Research ArticleCancer

Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer

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Science Translational Medicine  01 Apr 2020:
Vol. 12, Issue 537, eaaz3577
DOI: 10.1126/scitranslmed.aaz3577

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New ideas about neoantigens

Tumors with a low mutational burden are thought to have fewer neoantigens available for T cells to respond to and thus are not necessarily considered for checkpoint blockade therapy. Subudhi et al. treated patients with metastatic castration-resistant prostate cancer, which has a relatively low mutation burden, with ipilimumab. Patients who responded to the treatment had a T cell response signature and detectable neoantigen immunity. These results indicate that checkpoint blockade therapy with ipilimumab can instigate T cell responses to tumor neoantigens despite the tumor mutational burden status.

Abstract

Tumors with high mutational burden (TMB) tend to be responsive to immune checkpoint blockade (ICB) because there are neoantigens available for targeting by reinvigorated T cells, whereas those with low TMB demonstrate limited clinical responses. To determine whether antigen-specific T cell responses can be elicited after treatment with ICB in cancers that have a low TMB, we conducted a clinical trial with ipilimumab in 30 patients with metastatic castration-resistant prostate cancer. We identified two distinct cohorts by survival and progression times: “favorable” (n = 9) and “unfavorable” (n = 10). Patients in the favorable cohort had high intratumoral CD8 T cell density and IFN-γ response gene signature and/or antigen-specific T cell responses. Two patients with a relatively low TMB had T cell responses against unique neoantigens. Moreover, six of nine patients in the favorable group are still alive at the time of analysis, with survival ranging from 33 to 54 months after treatment. All 10 patients in the unfavorable cohort have succumbed to their disease and had survival ranging from 0.6 to 10.3 months. Collectively, our data indicate that immunological correlates associated with effector T cell responses are observed in patients with metastatic prostate cancer who benefit from ICB.

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