Induction of Wilms' tumor protein (WT1)-specific antitumor immunity using a truncated WT1-expressing adenovirus vaccine.
OBJECTIVE
Wilms' tumor protein (WT1) is overexpressed in most leukemias and many solid tumors and is a promising target for tumor immunotherapy. WT1 peptide-based cancer vaccines have been reported but have limited application due to HLA restriction of the peptides. We sought to vaccinate using adenoviral (Ad) vectors encoding tumor-associated antigens such as WT1 that can stimulate tumor-associated antigen-specific immunity across a broad array of HLA types and multiple class I and class II epitopes.


METHODS
We developed a novel Ad vector encoding a truncated version of WT1 (Ad-tWT1) lacking the highly conserved COOH terminus zinc finger domains and tested its ability to stimulate WT1-specific immune responses and antitumor immunity in two murine models of WT1-expressing tumors.


RESULTS
Despite encoding a transcription factor, we found that Ad-tWT1-transduced murine and human dendritic cells showed cytoplasmic expression of the truncated WT1 protein. In addition, vaccination of C57BL/6 mice with Ad-tWT1 generated WT1-specific cell-mediated and humoral immune responses and conferred protection against challenge with the leukemia cell line, mWT1-C1498. Moreover, in a tumor therapy model, Ad-tWT1 vaccination of TRAMP-C2 tumor-bearing mice significantly suppressed tumor growth.


CONCLUSIONS
This is the first report of a WT1-encoding Ad vector that is capable of inducing effective immunity against WT1-expressing malignancies. Based on these findings, Ad-tWT1 warrants investigation in human clinical trials to evaluate its applications as a vaccine for patients with WT1-expressing cancers.
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Takuya
T
Osada
Christopher Y
CY
Woo
Matthew
M
McKinney
Xiao Yi
XY
Yang
Gangjun
G
Lei
Heather G
HG
Labreche
Zachary C
ZC
Hartman
Donna
D
Niedzwiecki
Nelson
N
Chao
Andrea
A
Amalfitano
Michael A
MA
Morse
H Kim
HK
Lyerly
Timothy M
TM
Clay
D000818:Animals; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D005822:Genetic Vectors; D006801:Humans; D007167:Immunotherapy; D007938:Leukemia / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D025721:WT1 Proteins / Q000235:genetics / Q000276:immunology*
D019496:Cancer Vaccines; D025721:WT1 Proteins