Blocking TNF to Potentiate the ICI-dependent Immune Awakening in Melanoma

NCT05867004 | Recruiting

• 1 other identifier: 23RT01
• Study Type: observational
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

Cutaneous melanoma is a bad prognosis skin cancer, which can be treated with immune checkpoint inhibitors (ICI), such as anti-PD-1 (nivolumab, nivo) and anti-CTLA-4 (ipilimumab, ipi). However, about 50% of patients do not respond or relapse within 3 years post therapy induction, and immune-related adverse events (irAEs), such as colitis, are triggered and can be treated with TNF inhibitor (TNFi; ie, infliximab, inflix). The pharmacodynamic impact of TNFi on the immune and clinical responses remain to be clarified. The investigators previously demonstrated that TNFi enhance the efficacy of ICI in mouse melanoma models. Based on preclinical findings, the investigators implemented two clinical trials in advanced melanoma patients, TICIMEL and MELANFalpha. In TICIMEL, patients are concomitantly treated with TNFi \[certolizumab (certo) or inflix\] and ICI (ipi+nivo). In MELANFalpha, patients are treated with ICI alone. Preliminary results show both tritherapies promote systemic MART-1 specific CD8 T cell responses and that certo but not inflix may improve ICI efficacy and Th1 responses. In mouse melanoma models, TNFi enhance the response to ICI. Investigators' primary objective is to decipher how certolizumab and infliximab influence ICI-dependent anti-tumor immune responses in advanced melanoma patients. The secondary objectives are to analyse the cellular and molecular impact anti-TNF have on ICI-dependent anti-melanoma immune responses and clinical activities (irAEs and efficacy). By combining mouse and human data as well ex vivo functional assays, the investigators will dissect the impact treatments have on anti-melanoma immune responses by flow cytometry and transcriptomic analyses. The investigators expect to clarify (i) the mechanisms by which TNFi enhance ICI efficacy, (ii) identify the best TNFi to be combined with ICI in advanced melanoma patients and (iii) discover TNF-dependent biomarkers of resistance.

Conditions

Melanoma; Immune Defect; Tumor Skin

Keywords

Melanoma; Immune checkpoint inhibitors; TNF; Resistance

Outcome Measures

Primary Outcomes (1)

• To decipher how certolizumab and infliximab influence the ICI-dependent systemic immune responses in advanced melanoma patients

  In patients from the MELANFalpha trial as well as in patients from the second phase of TICIMEL, influence of the different therapies on the capacity of circulating CD4 and CD8 T cells to produce IFNgamma, TNF and IL-17 ex vivo will be counted by flow cytometry in PBMCs. In patients enrolled in the second part of TICIMEL and in the ipi/nivo cohort of MELANFalpha, the evaluation of poucentage of HLA-A2 positive melanoma patients displaying circulating CD8 T cells reactive towards the tyrosinase and/or MART-1 antigens will be evaluate after staining. CiteSeq scRNAseq on PBMCs from patients from the 3 cohorts, including two non-responders of the ipi/nivo/certo cohort will be realise. PBMC's RNA obtained at W0 and W6 will be compared.

  36 months

Secondary Outcomes (2)

• To analyse the impact TNFi have on ICI-dependent anti-melanoma immune responses in tumors in advanced melanoma patients

  36 months

• To analyse the impact TNFi have on ICI-dependent anti-melanoma immune responses in co-culture experiments and in mice

  36 months

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients with melanoma included in TICIMEL and MELANFalpha trials.

Sponsors & Collaborators

• Institut Claudius Regaud: lead
• Institut National de la Santé Et de la Recherche Médicale, France: collaborator

Study Sites (1)

Institut Claudius Regaud

Toulouse, 31059, France

RECRUITING

Related Publications (18)

• Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Marquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schoffski P, Carlino MS, Lebbe C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. doi: 10.1056/NEJMoa1910836. Epub 2019 Sep 28.

  PMID: 31562797 BACKGROUND

• Brahmer JR, Lacchetti C, Thompson JA. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline Summary. J Oncol Pract. 2018 Apr;14(4):247-249. doi: 10.1200/JOP.18.00005. Epub 2018 Mar 8. No abstract available.

