Prostate cancer is typically refractory to immunotherapy because of its ability to simultaneously activate 2 different pathways to evade host immune response, according to results from a recent study. This study also suggested a third mechanism of immune system evasion called VISTA.1
Researchers initiated a clinical trial testing anti-PD-1 drug nivolumab in combination with anti-CTLA4 drug ipilimumab in men with metastatic, castration-resistant prostate cancer (ClinicalTrials.gov identifier: NCT02985957) based on these results. Previous attempts to treat prostate cancer with either nivolumab or ipilimumab were not efficacious.
“We’ve known that prostate cancer is immunologically cold, or quiet, with very little penetration of the tumors or their surrounding microenvironment by immune cells,” said senior author Padmanee Sharma, MD, PhD, professor of genitourinary medical oncology and immunology, The University of Texas MD Anderson Cancer Center, Houston, in a news release from the facility.2
Immune checkpoint inhibitors allow T cells to recognize and attack tumors.
Researchers assessed additional pathways inhibiting the immune system in the tumor microenvironment by evaluating untreated and ipilimumab-treated tumor samples in patients in a presurgical clinical trial. In treated tumors, levels of PD-L1 and VISTA, both inhibitory molecules, increased on separate subsets of white blood cells.
These results suggest that driving T cells into the tumors, although important, is not enough for successful treatment; instead, inhibition of PD-1/PD-L1 and VISTA is needed. This realization motivated the initiation of the combined immunotherapy clinical trial.
“This paper highlights the importance of studying immune response longitudinally. Observing immune response at one point in time doesn’t reflect what’s going on because the immune system is so dynamic,” explained Dr Sharma.2
“So baseline sampling in prostate tumors shows minimal immune infiltrate. You can change that with ipilimumab, but what else changes becomes incredibly important. Understanding these changes using post-treatment or on-treatment biopsies is important to develop rational combination strategies for these immune-modulating drugs.”2
1. Gao J, Ward JF, Pettaway CA, et al. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer [published online March 27, 2017]. Nat Med. doi: 10.1038/nm.4308
2. Study provides path for new immunotherapy approaches to prostate cancer [news release]. Houston, TX: The University of Texas MD Anderson Cancer Center; March 27, 2017. https://www.mdanderson.org/newsroom/2017/03/study-provides-path-for-new-immunotherapy-approaches-to-prostate-cancer.html. Accessed April 11, 2017.