title: Phase I active immunotherapy with combination of two chimeric, human epidermal growth factor receptor 2, B-cell epitopes fused to a promiscuous T-cell epitope in patients with metastatic and/or recurrent solid tumors.
abstract: PURPOSE To evaluate the maximum-tolerated dose (MTD), safety profile, and immunogenicity of two chimeric, B-cell epitopes derived from the human epidermal growth factor receptor (HER2) extracellular domain in a combination vaccine with a promiscuous T-cell epitope (ie, MVF) and nor-muramyl-dipeptide as adjuvant emulsified in SEPPIC ISA 720. PATIENTS AND METHODS Eligible patients with metastatic and/or recurrent solid tumors received three inoculations on days 1, 22, and 43 at doses of total peptide that ranged from 0.5 to 3.0 mg. Immunogenicity was evaluated by enzyme-linked immunosorbent assay, flow cytometry, and HER2 signaling assays. Results Twenty-four patients received three inoculations at the intended dose levels, which elicited antibodies able to recognize native HER2 receptor and inhibited both the proliferation of HER2-expressing cell lines and phosphorylation of the HER2 protein. The MTD was determined to be the highest dose level of 3.0 mg of the combination vaccine. There was a significant increase from dose level 1 (0.5 mg) to dose level 4 (3.0 mg) in HER2-specific antibodies. Four patients (one each with adrenal, colon, ovarian, and squamous cell carcinoma of unknown primary) were judged to have stable disease; two patients (one each with endometrial and ovarian cancer) had partial responses; and 11 patients had progressive disease. Patients with stable disease received 6-month boosts, and one patient received a 20-month boost. CONCLUSION The combination vaccines were safe and effective in eliciting antibody responses in a subset of patients (62.5%) and were associated with no serious adverse events, autoimmune disease, or cardiotoxicity. There was preliminary evidence of clinical activity in several patients.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Reproductive Biology and Vaccine Research, Ohio StateUniversity, Columbus, OH 43210, USA. kaumaya.1@osu.edu
authors.forename: Pravin T P
authors.initials: PT
authors.lastname: Kaumaya
authors.forename: Kevin Chu
authors.initials: KC
authors.lastname: Foy
authors.forename: Joan
authors.initials: J
authors.lastname: Garrett
authors.forename: Sharad V
authors.initials: SV
authors.lastname: Rawale
authors.forename: Daniele
authors.initials: D
authors.lastname: Vicari
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Thurmond
authors.forename: Tammy
authors.initials: T
authors.lastname: Lamb
authors.forename: Aruna
authors.initials: A
authors.lastname: Mani
authors.forename: Yahaira
authors.initials: Y
authors.lastname: Kane
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Balint
authors.forename: Donald
authors.initials: D
authors.lastname: Chalupa
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Otterson
authors.forename: Charles L
authors.initials: CL
authors.lastname: Shapiro
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Fowler
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
authors.forename: Tanios S
authors.initials: TS
authors.lastname: Bekaii-Saab
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
mesh_terms: D000276:Adjuvants, Immunologic; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D018985:Epitopes, B-Lymphocyte / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000008:administration & dosage / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D007074:Immunoglobulin G; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C508053:ERBB2 protein, human