Ignite Creation Date:
2024-05-06 @ 7:01 PM
Last Modification Date:
2024-10-26 @ 2:59 PM
Study NCT ID:
NCT05867004
Status:
RECRUITING
Last Update Posted:
2023-05-26
First Post:
2023-04-28
Brief Title:
Blocking TNF to Potentiate the ICI-dependent Immune Awakening in Melanoma
Sponsor:
Institut Claudius Regaud
Organization:
Institut Claudius Regaud
Study Overview
Official Title:
Blocking TNF to Potentiate the ICI-dependent Immune Awakening in Melanoma
Status:
RECRUITING
Status Verified Date:
2023-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ATPIC
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 ipinivo 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
Detailed Description:
Background and originality of the project with regards to the state of the art
Despite the tremendous breakthrough immune checkpoint inhibitors ICI such as anti-PD-1 and anti-CTLA-4 brought for the treatment of advanced melanoma patients 60 of them do not respond or relapse within 5 years following treatment initiation Severe immune-related adverse events irAEs are triggered upon ICI therapy such as colitis which can be treated with inhibitors TNFi of the Tumor Necrosis Factor alpha TNF such as infliximab The pharmacodynamic impact of TNFi on the immune and clinical responses remains to be clarified
Although TNF has been identified as a soluble factor able to trigger tumor necrosis in mice the chronic production of TNF in the tumor microenvironment was shown to contribute to cancer progression The investigators and others have shown this cancer promoting property relies on multiple mechanisms including immune escape For instance the investigators showed that TNF triggers activation-induced cell death AICD in CD8 T cells thereby limiting the infiltration of CD8 T cells in mouse melanoma tumors In mouse models of melanoma breast and colon cancers TNFi enhance ICI anti-PD-1 anti-CTLA-4 efficacy and reduce the severity of irAEs such as colitis Hence combining TNF-blocking antibodies to ICI promotes therapy efficacy and tolerance in vivo
Investigators unpublished data show all treatments promoted the differentiation of circulating T cells towards an effector memory phenotype data not shown between baseline before treatment induction week 0 W0 and week 6 W6 post-treatment induction They also significantly 1- Background and originality of the project with regards to the state of the art Despite the tremendous breakthrough immune checkpoint inhibitors ICI such as anti-PD-1 and anti-CTLA-4 brought for the treatment of advanced melanoma patients 60 of them do not respond or relapse within 5 years following treatment initiation Severe immune-related adverse events irAEs are triggered upon ICI therapy such as colitis which can be treated with inhibitors TNFi of the Tumor Necrosis Factor alpha TNF such as infliximab The pharmacodynamic impact of TNFi on the immune and clinical responses remains to be clarified Although TNF has been identified as a soluble factor able to trigger tumor necrosis in mice the chronic production of TNF in the tumor microenvironment was shown to contribute to cancer progression The investigatorsand others have shown this cancer promoting property relies on multiple mechanisms including immune escape For instance the investigators showed that TNF triggers activation-induced cell death AICD in CD8 T cells thereby limiting the infiltration of CD8 T cells in mouse melanoma tumors In mouse models of melanoma breast and colon cancers TNFi enhance ICI anti-PD-1 anti-CTLA-4 efficacy and reduce the severity of irAEs such as colitis Hence combining TNF-blocking antibodies to ICI promotes therapy efficacy and tolerance in vivo Based on preclinical studies the investigators implemented two clinical trials TICIMEL and MELANFalpha in advanced melanoma patients stage IIIcIV treated with ICI anti-PD-1 nivolumab nivo anti-CTLA-4 ipilimumab ipi in combination TICIMEL or not MELANFalpha with TNFi certolizumab certo or infliximab inflix Whereas inflix is a bivalent anti-TNF chimeric IgG1 monoclonal antibody certo is a monovalent PEGylated Fab fragment of a humanized anti-TNF monoclonal All patients ie 92 have been enrolled between 2018 and 2021 TICIMEL n32 is a phase 1b clinical trial aiming at evaluating the safety and tolerability of co-administering ipi nivo and TNFi certo or inflix Investigators first data obtained from 14 patients indicate that both tritherapies are safe in humans with a promising high response rate in the certo cohort MELANFalpha n60 is a pilot study aiming at discovering predictive biomarkers of responseresistance to ICI It notably shows high TNF levels are detected upon ipinivo treatment in plasmas from non-responders Investigators unpublished data show all treatments promoted the differentiation of circulating T cells towards an effector memory phenotype between baseline before treatment induction week 0 W0 and week 6 W6 post-treatment induction They also significantly increased the proportion of Th1 T cells in patients blood However those effects were significantly amplified in the certolizumab cohort as compared to