  PMID: 29517954 BACKGROUND

• Chen AY, Wolchok JD, Bass AR. TNF in the era of immune checkpoint inhibitors: friend or foe? Nat Rev Rheumatol. 2021 Apr;17(4):213-223. doi: 10.1038/s41584-021-00584-4. Epub 2021 Mar 8.

  PMID: 33686279 BACKGROUND

• Montfort A, Virazels M, Colacios C, Meyer N, Segui B. Combining TNF blockade with immune checkpoint inhibitors in patients with cancer. Nat Rev Rheumatol. 2021 Sep;17(9):577. doi: 10.1038/s41584-021-00653-8. No abstract available.

  PMID: 34226729 BACKGROUND

• Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3666-70. doi: 10.1073/pnas.72.9.3666.

  PMID: 1103152 BACKGROUND

• Balkwill F. Tumour necrosis factor and cancer. Nat Rev Cancer. 2009 May;9(5):361-71. doi: 10.1038/nrc2628. Epub 2009 Apr 3.

  PMID: 19343034 BACKGROUND

• Montfort A, Colacios C, Levade T, Andrieu-Abadie N, Meyer N, Segui B. Corrigendum: The TNF Paradox in Cancer Progression and Immunotherapy. Front Immunol. 2019 Oct 22;10:2515. doi: 10.3389/fimmu.2019.02515. eCollection 2019.

  PMID: 31695705 BACKGROUND

• Bertrand F, Rochotte J, Colacios C, Montfort A, Tilkin-Mariame AF, Touriol C, Rochaix P, Lajoie-Mazenc I, Andrieu-Abadie N, Levade T, Benoist H, Segui B. Blocking Tumor Necrosis Factor alpha Enhances CD8 T-cell-Dependent Immunity in Experimental Melanoma. Cancer Res. 2015 Jul 1;75(13):2619-28. doi: 10.1158/0008-5472.CAN-14-2524. Epub 2015 May 14.

  PMID: 25977337 BACKGROUND

• Bertrand F, Montfort A, Marcheteau E, Imbert C, Gilhodes J, Filleron T, Rochaix P, Andrieu-Abadie N, Levade T, Meyer N, Colacios C, Segui B. TNFalpha blockade overcomes resistance to anti-PD-1 in experimental melanoma. Nat Commun. 2017 Dec 22;8(1):2256. doi: 10.1038/s41467-017-02358-7.

  PMID: 29273790 BACKGROUND

• Perez-Ruiz E, Minute L, Otano I, Alvarez M, Ochoa MC, Belsue V, de Andrea C, Rodriguez-Ruiz ME, Perez-Gracia JL, Marquez-Rodas I, Llacer C, Alvarez M, de Luque V, Molina C, Teijeira A, Berraondo P, Melero I. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy. Nature. 2019 May;569(7756):428-432. doi: 10.1038/s41586-019-1162-y. Epub 2019 May 1.

  PMID: 31043740 BACKGROUND

• Montfort A, Dufau C, Colacios C, Andrieu-Abadie N, Levade T, Filleron T, Delord JP, Ayyoub M, Meyer N, Segui B. Anti-TNF, a magic bullet in cancer immunotherapy? J Immunother Cancer. 2019 Nov 14;7(1):303. doi: 10.1186/s40425-019-0802-y.

  PMID: 31727152 BACKGROUND

• Montfort A, Filleron T, Virazels M, Dufau C, Milhes J, Pages C, Olivier P, Ayyoub M, Mounier M, Lusque A, Brayer S, Delord JP, Andrieu-Abadie N, Levade T, Colacios C, Segui B, Meyer N. Combining Nivolumab and Ipilimumab with Infliximab or Certolizumab in Patients with Advanced Melanoma: First Results of a Phase Ib Clinical Trial. Clin Cancer Res. 2021 Feb 15;27(4):1037-1047. doi: 10.1158/1078-0432.CCR-20-3449. Epub 2020 Dec 3.

