Safety and Immunological Efficacy of a DNA Vaccine Encoding the Androgen Receptor Ligand-Binding Domain (AR-LBD).
BACKGROUND
The androgen receptor (AR) is a key oncogenic driver of prostate cancer, and has been the primary focus of prostate cancer treatment for several decades. We have previously demonstrated that the AR is also an immunological target antigen, recognized in patients with prostate cancer, and targetable by means of vaccines in rodent models with delays in prostate tumor growth. The current study was performed to determine the safety and immunological efficacy of a GMP-grade plasmid DNA vaccine encoding the ligand-binding domain (LBD) of the AR, pTVG-AR.


METHODS
Groups of male mice (n = 6-10 per group) were evaluated after four or seven immunizations, using different schedules and inclusion of GM-CSF as a vaccine adjuvant. Animals were assessed for toxicity using gross observations, pathological analysis, and analysis of serum chemistries. Animals were analyzed for evidence of vaccine-augmented immunity by tetramer analysis. Survival studies using different immunization schedules and inclusion of GM-CSF were conducted in an autochthonous genetically engineered mouse model.


RESULTS
No significant toxicities were observed in terms of animal weights, histopathology, hematological changes, or changes in serum chemistries, although there was a trend to lower serum glucose in animals treated with the vaccine. There was specifically no evidence of toxicity in other tissues that express AR, including liver, muscle, hematopoietic, and brain. Vaccination was found to elicit AR LBD-specific CD8+ T cells. In a subsequent study of tumor-bearing animals, animals treated with vaccine had prolonged survival compared with control-immunized mice.


CONCLUSIONS
These studies demonstrate that, in immunocompetent mice expressing the target antigen, immunization with the pTVG-AR vaccine was both safe and effective in eliciting AR-specific cellular immune responses, and prolonged the survival of prostate tumor-bearing mice. These findings support the clinical evaluation of pTVG-AR in patients with recurrent prostate cancer. Prostate 77:812-821, 2017. © 2017 Wiley Periodicals, Inc.
University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin.
Brian M
BM
Olson
University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin.
Eric S
ES
Bradley
University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin.
Thomas
T
Sawicki
Department of Pathology, University of Wisconsin, Madison, Wisconsin.
Weixiong
W
Zhong
Department of Pathology, University of Wisconsin, Madison, Wisconsin.
Erik A
EA
Ranheim
University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin.
Jordan E
JE
Bloom
University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin.
Viswa T
VT
Colluru
University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin.
Laura E
LE
Johnson
University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin.
Brian T
BT
Rekoske
Department of Biostatistics, University of Wisconsin, Madison, Wisconsin.
Jens C
JC
Eickhoff
University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin.
Douglas G
DG
McNeel
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D015166:Monitoring, Immunologic / Q000379:methods; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D011944:Receptors, Androgen / Q000276:immunology*; D016896:Treatment Outcome; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D011944:Receptors, Androgen; D019444:Vaccines, DNA; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
DNA vaccine; androgen receptor; mouse; prostate cancer; toxicology