An adenoviral vaccine encoding full-length inactivated human Her2 exhibits potent immunogenicty and enhanced therapeutic efficacy without oncogenicity.
OBJECTIVE
Overexpression of the breast cancer oncogene HER2 correlates with poor survival. Current HER2-directed therapies confer limited clinical benefits and most patients experience progressive disease. Because refractory tumors remain strongly HER2+, vaccine approaches targeting HER2 have therapeutic potential, but wild type (wt) HER2 cannot safely be delivered in immunogenic viral vectors because it is a potent oncogene. We designed and tested several HER2 vaccines devoid of oncogenic activity to develop a safe vaccine for clinical use.


METHODS
We created recombinant adenoviral vectors expressing the extracellular domain of HER2 (Ad-HER2-ECD), ECD plus the transmembrane domain (Ad-HER2-ECD-TM), and full-length HER2 inactivated for kinase function (Ad-HER2-ki), and determined their immunogenicity and antitumor effect in wild type (WT) and HER2-tolerant mice. To assess their safety, we compared their effect on the cellular transcriptome, cell proliferation, anchorage-dependent growth, and transformation potential in vivo.


RESULTS
Ad-HER2-ki was the most immunogenic vector in WT animals, retained immunogenicity in HER2-transgenic tolerant animals, and showed strong therapeutic efficacy in treatment models. Despite being highly expressed, HER2-ki protein was not phosphorylated and did not produce an oncogenic gene signature in primary human cells. Moreover, in contrast to HER2-wt, cells overexpressing HER2-ki were less proliferative, displayed less anchorage-independent growth, and were not transformed in vivo.


CONCLUSIONS
Vaccination with mutationally inactivated, nononcogenic Ad-HER2-ki results in robust polyclonal immune responses to HER2 in tolerant models, which translates into strong and effective antitumor responses in vivo. Ad-HER2-ki is thus a safe and promising vaccine for evaluation in clinical trials.
Hartman
Zachary C
ZC
Department of Surgery, Medicine, Division of Medical Oncology, Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, North Carolina, USA.
Wei
Junping
J
Osada
Takuya
T
Glass
Oliver
O
Lei
Gangjun
G
Yang
Xiao-Yi
XY
Peplinski
Sharon
S
Kim
Dong-Wan
DW
Xia
Wenle
W
Spector
Neil
N
Marks
Jeffrey
J
Barry
William
W
Hobeika
Amy
A
Devi
Gayathri
G
Amalfitano
Andrea
A
Morse
Michael A
MA
Lyerly
H Kim
HK
Clay
Timothy M
TM
D000256:Adenoviridae; D000818:Animals; D015153:Blotting, Western; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D018734:Genes, erbB-2 / Q000235:genetics / Q000276:immunology; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014611:Vaccination / Q000379:methods*
D019496:Cancer Vaccines; D018719:Erb-b2 Receptor Tyrosine Kinases