the ipinivo one Accordingly the investigators observed increased IFN-gamma plasma concentrations in the certolizumab cohort Proportions of Th2 Th17 and Th117 T cells were not significantly affected by the three treatment regimens Moreover TNFi combination with ICI was associated with increased proportions of circulating MART-1-specific CD8 T cells These cells mainly exhibited a centraleffector memory phenotype and show increased expression of CXCR3 Fig 1D-F The investigators performed CiteSeq single cell RNA sequencing scRNAseq on peripheral blood mononuclear cells PBMCs obtained before W0 and at W6 from 4 advanced melanoma patients enrolled in each of the 3 cohorts Signs of activation and maturation of immune responses were obvious in all patients from TICIMEL but one at W6 This indicates TNFi unlikely compromise the immune boost observed in patients treated with ipinivo Moreover the investigators show in a mouse melanoma model B16Ova whereby treatment conditions mimic that of TICIMEL and MELANFalpha alphaPD-1alphaCTLA-4- TNFi anti-mouse TNF clone XT311 that the tritherapy increased the frequency of total tumor regressions and overall survival as compared to the bitherapy Mice cured upon tritherapy developed anti-melanoma memory responses as evidenced by a rechallenge experiment Understanding how TNF blockade increases the awakening of patients anti-melanoma immune responses upon ICI and how the properties of TNFi may differentially modulate these responses is pivotal to
i get a better understanding of the cellular and molecular pathways which need to be engaged to overcome some of the mechanisms responsible for ICI resistance
ii identify new and potentially better strategies to promote these responses
iii identify patients who might benefit the most from such therapies
Hypothesis main objectives and endpoints of the project
Considering investigators recently published and unpublished data the investigators hypothesize that TNF blockade may promote ICI efficacy in patients This effect may however be affected by the structural properties of the TNF blocking agent used To evaluate this hypothesis the investigators will compare the clinicobiological responses of patients from the TICIMEL ipinivocerto or inflix and MELANFalpha ipinivo without TNFi clinical trials To clarify the molecular mechanisms by which certo and inflix differently impact on immune responses the investigators will perform ex vivo and in vivo experiments in co-culture systems as well as in a unique mouse melanoma model respectively
Project plan describing the methodology and work to be performed To reach the primary and secondary objectives the proposal is divided into three main WPs
WP1 To decipher how certolizumab and infliximab influence the ICI-dependent systemic immune responses in advanced melanoma patients
WP2 To analyse the impact TNFi have on ICI-dependent anti-melanoma immune responses in tumors in advanced melanoma patients The investigators already performed immunohistochemistry IHC on formalin-fixed paraffin-embedded FFPE melanoma biopsies from patients enrolled in the first part of TICIMEL to evaluate the tumor-infiltrating leukocytes before and along therapy CD3 CD8 CD4 FOXP3 CD68
WP3 To analyse the impact TNFi have on ICI-dependent anti-melanoma immune responses in co-culture experiments and in mice
Despite the tremendous breakthrough immune checkpoint inhibitors ICI such as anti-PD-1 and anti-CTLA-4 brought for the treatment of advanced melanoma patients 60 of them do not respond or relapse within 5 years following treatment initiation Severe immune-related adverse events irAEs are triggered upon ICI therapy such as colitis which can be treated with inhibitors TNFi of the Tumor Necrosis Factor alpha TNF such as infliximab The pharmacodynamic impact of TNFi on the immune and clinical responses remains to be clarified
Although TNF has been identified as a soluble factor able to trigger tumor necrosis in mice the chronic production of TNF in the tumor microenvironment was shown to contribute to cancer progression The investigators and others have shown this cancer promoting property relies on multiple mechanisms including immune escape For instance the investigators showed that TNF triggers activation-induced cell death AICD in CD8 T cells thereby limiting the infiltration of CD8 T cells in mouse melanoma tumors In mouse models of melanoma breast and colon cancers TNFi enhance ICI anti-PD-1 anti-CTLA-4 efficacy and reduce the severity of irAEs such as colitis Hence combining TNF-blocking antibodies to ICI promotes therapy efficacy and tolerance in vivo
