Pr. Bruno Segui , invited by Majid Khatib, team 2 Reprograming tumor activitY and associaTed MicroenvironmEnt (Rytme).
Co-head of the team MELASPHINX: Ceramide metabolism in melanoma: from basic mechanisms to immunotherapy in the Toulouse Cancer Research Center (CRCT)

Title : TNF blockade with certolizumab, but not infliximab, improves efficacy of anti-PD-1 and anti-CTLA-4 combination in melanoma

Abstract

The combination of anti-PD-1 and anti-CTLA-4 boosts the anti-cancer immune response in patients with advanced melanoma. However, 60% of patients fail to respond or relapse early after induction, and 95% develop immune-related adverse events (irAEs) such as colitis, which can be treated with infliximab, a tumour necrosis factor-alpha inhibitor (TNFi). The impact of TNFi on immune and clinical responses remains to be elucidated. Here we provide evidence that TNF blockade can improve the response to the anti-PD-1 and anti-CTLA-4 combination not only in mice but also in patients enrolled in a phase 1b clinical trial (TICIMEL, NTC03293784). However, certolizumab, but not infliximab, strongly stimulates immune and therapeutic responses to ICI. Mechanistically, we have shown that the IgG1 Fc fragment of infliximab impairs the ability of TNF blockade to stimulate the efficacy of ICI therapy. When combined with ICI, certolizumab decreased the proportion of regulatory T cells (Tregs) and exhausted T cells, while increasing the proportion of effector T cells in tumors as assessed by single-cell RNA sequencing and spectral flow cytometry. In conclusion, our study shows that TNF impairs the immune response to melanoma and that the type of TNFi must be well selected to improve the efficacy of ICI in melanoma.

📆 Tuesday, May 13 9:30 a.m.
📌 Amphi BBS (Bordeaux Biologie Santé) 2 rue du Dr Hoffmann Martinot

Bruno Ségui

CV overview:

2000: PhD in human pathophysiology (Toulouse University).

2000-2002: Postdoctoral position (University College London, UK).

2006: HDR (Toulouse University).

2002-2011: Assistant Professor of Immunology, Faculty of Pharmacy (Toulouse III).

Since 2011: Professor of Cell Biology, Faculty of Pharmacy (Toulouse III).

Research activity in the Cancer Research Center of Toulouse (CRCT).

Since 2019: Deputy Director of the CARe graduate school on Cancer Aging and Rejuvenation.

Since 2021: Team leader of MELASPHINX at the Cancer Research Center of Toulouse,

co-PI: Dr. N. Andrieu-Abadie.

Overview of research activities:

Over the last 25 years, I have been studying the signalling pathways triggered by some members of the TNF receptor superfamily, including CD40, Fas/CD95 and TNFR1/CD120a. In this context, we have highlighted the role of sphingolipids in the modulation of both apoptosis and immune responses (Ségui et al., J. Biol. Chem., 1999; Ségui et al, J. Clin. Invest. 2001; Montfort et al., J. Immunol. 2009; Lafont et al., Cell Death Differ. 2010). More recently, we have shown that TNF blockade enhances the CD8 T cell-dependent immune response (Bertrand et al., Cancer Res. 2015) and overcomes the resistance to anti-PD-1 (Bertrand et al., Nat. Commun. 2017) in mouse melanoma models. Mechanistically, TNF triggers the activation-induced cell death of CD8+ tumour-infiltrating lymphocytes. We have translated our concept into the clinic in advanced melanoma patients, where we have shown that two triple therapies combining TNF blockers (infliximab or certolizumab) with anti-PD-1 (nivolumab) and anti-CTLA-4 (certolizumab) are safe for patients, with promising signs of efficacy in the certolizumab cohort (Montfort et al., Clin. Cancer Res 2021). Moreover, Elevated plasma TNF and enriched TNF pathways in T cells are associated with poorer clinical outcome in patients with advanced melanoma, reinforcing the notion that TNF may dampen the efficacy of immune checkpoint inhibitors (Virazels et al., Int J Cancer, in press).