Despite the synergistic efficacy of nivolumab and ipilimumab in some advanced-stage solid tumours, serious immune-related adverse events (irAEs) are common. A new study now demonstrates that prophylactic tumour necrosis factor (TNF) blockade reduces gastrointestinal irAEs in mice treated with dual immune-checkpoint inhibition (DCI).
The group of Ignacio Melero (University of Navarra, Spain) first demonstrated that DCI exacerbated dextran sulfate sodium (DSS)-induced autoimmune colitis in mice, which was ameliorated with prophylactic administration of an anti-TNF antibody or the TNF inhibitor etanercept. Importantly, TNF blockade before DCI did not impair antitumour efficacy in syngeneic mouse models of colon cancer and melanoma, and even improved the survival and xenograft-rejection rate in DSS-treated syngeneic mouse models.
TNF blockade was found to enhance DCI-induced CD8+ T cell infiltration (in the tumour and lymph nodes) and decrease activation-induced cell death in DCI-treated CD8+ T cells in vitro and in vivo, providing a mechanistic rationale for these observations.
prophylactic TNF inhibition could improve the safety of DCI regimens while preserving — or even enhancing — efficacy
The expression of TNF-related transcripts and genes was found to be upregulated in normal colonic mucosal tissues from a group of four patients treated with DCI who developed colitis compared with those from four healthy individuals without bowel inflammation or cancer. In a graft-versus-host disease mouse model, prophylactic etanercept treatment reduced DCI-induced exacerbation of colitis. Similarly, in a colon cancer xenograft-induced humanized mouse model of colitis, concomitant etanercept treatment did not weaken the antitumour effects of nivolumab–ipilimumab, and, importantly, it diminished xenograft-induced colitis.
The findings have clear translational relevance, whereby prophylactic TNF inhibition could improve the safety of DCI regimens while preserving — or even enhancing — efficacy, and perhaps enabling ipilimumab doses to be safely increased.
“An ongoing pilot trial in France (NCT03293784) is testing safety of the combined strategy, and a larger randomized phase II trial should soon test efficacy,” adds Melero.
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Perez-Ruiz, E. et al. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy. Nature https://doi.org/10.1038/s41586-019-1162-y (2019)
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Bradley, C.A. Prophylactic TNF blockade reduces autoimmune toxicity. Nat Rev Cancer 19, 364 (2019). https://doi.org/10.1038/s41568-019-0152-6
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DOI: https://doi.org/10.1038/s41568-019-0152-6