Key Points

  • Nivolumab, as a monotherapy, led to complete responses in 5/7 r/r EBV-HLH patients and EBV clearance in 4 of them.

  • Nivolumab restored an anti-EBV program in CD8 T cells, revealed by scRNA-seq analysis.

Epstein-Barr virus-associated hemophagocytic lymphohistocytosis (EBV-HLH) is a life-threatening hyperinflammatory syndrome triggered by EBV infection. It often becomes relapsed or refractory (r/r), given that etoposide-based regimens cannot effectively clear the virus. r/r EBV-HLH is invariably lethal in adults if without allogeneic hematopoietic stem cell transplantation. Here, we retrospectively analyzed the data of seven r/r EBV-HLH patients treated with nivolumab on compassionate use in West China Hospital. Six patients responded. Five of them achieved and remained in clinical complete remission for a median follow-up of 16 months (range 11.4-18.9 months). Importantly, both plasma and cellular EBV were completely eradicated in four patients. Single cell RNA sequencing analysis showed that hyperactive monocytes/macrophages and ineffective CD8 T cells with an unbalanced activation program were associated with the syndrome. Nivolumab treatment expanded PD-1+ T cells and restored the expressions of HLH-associated degranulation and co-stimulatory genes in CD8 T cells. Our data suggest that nivolumab, as a monotherapy, provides a cure promise for r/r EBV-HLH, presumably by restoring the unbalanced anti-EBV program of the immune system.

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