TNF blockade with certolizumab improves the efficacy of anti-PD-1 and anti-CTLA-4 combination therapy for melanoma

Abstract The phase 1b TICIMEL clinical trial evaluated the safety, tolerability, and anti-tumor activity of combining the immune checkpoint inhibitors (ICI), ipilimumab and nivolumab, with tumor necrosis factor (TNF) blockers, certolizumab or infliximab, to treat advanced melanoma patients. A higher proportion of responses was observed in patients receiving ICI and certolizumab, while patients treated with ICI and infliximab demonstrated superior tolerability. Moreover, CITE-Seq analyses of circulating CD8 T cells showed that ICI plus certolizumab promoted an IFN signature, whereas ICI plus infliximab reduced the induction of genes associated with T cell activation. In preclinical models, ICI and TNF blockade with certolizumab increased IFN-γ + CD8 T cells and reduced regulatory T cells in tumors. The IgG1 Fc fragment of infliximab was identified as counteracting the benefits of TNF blockade. These findings underscore the importance of selecting the optimal TNF blocker to combine with ICI to enhance therapy efficacy in melanoma patients. ClinicalTrials.gov identifiers: NCT03293784 ; NCT05867004 .