Wisconsin Prostate Cancer SPORE

Project Co-Leaders: Joshua Lang, MD, MS, and Sheena Kerr, PhD

There is an increasing incidence of men with newly diagnosed prostate cancer (PC) presenting with locally advanced or metastatic disease, a population that comprises >60% of the men who die from the disease. The failure of early detection has led to the initiation of multiple clinical trials testing neoadjuvant therapies in an attempt to cure these patients. Analysis of pre-treatment samples from neoadjuvant trials have identified genomic alterations that associate with a treatment resistance. More recent studies indicate the tumor microenvironment (TME) can initiate the metastatic cascade. However, it remains unclear how and when genomic alterations co-opt different cell types in a complex 3-dimensional TME to initiate the metastatic cascade. We have recently found that activated fibroblasts and macrophage sub-populations induce lymphovascular sprouting and permeability. Based on these data sets, we hypothesize that somatic alterations in tumor DNA co-opt stromal and immune cells in the TME to promote invasion and intravasation of lympho-vascular channels. To test this hypothesis, we have three cohorts of patients with high-risk prostate cancer (surgery alone, neoadjuvant Abiraterone, and neoadjuvant chemohormonal therapy) that undergo PSMA PET/MRI scans prior to surgery. This scan is used to develop 3D mold of the prostate to perform whole mount sectioning and dissection of multi-focal PC for multi-plex molecular analysis. Samples from these specimens are used to create patient-specific “TMEs on a Chip” using a humanized Micro-Physiologic System (MPS) of the prostate with surrounding lympho-vasculature. This novel model system allows culture of patient tumor cells and stromal cells to identify the factors that induce lymphatic permeability and culminate in tumor invasion and intravasation.

Project Co-Leaders: Christos Kyriakopoulos, MD, and Douglas McNeel, MD, PhD

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 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.

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.

Project Co-Leaders: Robert Jeraj, PhD, and Glenn Liu, MD

Development of treatment resistance is the main reason for disease progression in patients with mCRPC. What is under-appreciated is that many patients who are experiencing progression have the majority of individual lesions that continue to respond to therapy. Identification of resistant lesions would allow for administration of localized ablative therapies, especially if the systemic therapy is still effective for the majority of metastases. We hypothesize that selective treatment of resistant lesions (e.g. with stereotactic body radiation therapy) will extend duration of clinical benefit in men with mCRPC. We will identify resistant lesions by employing our unique advanced quantitative molecular image analytics – Quantitative Total Extensible Imaging (QTxI) which allows lesion-level assessment of treatment dynamics.