Triple combination of anti-CTLA-4, anti-PD-1 and anti-TNF in mouse melanoma models and advanced melanoma patients.
Résumé
CTLA-4 and PD-1 inhibitors improve Progression Free survival (PFS) and Overall Survival (OS) in advanced melanoma patients. TNF production is increased upon immune checkpoint inhibitors (ICI) and impedes ICI therapy efficacy in preclinical melanoma and colon cancer models. Herein, anti-TNF improved the efficacy of anti-CTLA-4 and anti-PD-1 in B16-Ova melanoma bearing mice, with an increased frequency of complete and long-term responses. Unbiased RNA Seq analyses from B16-Ova tumours indicated that anti-TNF increased immune responses when combined with anti-CTLA-4 and anti-PD-1. This was further documented by flow cytometry analyses. To evaluate the putative benefit of combining anti-TNF with ICI in patients, we conducted an open label phase Ib clinical trial TICIMEL (NCT03293784) in advanced melanoma patients with two parallel cohorts: ipilimumab/nivolumab/certolizumab (C cohort) and ipilimumab/nivolumab/infliximab (I cohort). The objective was to evaluate safety and to screen for preliminary anti-tumor activity of these triple combinations. Between 2018 and 2021, 33 patients were included, 20 in the C cohort and 13 in the I cohort. One patient from I cohort did not receive any treatment and was not evaluable for safety and anti-tumor activity. Fifteen patients in the C cohort and 4 in the I cohort displayed grade 3/4 drug-related adverse events (AE), indicating that infliximab is better tolerated when combined with ICI. Drug-related AE were mostly hepatobiliary, gastrointestinal and respiratory disorders. In the C and I cohorts, an objective response was observed in 12 out of 20 and 6 out of 12 patients, respectively. Our study shows that the systemic co-administration of the triple combination of anti-CTLA-4, anti-PD-1 and anti-TNF (i) improves ICI efficacy in a mouse melanoma model, (ii) is safe in advanced melanoma patients, with a promising response rate in the C cohort, and a better tolerability profile in the I cohort.
