Synergism from combined immunologic and pharmacologic inhibition of HER2 in vivo.
The monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib improve the clinical outcome of patients with HER2-overexpressing breast cancer. However, the majority of metastatic cancers will eventually progress, suggesting the need for other therapies. Because HER2 overexpression persists, we hypothesized that the anti-HER2 immune response induced by cancer vaccines would be an effective strategy for treating trastuzumab- and lapatinib-refractory tumors. Furthermore, we hypothesized that the antibody response could synergize with lapatinib to enhance tumor inhibition. We developed a recombinant adenoviral vector expressing a kinase-inactive HER2 (Ad-HER2-ki) to use as a cancer vaccine. Vaccine-induced polyclonal HER2-specific antiserum was analyzed for receptor internalization and signaling effects alone and in combination with lapatinib. Ad-HER2-ki vaccine-induced potent T cell and antibody responses in mice and the vaccine-induced polyclonal HER2-specific antiserum mediated receptor internalization and degradation much more effectively than trastuzumab. Our in vitro studies demonstrated that HER2 vaccine-induced antibodies effectively caused a decrease in HER2 expression, but when combined with lapatinib caused significant inhibition of HER2 signaling, decreased pERK and pAKT levels and reduced breast tumor cell proliferation. In addition, a known mechanism of resistance to lapatinib, induction of survivin, was inhibited. The combination of Ad-HER2-ki plus lapatinib also showed superior antitumor efficacy in vivo. Based on these results, we feel clinical studies using this approach to target HER2-overexpressing breast cancer, including trastuzumab- and lapatinib-resistant tumors is warranted.
Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Michael A
MA
Morse
Junping
J
Wei
Zachary
Z
Hartman
Wenle
W
Xia
Xiu-Rong
XR
Ren
Gangjun
G
Lei
William T
WT
Barry
Takuya
T
Osada
Amy C
AC
Hobeika
Sharon
S
Peplinski
Haixiang
H
Jiang
Gayathri R
GR
Devi
Wei
W
Chen
Neil
N
Spector
Andrea
A
Amalfitano
H Kim
HK
Lyerly
Timothy M
TM
Clay
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D019496:Cancer Vaccines; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases