A new immunotherapy strategy for melanoma patients.

Melanoma is a skin cancer with a poor prognosis and is usually treated with monoclonal antibodies that neutralise immune checkpoints such as anti-CTLA-4 (ipilimumab) or anti-PD-1 (nivolumab). Unfortunately, a significant proportion of patients do not respond to these treatments. Team 4 of the CRCT has shown that neutralisation of TNFα, a major inflammatory cytokine, potentiates the response to anti-PD-1 in mouse models of melanoma. This work provides the scientific rationale for the TICIMEL clinical trial, which aims to evaluate the safety, tolerability and anti-tumour activity of anti-TNFα molecules (certolizumab or infliximab) in combination with ipilimumab and nivolumab in patients with advanced melanoma. Initial results are promising, with signs of activation and maturation of the immune response, fewer side effects in the infliximab-treated patients, and to date a better clinical response rate in the certolizumab-treated cohort. Investigations are continuing in an expansion cohort.

If the promising clinical results are confirmed in the expansion cohort, a multi-centre phase 2 clinical trial could be set up including a larger number of patients with melanoma or other types of cancer that can be treated with immunotherapy.

In the long term, our work could lead to the generalisation of this new immunotherapy in patients with melanoma or other types of cancer. The use of anti-TNFs in cancer patients, whether or not in combination with immunotherapies targeting immune checkpoints, has been the subject of two international patents.

• New method to treat melanoma  (WO2015173259A1, US10144772B2, ES2748380T3, EP3142685B1)
• Methods and pharmaceutical composition for the treatment of cancer (US10918737B2)

Collaborations and acknowledgements

We thank Bristol-Myers Squibb Laboratories (BMS) for funding the clinical trial and part of the ancillary study. We thank the Fondation ARC pour la recherche sur le cancer, the Cancéropôle Grand Sud-Ouest (GSO) and the Institut Universitaire du cancer Toulouse-Oncopole (IUCT-O) for funding part of the ancillary study. We thank the Fondation Toulouse Cancer Santé (FTCS) and the Fondation pour la Recherche Médicale (FRM) for the payment of salaries.

One picture

Evidence of efficacy in patients treated with nivolumab, ipilimumab and anti-TNF. A, Best response in all patients in the certolizumab cohort and the infliximab cohort. B, CT images showing examples of target tumour regression in a patient in the certolizumab cohort with lung metastasis (left photos) and in a patient in the infliximab cohort with liver metastasis (right photos).