Clinical trial · Observational
Blocking TNF to Potentiate the ICI-dependent Immune Awakening in Melanoma
- Source
- ClinicalTrials.gov
- Retrieved
- Sep 8, 2026
- Layer
- normalized (units and labels harmonized; values unchanged)
- Run
- ING-CLINICALTRIALS-20260908-000001
Summary
Brief summary (as posted)
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
Conditions (3)
Free-text conditions as registered, with the CancerIndex entity they were reconciled to and the match type.
| Condition (as posted) | Mapped entity | Match | Confidence |
|---|---|---|---|
| Immune Defect | — | UNRESOLVED | — |
| Melanoma | Melanoma | ONTOLOGY_EXACT | 0.98 |
| Tumor Skin | Skin Neoplasm | PROBABILISTIC | 0.70 |
Interventions
Interventions (0)
Data not yet available
Design
Arms and outcomes
Arms (0)
[]Primary outcomes (1)
- measure
- To decipher how certolizumab and infliximab influence the ICI-dependent systemic immune responses in advanced melanoma patients
- timeFrame
- 36 months
- description
- 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.
Secondary outcomes (2)
- measure
- To analyse the impact TNFi have on ICI-dependent anti-melanoma immune responses in tumors in advanced melanoma patients
- timeFrame
- 36 months
- description
- To evaluate the tumor-infiltrating leukocytes before and along therapy (CD3, CD8, CD4, FOXP3, CD68), immunohistochemistry (IHC) on tumor samples on biopsies from patients enrolled in the second part of TICIMEL and on FFPE biopsies from MELANFalpha patients will be realised. To further characterize immune responses in tumors from patients enrolled in TICIMEL and MELANFalpha, RNAseq analyses on RNA extracted from pre-treatment and, when possible, matched post-treatment FFPE tumor biopsies will be performed. Differential immune signatures according to treatment and response will be assessed. To combine all biological and clinical data from patients by biostatistical and bioinformatic analyses. Flow cytometry, CiteSeq scRNAseq data obtained on circulating immune cells as well as IHC and RNAseq data from tumor biopsies will be combined to clinical data using machine learning methods.
Eligibility
Eligibility (as posted)
- Sex
- All
- Minimum age
- 18 Years
Show eligibility criteria text
Inclusion Criteria: * Inclusion in TICIMEL clinical trial (NCT03293784), * Inclusion in MELANFα trial (NCT03348891) Exclusion Criteria: * NA
References
Publications (18)
- BACKGROUNDLarkin 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
- BACKGROUNDBrahmer 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
- BACKGROUNDChen 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
- BACKGROUNDMontfort 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
- BACKGROUNDCarswell 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
- BACKGROUNDBalkwill 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
- BACKGROUNDMontfort 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.