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              <p>Immune checkpoint blockers (ICB) targeting PD-1 and/or CTLA-4 have become the gold standard treatments for metastatic melanoma patients with up to 36% of them achieving 5-year progression free survival1. However, a high proportion of patients still resist or relapse following treatment initiation highlighting the need for improved therapeutical strategies.We and others have shown that tumour necrosis factor alpha (TNF) can impede anti-tumour responses through multiple mechanisms, including the inhibition of anti-tumour responses2, 3 and the induction of epithelial-to-mesenchymal transition/de-differentiation of tumour cells4. Hence, we demonstrated that blocking TNF promotes the efficacy of ICB in mouse melanoma models5. Building upon our pre-clinical work, we started in 2018 a phase 1b clinical trial (TICIMEL, NCT03293784), which aims at evaluating the safety and efficacy of combining anti-TNF (infliximab [inflix] or certolizumab [certo]) to anti-PD-1 (nivolumab [nivo]) and anti-CTLA-4 (ipilimumab [ipi]) to treat advanced melanoma patients. Results from the first phase of this trial show that both tritherapies are safe with a higher incidence of treatment related adverse event event in the ipi/nivo/certo cohort as compared to the ipi/nivo/inflix one. This is correlated to promising sign of efficacy in patients enrolled in the certolizumab cohort5. When assessing the impact of treatments on systemic immune responses we observed an increase in the maturation and proliferation of systemic T cells in patients from both cohorts. This was accompanied by a decrease in the proportions of systemic myeloid-derived suppressor cells. Overall, these results suggest that anti-TNF may promote anti-melanoma immune responses in patients, a phenomenon we are further investigating in the second part of TICIMEL. Whether the nature of the TNF blocking agents used in this combination therapy leads to a differential modulation of the systemic and tumor immune landscapes in advanced melanoma patients is being investigated.1.Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. Oct 17 2019;381(16):1535-1546. doi:10.1056/NEJMoa19108362.Schioppa T, Moore R, Thompson RG, et al. B regulatory cells and the tumor-promoting actions of TNF-alpha during squamous carcinogenesis. Proc Natl Acad Sci U S A. Jun 28 2011;108(26):10662-7. doi:10.1073/pnas.11009941083.Bertrand F, Rochotte J, Colacios C, et al. Blocking Tumor Necrosis Factor alpha Enhances CD8 T-cell-Dependent Immunity in Experimental Melanoma. Cancer Res. Jul 1 2015;75(13):2619-28. doi:10.1158/0008-5472.CAN-14-25244.Landsberg J, Kohlmeyer J, Renn M, et al. Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation. Nature. Oct 18 2012;490(7420):412-6. doi:10.1038/nature115385.Bertrand F, Montfort A, Marcheteau E, et al. TNFalpha blockade overcomes resistance to anti-PD-1 in experimental melanoma. Nat Commun. Dec 22 2017;8(1):2256. doi:10.1038/s41467-017-02358-7</p>
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