Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer.
OBJECTIVE
The primary objectives of this phase I/II study were to evaluate the safety and immunogenicity of combination therapy consisting of concurrent trastuzumab and human epidermal growth factor receptor 2 (HER2)/neu-specific vaccination in patients with HER2/neu-overexpressing metastatic breast cancer.


METHODS
Twenty-two patients with stage IV HER2/neu-positive breast cancer receiving trastuzumab therapy were vaccinated with an HER2/neu T-helper peptide-based vaccine. Toxicity was graded according to National Cancer Institute criteria, and antigen specific T-cell immunity was assessed by interferon gamma enzyme-linked immunosorbent spot assay. Data on progression-free and overall survival were collected.


RESULTS
Concurrent trastuzumab and HER2/neu vaccinations were well tolerated, with 15% of patients experiencing an asymptomatic decline in left ventricular ejection fraction below the normal range during combination therapy. Although many patients had pre-existing immunity specific for HER2/neu and other breast cancer antigens while treated with trastuzumab alone, that immunity could be significantly boosted and maintained with vaccination. Epitope spreading within HER2/neu and to additional tumor-related proteins was stimulated by immunization, and the magnitude of the T-cell response generated was significantly inversely correlated with serum transforming growth factor beta levels. At a median follow-up of 36 months from the first vaccine, the median overall survival in the study population has not been reached.


CONCLUSIONS
Combination therapy with trastuzumab and a HER2/neu vaccine is associated with minimal toxicity and results in prolonged, robust, antigen-specific immune responses in treated patients.
Disis
Mary L
ML
Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, WA 98195-8050, USa. ndisis@u.washington.edu
Wallace
Danelle R
DR
Gooley
Theodore A
TA
Dang
Yushe
Y
Slota
Meredith
M
Lu
Hailing
H
Coveler
Andrew L
AL
Childs
Jennifer S
JS
Higgins
Doreen M
DM
Fintak
Patricia A
PA
dela Rosa
Corazon
C
Tietje
Kathleen
K
Link
John
J
Waisman
James
J
Salazar
Lupe G
LG
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D003131:Combined Modality Therapy; D005221:Fatigue / Q000209:etiology; D005260:Female; D006261:Headache / Q000209:etiology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D010146:Pain / Q000209:etiology; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000097:blood; D000068878:Trastuzumab; D016896:Treatment Outcome; D014611:Vaccination / Q000009:adverse effects / Q000379:methods*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases; D016212:Transforming Growth Factor beta; D000068878:Trastuzumab