title: A non-randomized dose-escalation Phase I trial of a protein-based immunotherapeutic for the treatment of breast cancer patients with HER2-overexpressing tumors.
abstract: This Phase I dose-escalation study (NCT00058526) assessed the safety and immunogenicity of an anti-cancer immunotherapeutic (recombinant HER2 protein (dHER2) combined with the immunostimulant AS15) in patients with early-stage HER2-overexpressing breast cancer (BC). Sixty-one trastuzumab-naive patients with stage II-III HER2-positive BC received the dHER2 immunotherapeutic after surgical resection and adjuvant therapy. They were allocated into four cohorts receiving different doses of dHER2 (20, 100, 500 µg) combined with a fixed AS15 dose. Safety and immunogenicity (dHER2-specific antibody responses) were assessed. After completing the immunization schedule (three or six doses over 14 weeks) and a six-month follow-up, the patients were followed for 5 years for late toxicity, long-term immunogenicity, and clinical status. The immunizations were well tolerated, and increasing doses of dHER2 had no impact on the frequency or severity of adverse events. Few late toxicities were reported, and after 5 years 45/54 patients (83.3 %) were still alive, while 28/45 (62 %) with known disease status were disease free. Regarding the immunogenicity of the compound, a positive association was found between the dHER2 dose, the immunization schedule, and the prevalence of dHER2-specific humoral responses. Among the patients receiving the most intense immunization schedule with the highest dHER2 dose, 6/8 maintained their dHER2-specific antibody response 5 years after immunization. The dHER2 immunotherapeutic had an acceptable safety profile in early HER2-positive BC patients. dHER2-specific antibody responses were induced, with the rate of responders increasing with the dHER2 dose and the number and frequency of immunizations.
authors.affiliation: Levine Cancer Institute, Charlotte, NC, USA. steven.limentani@msj.org.|Mission Health Asheville, Asheville, NC, USA. steven.limentani@msj.org.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Limentani
authors.affiliation: Institut de Cancérologie de l'Ouest, Nantes, France.
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
authors.affiliation: Department of Medical Oncology, Institut Curie, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Dorval
authors.affiliation: Early Drug Development for Innovative Therapies Division, Istituto Europeo di Oncologia, Via Ripamonti, 435, 20141, Milan, Italy. giuseppe.curigliano@ieo.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Curigliano
authors.affiliation: Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: de Boer
authors.affiliation: Sylvester Comprehensive Cancer Center at Deerfield Beach, Miller School of Medicine, University of Miami, Miami, FL, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Vogel
authors.affiliation: The Northern Hospital, Cooper St, Epping, Australia.
authors.forename: Shane
authors.initials: S
authors.lastname: White
authors.affiliation: Department of Medical Oncology, Léon-Bérard Centre, Lyon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachelot
authors.affiliation: Oncology-Hematology Department, Grand Hopital de Charleroi, Charleroi, Belgium.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Canon
authors.affiliation: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, WA, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Disis
authors.affiliation: Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Awada
authors.affiliation: Clinique du sein, Centre du Cancer, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Martine
authors.initials: M
authors.lastname: Berlière
authors.affiliation: Department of Oncology, KU Leuven and Department of Gynecologic Oncology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Amant
authors.affiliation: Roswell Park Cancer Institute, Buffalo, USA.
authors.forename: Ellis
authors.initials: E
authors.lastname: Levine
authors.affiliation: GSK Vaccines, Rixensart, Belgium.
authors.forename: Wivine
authors.initials: W
authors.lastname: Burny
authors.affiliation: GSK Vaccines, Rixensart, Belgium.
authors.forename: Andrea
authors.initials: A
authors.lastname: Callegaro
authors.affiliation: GSK Vaccines, Rixensart, Belgium.|Celyad, Mont-Saint-Guibert, Belgium.
authors.forename: Pedro Miguel
authors.initials: PM
authors.lastname: de Sousa Alves
authors.affiliation: GSK Vaccines, Rixensart, Belgium.
authors.forename: Jamila
authors.initials: J
authors.lastname: Louahed
authors.affiliation: GSK Vaccines, Rixensart, Belgium.|Vianova-Biosciences, Lasne, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Brichard
authors.affiliation: GSK Vaccines, Rixensart, Belgium.|Celyad, Mont-Saint-Guibert, Belgium.
authors.forename: Frédéric F
authors.initials: FF
authors.lastname: Lehmann
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000378:metabolism / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000009:adverse effects; D007167:Immunotherapy; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000276:immunology; D016019:Survival Analysis; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D007155:Immunologic Factors; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins
keywords: Cancer immunotherapeutic; HER2-overexpressing breast cancer; Vaccine; dHER2 protein