Melanoma is a poor-prognosis skin cancer. Immunotherapy based on the use of monoclonal antibodies (anti-CTLA-4 and anti-PD-1) activates the immune system to fight melanoma and has improved the prognosis of this cancer. Those antibodies block checkpoints, which act as breaks to prevent the attack of cancer cells by T lymphocytes. However, a large proportion of patients do not respond to such immunotherapies and/or develop severe side effects, some of which can be treated by potent anti-inflammatory drugs, such as the anti-TNF[alpha].
In this context, a preclinical study carried out by researchers from the Cancer Research Center of Toulouse (CRCT) (UMR 1037 Inserm / CNRS / Université Toulouse III – Paul Sabatier) under the supervision of Prof. Bruno Ségui, shows that blockade of TNF or its receptor, TNFR1, enhances response to anti-PD-1 in melanoma, lung and breast cancer models.
This work, based on tight collaborations with the departments of Pathology and Biostatistics of the Cancer University Institute from the Toulouse-Oncopole (IUCT-O), leads to (i) a publication in Nature Communications (ii) an international patent and (iii) two clinical trials (TICIMEL et MELANF[alpha]) in advanced melanoma patients at the IUCT-O in 2018 (PI Nicolas Meyer, CHU Toulouse).
Whereas the administration of anti-PD-1 or anti-TNF[alpha] alone reduces tumor growth in preclinical models, most of the tumors relapse. Interestingly, the combination of both therapies triggers melanoma regression associated with a strong increase in the infiltration of the tumor by anti-cancer immune cells such as CD8+ T lymphocytes. Moreover, this combination therapy induces long-term vaccination against melanoma.
The pro-tumoral effect of TNF[alpha] is due to the ability of TNF[alpha] to trigger the death of activated T lymphocytes in the tumor. Moreover, anti-PD-1 alone induces a strong production of TNF in the tumor microenvironment, leading to an increased expression of secondary immune checkpoints (i.e., TIM-3). This impairs the activity of immune cells and confers resistance to immunotherapies. Thus, TNF blockade has a dual stimulating effect on immune cells and acts in synergy with the anti-PD-1 therapy against cancer.
This preclinical study constitutes a strong scientific rationale to use anti-TNF[alpha] in combination with immunotherapies in patients affected with advanced melanoma or other type of solid cancers such as lung or breast cancers. This project demonstrates the interest of the Toulouse Oncopole structure, allowing a rapid transfer from fundamental data produced at the CRCT to the clinic at the IUCT.
TNF[alpha] blockade overcomes resistance to anti-PD-1 in experimental melanoma
Florie Bertrand1,2, Anne Montfort1,2, Elie Marcheteau1,2,3,4, Caroline Imbert1,2,3,4, Julia Gilhodes5, Thomas Filleron5, Philippe Rochaix5, Nathalie Andrieu-Abadie1,2, Thierry Levade1,2,3,4,6, Nicolas Meyer1,3,4,7, Céline Colacios1,2,3,4 and Bruno Ségui1,2,3,4
1INSERM UMR 1037, CRCT, 31037 Toulouse, France. 2Equipe Labellisée Ligue Contre Le Cancer, 31037 Toulouse, France. 3Université Toulouse III – Paul Sabatier, 31062 Toulouse, France. 4Université Fédérale de Toulouse Midi-Pyrénées, France. 5Institut Universitaire du Cancer, 31059 Toulouse, France. 6Laboratoire de Biochimie, Institut Fédératif de Biologie, CHU Purpan, Toulouse, France. 7Institut Universitaire du Cancer, Toulouse, Hôpital Larrey et Oncopôle, 31059 Toulouse, France.
Nat. Commun. 2017 Dec 22;8(1):2256. doi: 10.1038/s41467-017-02358-7.
International Patent filed by Inserm-transfert (on Jan. 28, 2016):
Methods and pharmaceutical composition for the treatment of cancer (WO 2017129790 A1)
Co-inventors: Florie Bertrand, Céline Colacios, Nicolas Meyer, Nathalie Andrieu-Abadie, Thierry Levade and Bruno Ségui