BackgroundCAPRA (NCT02565992) evaluated Coxsackievirus A21 (V937) + pembrolizumab for metastatic/unresectable stage IIIB–IV melanoma.MethodsPatients received intratumoral V937 on days 1, 3, 5, and 8 (then every 3 weeks [Q3W]) and intravenous pembrolizumab 2 mg/kg Q3W from day 8. Primary endpoint was safety.ResultsMedian time from first dose to data cutoff was 32.0 months. No dose-limiting toxicities occurred; 14% (5/36) of patients experienced grade 3‒5 treatment-related adverse events. Objective response rate was 47% (complete response, 22%). Among 17 responders, 14 (82%) had responses ≥ 6 months. Among 8 patients previously treated with immunotherapy, 3 responded (1 complete, 2 partial). Responses were associated with increased serum CXCL10 and CCL22, suggesting viral replication contributes to antitumor immunity. For responders versus nonresponders, there was no difference in baseline tumor PD-L1 expression,ICAM1expression, or CD3+infiltrates. Surprisingly, the baseline cell density of CD3+CD8−T cells in the tumor microenvironment was significantly lower in responders compared with nonresponders (P= 0.0179).ConclusionsThese findings suggest responses to this combination may be seen even in patients without a typical “immune-active” microenvironment.Trial registration numberNCT02565992.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00262-022-03314-1.