A subset of patients with metastatic prostate cancer who showed evidence of pretreatment of active T-cell responses in tumors experienced prolonged survival data as a result of treatment with ipilimumab, according to a study published in Science Translational Medicine.1
The phase II trial found that a group of patients with metastatic castration-resistant prostate cancer, which typically has a limited response to immunotherapy, could benefit from immune checkpoint inhibitors and provide future biomarkers to identify this subgroup.
“Our results indicate that immune checkpoint blockade can instigate T-cell responses to tumor neoantigens despite a low tumor mutational burden in prostate cancer,” said lead author Sumit Subudhi, MD, PhD, in a press release.2 “We found specific markers among a subset of patients with the greatest benefit, such as T-cell density and interferon-γ signaling, that may help improve our ability to select patients for treatment with checkpoint blockade.”
The researchers identified 2 separate cohorts by survival and progression time for patients: favorable and unfavorable. The favorable group saw “high intratumoral CD8 T cell density and IFN- γ response gene signature and/or antigen-specific T cell responses.” Even more, 6 of the 9 patients included in the favorable group were still alive at the time of analysis, with survival after treatment length ranging from 33 to 54 months. All 10 patients in the unfavorable cohort died of their diseases, with survival data ranging from 0.6 to 10.3 months.
The clinical trial was conducted with 30 patients of metastatic castration-resistant prostate cancer receiving ipilimumab with the hopes of determining if antigen-specific T-cell responses can be elicited after treatment with immune checkpoint blockade in cancers that have a low tumor with high mutational function.
“We were encouraged to see that prostate cancers with a low mutational burden do in fact express neoantigens that elicit T-cell responses that lead to favorable clinical outcomes,” said co-lead corresponding author Padmanee Sharma, MD, PhD, in the release. “Our findings indicate that anti-CTLA-4 immune checkpoint therapy warrants additional studies in order to develop treatment strategies that may improve survival of patients with metastatic prostate cancer.”
Among the entire population of patients, the median progression-free survival was 3 months, and median overall survival was 24.3 months. A total of 8 patients (28%) experienced grade 3 toxicities, with dermatitis and diarrhea among the most common.
Compared to other forms of cancer like melanoma and lung cancer, which tend to respond to immune checkpoint inhibitors strongly, prostate cancer has relatively low mutation levels and fewer neoantigens present. Higher levels of underlying gene mutations lead to the higher production of neoantigens, which that are recognized as abnormal by the immune system.
Moving forward, the researchers plan to pursue more multi-institutional trials in the hopes of validating the data collected in this phase II trial.
“Our results suggest that a particular subset of patients may benefit from (immune checkpoint blockade), despite having a relatively low (tumors with high mutational burden),” wrote the researchers. “In summary, our clinical study provides data to support further testing of immunotherapy strategies in patients with meta- static prostate cancer.”
1. Subudhi SK, Vence L, Zhao H, et al. Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer. Sci Transl Med. DOI: 10.1126/scitranslmed.aaz3577.
2. Immunotherapy effective in metastatic prostate cancers with specific markers of immune activation [news release]. Published April 1, 2020. https://www.mdanderson.org/newsroom/immunotherapy-effective-in-metastatic-prostate-cancers-with-specific-markers-of-immune-activation.h00-159381156.html. Accessed April 2, 2020.