Combining TNF-targeting antibodies to immune checkpoint inhibitors in melanoma

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Montfort, Anne | Bertrand, Florie | Marcheteau, Elie | Imbert, Caroline | Gilhodes, Julia | Rochaix, Philippe | Filleron, Thomas | Ayyoub, Maha | Andrieu-Abadie, Nathalie | Levade, Thierry | Colacios, Céline | Meyer, Nicolas | Ségui, Bruno

Edité par CCSD -

International audience. Purpose:Anti-PD-1 therapy has significantly improved the care of melanoma patients. However, more than 50% of them do not display optimal response to treatment and a significant proportion of responders relapse. In addition, about 50% of patients will experience mild to severe immune-related adverse events (irAEs). Our goal is to evaluate, both in pre-clinical and clinical settings, the impact of combining immune checkpoint inhibitors (ICI) to TNF blockade in the treatment of melanoma.Experimental Design:In pre-clinical analyses using the B16K1 (B16F10 MHC1high) mouse melanoma model we studied the impact of TNF deficiency /blockade on response to PD-1. The parameters assessed included tumor growth, overall survival (OS) of mice as well as analyses of the immune contexture of tumors1,2.Clinical analyses will be performed as a phase 1b clinical trial (TICIMEL: NCT03293784) assessing the safety and tolerance of combining ICI (Nivolumab + Ipilimumab) to anti-TNF (Infliximab or Certolizumab) for the treatment of metastatic melanoma patients. Results:Our pre-clinical studies demonstrated that blocking the TNF/TNFR1 pathway potentiates the CD8+ T cell-dependent anti-melanoma immune response in mouse. Moreover, blocking the TNF/TNFR1 pathway synergizes with anti-PD-1 treatment to impair tumor growth in mouse. In this context, anti-TNF prevent the anti-PD-1-dependent upregulation of TIM-3 on Tumor-infiltrating T cells as well as activation-induced cell death thus favoring CD8+ T cell accumulation in tumors1,2.Specifics of the clinical trial, which will begin by the end of 2017, will be presented.Conclusion:Our pre-clinical data support the use of TNF blocking antibodies to enhance response of melanoma patients to immune checkpoint inhibitors. References :1Bertrand F et al. Blocking tumor necrosis factor alpha enhances CD8 T-cell-dependent immunity in experimental melanoma. (2015) Cancer Res., 75(13):2619-282Bertrand F. et al. TNF blockade overcomes PD-1 resistance in melanoma. Accepted at Nature Communications, November 2017.

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