TNF plasma levels in advanced melanoma patients treated with immune checkpoint inhibitors: results from the MELANFα clinical study.

Resistance mechanisms to immune checkpoint inhibitors (ICI) in cancer patients are not fully understood and predictive biomarkers are lacking. TNF is a pleiotropic cytokine that can be detrimental in cancer and TNF blockade potentiates ICI efficacy in preclinical models. MELANFα (NCT03348891) is a translational proof-of-concept, open-label, prospective, multicenter cohort study of 60 advanced melanoma patients (ipilimumab + nivolumab (Ipi/Nivo); pembolizumab or nivolumab). Its primary objective was to study whether the evolution of plasma TNF between baseline (W0) and week 12 (W12) could identify patients presenting non-progressive disease at W12. Secondary objectives aimed at assessing the correlation between the evolution of TNF plasma levels and circulating T cell subpopulations. TNF plasma levels increased along therapy but the evolution from W0 to W12 was not associated with non-progressive disease at W12. Whereas TNF plasma levels at W0 did not differ in responders (R) and non-responders (NR), they were significantly higher at W12 in NR versus R. Along therapy, circulating T cell populations were predominantly modulated in the Ipi/Nivo arm. Moreover, effector memory (EM) CD8 T cells increased and this evolution correlated with augmented TNF plasma concentrations between W0 and W12. Increased levels of CD8 EM were significantly associated with a lack of objective response (OR) of ICI-treated patients at W12. In contrast, central memory (CM) CD8 T cells increased between W0 and W6 in R compared to NR. Th1 cells were increased along Ipi/Nivo treatment and their evolution from W0 to W6 was associated to R without being correlated to TNF plasma evolution. Our results show that elevated TNF plasma levels along therapy are associated with a poorer clinical outcome and reinforces the notion that TNF might dampen ICI efficacy.