The Prostate Cancer Foundation (PCF) recently announced that a PCF-funded research team has defined the mechanism allowing advanced prostate cancer to become resistant to immunotherapy treatment and also determined a new approach to reprogram cancer cells to become responsive to immunotherapy.
According to Cision PR Newswire, the research team was led by Dr. Akash Patnaik, who studied the mechanisms of highly aggressive metastatic castration-resistant prostrate cancer (mCRPC). This has been shown in the past to be resistant to treatments, and immunotherapies have limited effectiveness in treating this type of prostate cancer.
"These findings represent an exciting new opportunity to reprogram prostate cancer cells to be more sensitive to immunotherapy and a promising combination therapy approach for metastatic castration-resistant prostate cancer,” Howard Soule, the executive vice president and chief science officer of PCF, told Cision PR Newswire. “PCF commends Dr. Patnaik and the research team on their achievement and proudly supports their work to bring us closer to our mission to eliminate death and suffering from prostate cancer.”
In many cancers, which includes prostate cancer, alterations with the tumor microenvironment (TME) can affect responsiveness to immunotherapy. In particular, an increase in tumor infiltrating T-cells in the TME, a ’T-cell inflamed gene signature,’ will enhance immunotherapy responsiveness and a non-inflamed or immunology “cold” TME will reduce immunotherapy responsiveness.
One of the common alterations that has been seen in 75% of mCRPC patients and following androgen deprivation therapy (ADT), is a loss or silence of retinoblastoma (Rb) tumor suppressor-signaling pathway. The loss of Rb leads to cancer progression, as well as poor prognosis and poor responsiveness to treatments. Patnaik and his research team from the University of Chicago researched how the loss of Rb alters the tumor to target molecular pathways that make immunotherapy more effective.
Researchers analyzed human tumor samples for expression to explore the aggressive Rb-deficient form of mCRPC. They found that Rb loss was most associated with an immunologically cold microenvironment. Experiments on mice showed that there was a reduction in immune infiltration. This was also observed in Rb-deficient mCRPC patients. Researchers also tested BET inhibitor alone and in combination with immune checkpoint blockage and ADT.
Mice that were treated with the BET inhibitor showed a four-fold increase in the amount of T-cells in comparison to control groups. When the inhibitor was administered, along with anti-PD-1 immunotherapy and ADT, there was a significant increase in the anti-cancer response. This shows that the BET inhibition can reprogram the cold Rb-deficient microenvironment and make mCRPC more responsive to immunotherapy.
Patnaik and colleagues are moving into a second phase of clinical trials, where they will be testing the efficacy of the combination approach on mCRPC patients with Rb deficiencies following intensified ADT treatment. If it is successful, a new precision immunotherapy regimen could be available for these patients.
