Blocking TNF to Potentiate the ICI-dependent Immune Awakening in Melanoma
Trial statusRecruiting
Trial phaseNot listed
Trial typeObservational
Biological sexAll
Age18+
SponsorInstitut Claudius Regaud
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Inclusion in TICIMEL clinical trial (NCT03293784),
Inclusion in MELANFα trial (NCT03348891)
Disqualifiers
NA
Trial population
Patients with melanoma included in TICIMEL and MELANFalpha trials.
Trial design
Design model
Cohort
Time perspective
Retrospective
Treatments tested in this trial
Not listed
Trial groups
No trial groups listed
Trial outcomes
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.
Time frame
36 monthsSecondary outcomes
1
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.
Time frame
36 months2
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.
Time frame
36 monthsSponsors and contacts
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Institut Claudius Regaud
Lead sponsor
Institut National de la Santé Et de la Recherche Médicale, France
Collaborator
Source ClinicalTrials.gov