Phase 1 clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibition [corrected].
BACKGROUND
Patients with HER2-overexpressing metastatic breast cancer, despite initially benefiting from the monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib, will eventually have progressive disease. HER2-based vaccines induce polyclonal antibody responses against HER2 that demonstrate enhanced anti-tumor activity when combined with lapatinib in murine models. We wished to test the clinical safety, immunogenicity, and activity of a HER2-based cancer vaccine, when combined with lapatinib.


METHODS
We immunized women (n = 12) with metastatic, trastuzumab-refractory, HER2-overexpressing breast cancer with dHER2, a recombinant protein consisting of extracellular domain (ECD) and a portion of the intracellular domain (ICD) of HER2 combined with the adjuvant AS15, containing MPL, QS21, CpG and liposome. Lapatinib (1250 mg/day) was administered concurrently. Peripheral blood antibody and T cell responses were measured.


RESULTS
This regimen was well tolerated, with no cardiotoxicity. Anti-HER2-specific antibody was induced in all patients whereas HER2-specific T cells were detected in one patient. Preliminary analyses of patient serum demonstrated downstream signaling inhibition in HER2 expressing tumor cells. The median time to progression was 55 days, with the majority of patients progressing prior to induction of peak anti-HER2 immune responses; however, 300-day overall survival was 92% (95% CI: 77-100%).


CONCLUSIONS
dHER2 combined with lapatinib was safe and immunogenic with promising long term survival in those with HER2-overexpressing breast cancers refractory to trastuzumab. Further studies to define the anticancer activity of the antibodies induced by HER2 vaccines along with lapatinib are underway.


BACKGROUND
ClinicalTrials.gov NCT00952692.
Department of Surgery, Division of General Surgery, Duke University Medical Center, Durham, NC, USA. lyerl001@mc.duke.edu
Erika
E
Hamilton
Kimberly
K
Blackwell
Amy C
AC
Hobeika
Timothy M
TM
Clay
Gloria
G
Broadwater
Xiu-Rong
XR
Ren
Wei
W
Chen
Henry
H
Castro
Frederic
F
Lehmann
Neil
N
Spector
Junping
J
Wei
Takuya
T
Osada
H Kim
HK
Lyerly
Michael A
MA
Morse
D000368:Aged; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology; D003710:Demography; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D007167:Immunotherapy; D053208:Kaplan-Meier Estimate; D000077341:Lapatinib; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome; D014611:Vaccination
D000939:Epitopes; D000077341:Lapatinib; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases