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Safety and Immunological Efficacy of a DNA Vaccine Encoding the Androgen Receptor Ligand-Binding Domain (AR-LBD)
Brian M Olson1, Eric S Bradley1, Thomas Sawicki1
1University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin.
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.
Insights
This study shows that the pTVG-AR DNA vaccine is safe and effective in mice for treating prostate cancer by eliciting an immune response against the androgen receptor (AR). The vaccine prolonged survival in tumor-bearing mice, supporting its clinical evaluation.
Area of Science:
- Oncology
- Immunology
- Vaccine Development
Background:
- The androgen receptor (AR) is a critical driver of prostate cancer, making it a primary therapeutic target.
- Previous research identified the AR as an immunological target antigen, with vaccines showing potential in delaying tumor growth in rodent models.
- This study evaluates the safety and immunological efficacy of pTVG-AR, a plasmid DNA vaccine encoding the AR ligand-binding domain (LBD).
Purpose of the Study:
- To determine the safety and immunological efficacy of the pTVG-AR DNA vaccine.
- To assess the vaccine's ability to elicit an immune response against the AR LBD.
- To evaluate the impact of the pTVG-AR vaccine on survival in a prostate cancer mouse model.
Main Methods:
- Male mice received multiple immunizations with the pTVG-AR vaccine, with varying schedules and the inclusion of GM-CSF as an adjuvant.
- Toxicity was assessed through gross observations, pathological analysis, and serum chemistry.
- Immunological efficacy was evaluated using tetramer analysis to detect vaccine-augmented immunity.
- Survival studies were conducted in an autochthonous genetically engineered mouse model.
Main Results:
- The pTVG-AR vaccine demonstrated no significant toxicity in terms of animal weight, histopathology, hematology, or serum chemistries.
- No toxicity was observed in AR-expressing tissues such as the liver, muscle, hematopoietic system, and brain.
- Vaccination successfully elicited AR LBD-specific CD8+ T cell responses.
- Tumor-bearing mice treated with the vaccine exhibited prolonged survival compared to control groups.
Conclusions:
- The pTVG-AR vaccine is safe and effective in eliciting AR-specific cellular immune responses in immunocompetent mice.
- The vaccine prolonged the survival of mice bearing prostate tumors.
- These findings provide a strong rationale for the clinical evaluation of the pTVG-AR vaccine in patients with recurrent prostate cancer.
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