Resistance to immune checkpoint inhibitors (ICI) in cancer patients is not fully understood, and predictive biomarkers are lacking. MELANFα (NCT03348891) is an open‐label, prospective, multicenter cohort of 60 patients with advanced melanoma receiving ICI (bitherapy: ipilimumab + nivolumab; monotherapy: pembrolizumab or nivolumab). The primary objective was to evaluate whether changes in plasma TNF between baseline (W0) and week 12 (W12) identified patients with non‐progressive disease at W12. Secondary and exploratory objectives were to assess the association between plasma TNF, tumor response, and changes in circulating T cells. Plasma TNF increased along therapy, but its W12/W0 fold change was not associated with non‐progressive disease at W12. However, plasma TNF levels at W12 were significantly higher in non‐responders than in responders across therapies ( p = .0129). The remodeling of circulating T cell subpopulations was mostly triggered by bitherapy. Increased proportions of circulating central memory and effector memory CD8 T cells after bitherapy were positively and negatively associated with response to treatment, respectively. In this cohort, circulating T cells from responders and non‐responders also displayed distinct molecular characteristics. Indeed, responders showed an increased proportion of CD8 T cells with low enrichment of TNF‐related pathways and high cytotoxic potential, while non‐responders displayed increased proportions of circulating CD8 EM T cells enriched for TNF‐related pathways and directed toward cytokine expression. In conclusion, our study shows that elevated plasma TNF and enriched TNF pathways in T cells are associated with poorer clinical outcomes, reinforcing the notion that TNF may dampen ICI efficacy.

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Malgré l’efficacité des anti-PD-1 et anti-CTLA-4 pour le traitement des mélanomes avancés, plus de 40 % des patients résistent ou rechutent dans les 5 ans suivant l’initiation du traitement et plus de 50 % des patients développent des effets indésirables inflammatoires de grade 3/4, dont des colites qui peuvent être traitées par anti-TNFa. Notre équipe a montré que le TNF limite l’efficacité des anti-PD-1 dans des modèles murins de mélanome. TICIMEL (NTC3293784) est un essai clinique de phase 1b qui a pour objectif d’évaluer la sécurité de l’association des anti-TNF (infliximab [5 mg/kg] ou certolizumab [400/200 mg]) à la combinaison nivolumab (1 mg/kg)/ipilimumab (3 mg/kg) (ipi3/nivo1) pour le traitement du mélanome avancé. L’objectif secondaire de TICIMEL est d’évaluer l’activité anti-tumorale. La sévérité des effets indésirables a été évaluée selon la terminologie CTCAE et la réponse selon les critères RECIST 1.1. Au cours de la première partie de cet essai, 6 et 8 patients ont été respectivement inclus dans les cohortes infliximab et certolizumab. Un seul patient, inclus dans la cohorte infliximab, développait une DLT (toxicité limitant la dose). La nature des effets indésirables chez les patients des deux cohortes était similaire à celle décrite précédemment avec ipi3/nivo1. Un nombre plus élevé d’évènements indésirables était observé chez les patients traités par certolizumab (n = 8) que chez les patients traités par infliximab (n = 6). Sur les 8 patients inclus dans la cohorte certolizumab, 7 étaient évaluables pour la réponse. Tous étaient en réponse objective 12 semaines après l’initiation du traitement incluant 4 réponses complètes (RC). Dans la cohorte infliximab, 3 patients présentaient une réponse objective (1 RC et 2 réponses partielles [RP]) et 3 patients avaient progressé. Enfin, nos analyses exploratoires montrent que les deux trithérapies potentialisent l’activation et la maturation des lymphocytes T dans le sang des patients. Nous observons également une augmentation des taux plasmatiques d’IFNg, une cytokine essentielle aux réponses immunitaires anti-tumorales. Nos premiers résultats montrent que l’association d’anti-TNF à la combinaison ipi3/nivo1 est sûre. Nos résultats exploratoires associés au taux élevé de réponse des patients traités par certolizumab suggèrent une potentielle synergie entre l’association ipi3/nivo1 et cet anti-TNF. Les cohortes d’expansion de l’essai sont en cours de recrutement.

Abstract Purpose: TNF blockers can be used to manage gastrointestinal inflammatory side effects following nivolumab and/or ipilimumab treatment in patients with advanced melanoma. Our preclinical data showed that anti-TNF could promote the efficacy of immune checkpoint inhibitors. Patients and Methods: TICIMEL (NTC03293784) is an open-label, two-arm phase Ib clinical trial. Fourteen patients with advanced and/or metastatic melanoma (stage IIIc/IV) were enrolled. Patients were treated with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) combined to infliximab (5 mg/kg, N = 6) or certolizumab (400/200 mg, N = 8). The primary endpoint was safety and the secondary endpoint was antitumor activity. Adverse events (AEs) were graded according to the NCI Common Terminology Criteria for Adverse Events and response was assessed following RECIST 1.1. Results: Only one dose-limiting toxicity was observed in the infliximab cohort. The two different combinations were found to be safe. We observed lower treatment-related AEs with infliximab as compared with certolizumab. In the certolizumab cohort, one patient was not evaluable for response. In this cohort, four of eight patients exhibited hepatobiliary disorders and seven of seven evaluable patients achieved objective response including four complete responses (CRs) and three partial responses (PRs). In the infliximab cohort, we observed one CR, two PRs, and three progressive diseases. Signs of activation and maturation of systemic T-cell responses were seen in patients from both cohorts. Conclusions: Our results show that both combinations are safe in human and provide clinical and biological activities. The high response rate in the certolizumab-treated patient cohort deserves further investigations.

Cutaneous melanoma is a deadly skin cancer whose aggressiveness is directly linked to its metastatic potency. Despite remarkable breakthroughs in term of treatments with the emergence of targeted therapy and immunotherapy, the prognosis for metastatic patients remains uncertain mainly because of resistances. Better understanding the mechanisms responsible for melanoma progression is therefore essential to uncover new therapeutic targets. Interestingly, the sphingolipid metabolism is dysregulated in melanoma and is associated with melanoma progression and resistance to treatment. This review summarises the impact of the sphingolipid metabolism on melanoma from the initiation to metastatic dissemination with emphasis on melanoma plasticity, immune responses and resistance to treatments.