripheral blood and a node draining a secondary vaccine site (sentinel immunized node) were harvested during the course of vaccination and T-cell responses to the peptides were evaluated using an enzyme-linked immunosorbent spot assay. CD8 T-cell responses were detected in 1 participant ex vivo and in 8 of 9 participants (89%) after in vitro stimulation. All 4 HLA-A2 and HLA-A3-restricted peptides were immunogenic. This includes 2 peptides, folate binding protein (FBP191-199) and Her-2/neu754-762, which had not previously been evaluated in vaccines in humans. Responding T cells required over 200 nM for half-maximal reactivity. These data support continued investigation of these peptides as immunogens for patients with ovarian cancer but, owing to low potency, also suggest a need for additional immunomodulation in combination with vaccines to increase the magnitude and to improve the quality of the T-cell responses.
authors.affiliation: Department of Surgery, Division of Surgical Oncology, Human Immune Therapy Center, University of Virginia, Charlottesville, VA 22908, USA. kb9d@virginia.edu
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Chianese-Bullock
authors.forename: William P
authors.initials: WP
authors.lastname: Irvin
authors.forename: Gina R
authors.initials: GR
authors.lastname: Petroni
authors.forename: Cheryl
authors.initials: C
authors.lastname: Murphy
authors.forename: Mark
authors.initials: M
authors.lastname: Smolkin
authors.forename: Walter C
authors.initials: WC
authors.lastname: Olson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Coleman
authors.forename: Scott A
authors.initials: SA
authors.lastname: Boerner
authors.forename: Carmel J
authors.initials: CJ
authors.lastname: Nail
authors.forename: Patrice Y
authors.initials: PY
authors.lastname: Neese
authors.forename: Arlene
authors.initials: A
authors.lastname: Yuan
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Hogan
authors.forename: Craig L
authors.initials: CL
authors.lastname: Slingluff
mesh_terms: D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000009:adverse effects; D004265:DNA Helicases / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000008:administration & dosage; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006801:Humans; D016056:Immunodominant Epitopes / Q000008:administration & dosage / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008353:Mannitol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins / Q000008:administration & dosage / Q000276:immunology; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D009829:Oleic Acids / Q000008:administration & dosage / Q000009:adverse effects; D010051:Ovarian Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D010534:Peritoneal Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016601:RNA-Binding Proteins; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016896:Treatment Outcome; D014611:Vaccination / Q000009:adverse effects; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D004268:DNA-Binding Proteins; C492258:FUBP1 protein, human; C474513:HER-2 peptide E75 (369-377), human; D016056:Immunodominant Epitopes; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D009829:Oleic Acids; D010446:Peptide Fragments; D016601:RNA-Binding Proteins; D022223:Vaccines, Subunit; C477385:montanide ISA 51; D008353:Mannitol; D007371:Interferon-gamma; D004265:DNA Helicases