AUA 2018: Engaging the Immune System to Combat Prostate Cancer

San Francisco ( Dr. Harshman began by discussing the immune milieu of prostate cancer. It has been though that prostate cancers are T-cell poor tumors, with a relatively low number of CD8 cells compared to kidney or bladder tumors.  Additionally, prostate cancers have a relatively low number of somatic mutations.  Sipuleucel-T was the first FDA approved anti-cancer therapeutic vaccine.  It was the first immunotherapy proven in castrate resistant prostate cancer, and at the time, the second agent proven to increase survival.  However, clinical utilization was likely hampered by limited PSA response and lack of progression free survival increase. 

Dr. Harshman suggested that data and mechanism implies the concept of “immuno-editing”: Sipuleucel-T may not induce elimination but may push the battle back to equilibrium to slow disease progression. Retrospective data supports the hypothesis that immunotherapy may decrease tumor growth rates.  Proof of immune system activation is evident from the IMPACT Trial, where APC activation was evident with increased T cell activation and cytokine secretion with generation of persistent antigen specific humoral responses.  

Prostvac utilized a pox-based vector containing transgenes for PSA and a triad of T cell co-stimulatory molecules (TRICOM). A promising phase II study demonstrated no benefit in progression free survival but a 10 month increase in overall survival compared to placebo.  Although disappointing, it is thought that application earlier in disease course or with dual therapy may result in improved outcomes. An ongoing trial is randomizing biochemically recurrent patients to Prostvac or surveillance for 6 months followed by Prostvac for 6 months, with a primary endpoint of PSA response.  

Both CTLA4 inhibitors and PD1/PLD1 inhibitors have a role in immune checkpoint blockade in prostate cancer treatment.  Ipilimumab is a anti CTLA-4 antibody that has been studied in both the pre- and post-docetaxel setting, where in both settings only a 1 month improvement in median overall survival was demonstrated.  Therefore, physicians question the role of Ipilimumab in prostate cancer, where ongoing and future prospective studies are needed to elucidate this information. 

Potential future combination therapies to engage the immune system include hormonal therapy, radium-223, PARP inhibitors, chemotherapy, or newer targets. Brachyury is a transcription factor that induces mesenchymalization of epithelial cells that promotes metastasis in murine models.  It has been shown to be overexpressed in cancer in humans and correlates with aggressive disease.  A TRICOM vaccine was developed against Brachyury that has been shown to be well tolerated with good CD4 and CD8 T cell responses.

In summary, prostate cancer can be an immune-sensitive disease, with certain subsets that may be relevant to targets.  More biomarker discoveries are needed to identify other targets that likely need combination therapeutics to improve efficacy by synergistic effects.

Presenter: Lauren Harshman, MD, Dana-Farber Cancer Institute

Written by: David B. Cahn, DO, MBS,Fox Chase Cancer Center, Philadelphia, PA, @dbcahn at the 2018 AUA Annual Meeting - May 18 - 21, 2018 – San Francisco, CA USA