Anti-TNF, a magic bullet in cancer immunotherapy?

Abstract

Immune checkpoint blockers (ICB) have revolutionized cancer therapy. However, complete response is observed in a minority of patients and most patients develop immune-related adverse events (irAEs). These include colitis, which can be treated with anti-tumor necrosis factor (TNF) antibodies such as Infliximab. In a recent issue of the Journal for ImmunoTherapy of Cancer, Badran et al. reported that co-administering Infliximab together with ICB to five cancer patients prevents colitis recurrence, with four of them exhibiting overall disease stability. The basis for this treatment strategy stemmed from our pre-clinical demonstration that TNF contributes to resistance to anti-PD-1 therapy. In agreement with this concept, we have shown that TNF blockers improve the anti-tumor therapeutic activity of ICB in mice and based on these findings we are currently evaluating the combination in melanoma patients enrolled in the TICIMEL clinical trial. Herein, (i) we discuss the scientific rationale for combining anti-TNF and ICB in cancer patients, (ii) comment on the paper published by Badran et al. and (iii) provide the TICIMEL clinical trial design.

Keywords: Anti-CTLA-4; Anti-PD-1; Certolizumab; Immune-related adverse events; Infliximab; Melanoma; Resistance; Tumor necrosis factor.

Conflict of interest statement

N.M. and J.P.D. have worked as investigators and/or consultants and/or speakers for: BMS, MSD, Amgen, Roche, GSK, Novartis, Pierre Fabre, AstraZeneca. B.S. has worked as an investigator, consultant and speaker for BMS. M.A. has worked as consultant and/or speaker for: AstraZeneca, BMS and Pierre Fabre. The authors declare that they have no other conflict of interest.

Figures

Fig. 1

Scheme of the TICIMEL phase-1b clinical trial in 30 advanced melanoma patients. a, TICIMEL is split in 2 consecutive parts with the first part being conducted in 2 parallel cohorts (Cohort 1 and Cohort 2 with alternative patient allocation) to evaluate the safety profile of combining Nivolumab+Ipilimumab with TNF-Inhibitors (Certolizumab in cohort 1 and Infliximab in Cohort 2). Three patients are included at the unique dose. If there is no DLT or only one DLT, three other patients will be included. If no more than one patient among 6 presents a DLT, the combination (ICB + anti-TNF) will be considered as safe and allow to pursue the second part of the trial. The combination therapy selected for the second part of the study (cohort expansion study) will depend on safety, activity, and pharmacodynamics data from the first part of TICIMEL. b, Nivolumab and Ipilimumab are administered intravenously (IV) (infusion duration of 60 min for Nivolumab and 90 min for Ipilimumab); Certolizumab is administered subcutaneously (SC). Infliximab is administered IV (infusion duration of 120 min). All treatments are given on the same day as indicated in the induction phase. During the maintenance phase, Nivolumab and Certolizumab or Infliximab are/will be co-administered as indicated. Patients undergoing disease control (CR, PR or stable disease) beyond one-year treatment will have the possibility to be maintained on Nivolumab (3 mg/kg, Q2W). The end of Dose Limiting Toxicity (DLT) period evaluation is at day 84