Project Summary
Prostate cancer is a significant worldwide health problem for which new treatments are needed. The goal of our laboratory for the past twenty years has been to develop immunotherapy treatments for prostate cancer. We have evaluated multiple cancer-associated proteins as anti-tumor vaccine targets and have focused recent efforts on the ligand-binding domain of the androgen receptor (AR LBD) as a target. We demonstrated that a DNA vaccine encoding the AR LBD (pTVG-AR) can elicit epitope-specific cytolytic CD8+ T cells in HLA-A2 transgenic mice, and immunization of prostate tumor-bearing mice elicited anti-tumor responses and significantly prolonged their overall survival. Based on these results, we recently completed a multi-center phase I clinical trial using the pTVG-AR vaccine for patients with metastatic prostate cancer and demonstrated that vaccination is safe and immunologically active. Consistent with our preclinical studies, the development of T-cell immune response to the AR LBD was associated with a prolonged time to castration resistance. In preclinical studies, we have found that androgen deprivation (AD) leads to overexpression of the AR protein in prostate cancer cells, and this in turn makes them more recognized by CD8+ T cells activated by AR- targeted vaccination. We have subsequently demonstrated that AD can thus be used strategically with immunization. In other preclinical studies, we have further found that CD8+ T cells activated by vaccination express multiple immune checkpoint receptors (ICR), and
that blockade of certain ICR with vaccination leads to greater anti-tumor effects. Together, these findings have led to the hypothesis to be tested in this proposal that combined AD, with AR-targeted vaccination and T-cell checkpoint blockade, will lead to increased tumor-specific CD8+ T cell infiltration, tumor eradication, and persistent immune memory. We will use relevant murine models of prostate cancer to conduct a mechanistic evaluation of the effects of AD with vaccination and ICR blockade on the development of T cell memory and antigen spread. This approach will also be evaluated in an investigator- initiated clinical trial in patients with high-risk prostate cancer prior to prostatectomy, with a design amenable to modification of study arms depending on the outcomes from the preclinical studies. This proposal, consequently, capitalizes on development of a novel anti-tumor vaccine that has now completed phase I clinical trial evaluation, and explores methods to increase its therapeutic effect in preclinical models and in a biomarker-driven clinical his proposal will identify optimal strategies and clinical scenarios for further clinical development of this treatment approach.
Specific Aims:
Aim 1 – To determine whether different methods of AD affect the immune recognition of prostate tumors and lead to increased anti-tumor immune response in combination with AR-targeted vaccination.
Aim 2 – To determine whether AR-targeted vaccination, in combination with AD and ICR blockade, leads to increased AR-specific CD8+ T-cell infiltration and persistent anti-tumor immune memory.
Aim 3 – To determine whether AR-targeted vaccination, in combination with AD and PD-1 blockade, leads to increased tumor-infiltrating CD8+ T cells with memory and effector function, and persistent CD8+ T-cell memory, in patients with newly diagnosed high-risk prostate cancer.