Data from a small study indicated that high tumor mutational burden may not be necessary for selection of patients with metastatic castration-resistant prostate cancer (mCRPC) who may benefit from immune checkpoint blockade.
In fact, the study identified a small subgroup of patients that benefited from immune checkpoint blockade despite having a low tumor mutational burden.
“Some of the highest objective response rates to [immune checkpoint blockade] are observed in patients with melanoma and non–small cell lung cancer (NSCLC), tumors that have high tumor mutational burden and neoantigen frequency, both of which have been associated with clinical responses to [immune checkpoint blockade],” the researchers wrote.
“Because tumor neoantigens can be recognized by the immune system, it is expected that the presence of preexisting immune infiltrates within the tumor microenvironment is also associated with clinical benefit to [immune checkpoint blockade]. In comparison to melanoma and NSCLC, prostate cancers have a substantially lower prevalence of somatic mutations and frequency of mutant neoantigens,” they wrote.
In this study, they conducted a trial of 30 patients with mCRPC treated with ipilimumab. Two cohorts were identified based on survival and progression times and labeled as having favorable (9 patients) and unfavorable (10 patients) disease.
According to the study, those patients who were “favorable” had high intratumoral CD8 T-cell density and interferon-alfa response gene signature and/or antigen-specific T-cell responses.
Two patients with low tumor mutational burden had T-cell responses against unique neoantigens. Whereas all patients with “unfavorable” disease had succumbed to their disease, 6 of 9 (67%) patients with “favorable” disease were alive at the time of analysis, with a survival ranging from 33 to 54 months after treatments.
“Both CheckMate 650 and our current study identified similar median [tumor mutational burden] values (74.5 and 76 nonsynonymous mutations, respectively) for mCRPC, which were considerably lower than the median [tumor mutational burden] observed in melanoma and NSCLC (~200 nonsynonymous mutations),” the researchers wrote. “Despite the relatively lower [tumor mutational burden] and few mutations identified in mCRPC, our study demonstrates that some of these mutations are capable of inducing antigen-specific T-cell responses.”
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. 2020;12(537):eaaz3577. doi: 10.1126/scitranslmed.aaz3577