Melanoma Clinical Trial
— ATPICOfficial title:
Blocking TNF to Potentiate the ICI-dependent Immune Awakening in Melanoma
NCT number | NCT05867004 |
Other study ID # | 23RT01 |
Secondary ID | |
Status | Recruiting |
Phase | |
First received | |
Last updated | |
Start date | January 1, 2023 |
Est. completion date | December 31, 2026 |
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.
Status | Recruiting |
Enrollment | 100 |
Est. completion date | December 31, 2026 |
Est. primary completion date | November 30, 2023 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | Inclusion Criteria: - Inclusion in TICIMEL clinical trial (NCT03293784), - Inclusion in MELANFa trial (NCT03348891) Exclusion Criteria: - NA |
Country | Name | City | State |
---|---|---|---|
France | Institut Claudius Regaud | Toulouse |
Lead Sponsor | Collaborator |
---|---|
Institut Claudius Regaud | Institut National de la Santé Et de la Recherche Médicale, France |
France,
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. — View Citation
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. — View Citation
Balkwill F. Tumour necrosis factor and cancer. Nat Rev Cancer. 2009 May;9(5):361-71. doi: 10.1038/nrc2628. Epub 2009 Apr 3. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
* Note: There are 18 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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 | To analyse the impact TNFi have on ICI-dependent anti-melanoma immune responses in tumors in advanced melanoma patients | 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. |
36 months | |
Secondary | To analyse the impact TNFi have on ICI-dependent anti-melanoma immune responses in co-culture experiments and in mice | The baseline PBMCs proliferation and the production of IFNgamma will be measured in presence of autologous CD14+ monocytes and antigenic peptides from tyrosinase or MART-1. IFNgamma plasma concentration is determined by mesoscale (pg/mL). Proliferation is measured by flow cytometry. | 36 months |
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