Checkpoint inhibitor (CPI) therapy with anti-PD-1 antibodies has been associated with mixed outcomes in small cohorts of aggressive B-cell lymphoma patients following CAR T-cell therapy failure. To more definitively define CPI therapy efficacy in this population, we retrospectively evaluated clinical outcomes in a large cohort of 96 patients with aggressive B-cell lymphomas receiving CPI therapy after CAR-T failure across 15 U.S. academic centers. Most patients (53%) had DLBCL, were treated with axicabtagene ciloleucel (53%), relapsed early (≤180 days) after CAR-T (83%), and received pembrolizumab (49%) or nivolumab (43%). CPI therapy was associated with an overall response rate of 19% and a complete response rate of 10%. Median duration of response was 221 days. Median progression-free survival (PFS) and overall survival (OS) were 54 and 159 days, respectively. Outcomes to CPI therapy were significantly improved in patients with primary mediastinal B-cell lymphoma. PFS (128 versus 51 days) and OS (387 versus 131 days) were significantly longer in patients with late (>180 days) versus early (≤180 days) relapse after CAR-T. Grade ≥3 adverse events occurred in 19% of CPI-treated patients. Most patients (83%) died, commonly due to progressive disease. Only 5% had durable responses to CPI therapy. In the largest cohort of aggressive B-cell lymphoma patients treated with CPI therapy after CAR-T relapse, our results reveal poor outcomes, particularly among those relapsing early after CAR-T. In conclusion, CPI therapy is not an effective salvage strategy for most patients after CAR-T, where alternative approaches are needed to improve post-CAR-T outcomes