  PMID: 33272982 BACKGROUND

• Balanca CC, Salvioni A, Scarlata CM, Michelas M, Martinez-Gomez C, Gomez-Roca C, Sarradin V, Tosolini M, Valle C, Pont F, Ferron G, Gladieff L, Vergez S, Dupret-Bories A, Mery E, Rochaix P, Fournie JJ, Delord JP, Devaud C, Martinez A, Ayyoub M. PD-1 blockade restores helper activity of tumor-infiltrating, exhausted PD-1hiCD39+ CD4 T cells. JCI Insight. 2021 Jan 25;6(2):e142513. doi: 10.1172/jci.insight.142513.

  PMID: 33332284 BACKGROUND

• Atretkhany KN, Mufazalov IA, Dunst J, Kuchmiy A, Gogoleva VS, Andruszewski D, Drutskaya MS, Faustman DL, Schwabenland M, Prinz M, Kruglov AA, Waisman A, Nedospasov SA. Intrinsic TNFR2 signaling in T regulatory cells provides protection in CNS autoimmunity. Proc Natl Acad Sci U S A. 2018 Dec 18;115(51):13051-13056. doi: 10.1073/pnas.1807499115. Epub 2018 Nov 29.

  PMID: 30498033 BACKGROUND

• Imbert C, Montfort A, Fraisse M, Marcheteau E, Gilhodes J, Martin E, Bertrand F, Marcellin M, Burlet-Schiltz O, Peredo AG, Garcia V, Carpentier S, Tartare-Deckert S, Brousset P, Rochaix P, Puisset F, Filleron T, Meyer N, Lamant L, Levade T, Segui B, Andrieu-Abadie N, Colacios C. Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1. Nat Commun. 2020 Jan 23;11(1):437. doi: 10.1038/s41467-019-14218-7.

  PMID: 31974367 BACKGROUND

• Garandeau D, Noujarede J, Leclerc J, Imbert C, Garcia V, Bats ML, Rambow F, Gilhodes J, Filleron T, Meyer N, Brayer S, Arcucci S, Tartare-Deckert S, Segui B, Marine JC, Levade T, Bertolotto C, Andrieu-Abadie N. Targeting the Sphingosine 1-Phosphate Axis Exerts Potent Antitumor Activity in BRAFi-Resistant Melanomas. Mol Cancer Ther. 2019 Feb;18(2):289-300. doi: 10.1158/1535-7163.MCT-17-1141. Epub 2018 Nov 27.

  PMID: 30482853 BACKGROUND

• Montfort A, Bertrand F, Rochotte J, Gilhodes J, Filleron T, Milhes J, Dufau C, Imbert C, Riond J, Tosolini M, Clarke CJ, Dufour F, Constantinescu AA, Junior NF, Garcia V, Record M, Cordelier P, Brousset P, Rochaix P, Silvente-Poirot S, Therville N, Andrieu-Abadie N, Levade T, Hannun YA, Benoist H, Meyer N, Micheau O, Colacios C, Segui B. Neutral Sphingomyelinase 2 Heightens Anti-Melanoma Immune Responses and Anti-PD-1 Therapy Efficacy. Cancer Immunol Res. 2021 May;9(5):568-582. doi: 10.1158/2326-6066.CIR-20-0342. Epub 2021 Mar 16.

  PMID: 33727246 BACKGROUND

• Bilal F, Montfort A, Gilhodes J, Garcia V, Riond J, Carpentier S, Filleron T, Colacios C, Levade T, Daher A, Meyer N, Andrieu-Abadie N, Segui B. Sphingomyelin Synthase 1 (SMS1) Downregulation Is Associated With Sphingolipid Reprogramming and a Worse Prognosis in Melanoma. Front Pharmacol. 2019 Apr 30;10:443. doi: 10.3389/fphar.2019.00443. eCollection 2019.

  PMID: 31114500 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Blood and tumor biopsies

MeSH Terms

Conditions

Melanoma; Skin Neoplasms

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Bruno SEGUI, Pr

  Cancer Research Center of Toulouse

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Bruno SEGUI, Pr

CONTACT

+33 (0)5 82 74 16 21; bruno.segui@inserm.fr

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 28, 2023
• First Posted: May 19, 2023
• Study Start: January 1, 2023
• Primary Completion: July 3, 2025
• Study Completion (Estimated): December 31, 2026
• Last Updated: May 29, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)