Investigators unpublished data show all treatments promoted the differentiation of circulating T cells towards an effector memory phenotype data not shown between baseline before treatment induction week 0 W0 and week 6 W6 post-treatment induction They also significantly 1- Background and originality of the project with regards to the state of the art Despite the tremendous breakthrough immune checkpoint inhibitors ICI such as anti-PD-1 and anti-CTLA-4 brought for the treatment of advanced melanoma patients 60 of them do not respond or relapse within 5 years following treatment initiation Severe immune-related adverse events irAEs are triggered upon ICI therapy such as colitis which can be treated with inhibitors TNFi of the Tumor Necrosis Factor alpha TNF such as infliximab The pharmacodynamic impact of TNFi on the immune and clinical responses remains to be clarified Although TNF has been identified as a soluble factor able to trigger tumor necrosis in mice the chronic production of TNF in the tumor microenvironment was shown to contribute to cancer progression The investigatorsand others have shown this cancer promoting property relies on multiple mechanisms including immune escape For instance the investigators showed that TNF triggers activation-induced cell death AICD in CD8 T cells thereby limiting the infiltration of CD8 T cells in mouse melanoma tumors In mouse models of melanoma breast and colon cancers TNFi enhance ICI anti-PD-1 anti-CTLA-4 efficacy and reduce the severity of irAEs such as colitis Hence combining TNF-blocking antibodies to ICI promotes therapy efficacy and tolerance in vivo Based on preclinical studies the investigators implemented two clinical trials TICIMEL and MELANFalpha in advanced melanoma patients stage IIIcIV treated with ICI anti-PD-1 nivolumab nivo anti-CTLA-4 ipilimumab ipi in combination TICIMEL or not MELANFalpha with TNFi certolizumab certo or infliximab inflix Whereas inflix is a bivalent anti-TNF chimeric IgG1 monoclonal antibody certo is a monovalent PEGylated Fab fragment of a humanized anti-TNF monoclonal All patients ie 92 have been enrolled between 2018 and 2021 TICIMEL n32 is a phase 1b clinical trial aiming at evaluating the safety and tolerability of co-administering ipi nivo and TNFi certo or inflix Investigators first data obtained from 14 patients indicate that both tritherapies are safe in humans with a promising high response rate in the certo cohort MELANFalpha n60 is a pilot study aiming at discovering predictive biomarkers of responseresistance to ICI It notably shows high TNF levels are detected upon ipinivo treatment in plasmas from non-responders Investigators unpublished data show all treatments promoted the differentiation of circulating T cells towards an effector memory phenotype between baseline before treatment induction week 0 W0 and week 6 W6 post-treatment induction They also significantly increased the proportion of Th1 T cells in patients blood However those effects were significantly amplified in the certolizumab cohort as compared to the ipinivo one Accordingly the investigators observed increased IFN-gamma plasma concentrations in the certolizumab cohort Proportions of Th2 Th17 and Th117 T cells were not significantly affected by the three treatment regimens Moreover TNFi combination with ICI was associated with increased proportions of circulating MART-1-specific CD8 T cells These cells mainly exhibited a centraleffector memory phenotype and show increased expression of CXCR3 Fig 1D-F The investigators performed CiteSeq single cell RNA sequencing scRNAseq on peripheral blood mononuclear cells PBMCs obtained before W0 and at W6 from 4 advanced melanoma patients enrolled in each of the 3 cohorts Signs of activation and maturation of immune responses were obvious in all patients from TICIMEL but one at W6 This indicates TNFi unlikely compromise the immune boost observed in patients treated with ipinivo Moreover the investigators show in a mouse melanoma model B16Ova whereby treatment conditions mimic that of TICIMEL and MELANFalpha alphaPD-1alphaCTLA-4- TNFi anti-mouse TNF clone XT311 that the tritherapy increased the frequency of total tumor regressions and overall survival as compared to the bitherapy Mice cured upon tritherapy developed anti-melanoma memory responses as evidenced by a rechallenge experiment Understanding how TNF blockade increases the awakening of patients anti-melanoma immune responses upon ICI and how the properties of TNFi may differentially modulate these responses is pivotal to
i get a better understanding of the cellular and molecular pathways which need to be engaged to overcome some of the mechanisms responsible for ICI resistance
ii identify new and potentially better strategies to promote these responses
iii identify patients who might benefit the most from such therapies
Hypothesis main objectives and endpoints of the project
Considering investigators recently published and unpublished data the investigators hypothesize that TNF blockade may promote ICI efficacy in patients This effect may however be affected by the structural properties of the TNF blocking agent used To evaluate this hypothesis the investigators will compare the clinicobiological responses of patients from the TICIMEL ipinivocerto or inflix and MELANFalpha ipinivo without TNFi clinical trials To clarify the molecular mechanisms by which certo and inflix differently impact on immune responses the investigators will perform ex vivo and in vivo experiments in co-culture systems as well as in a unique mouse melanoma model respectively
Project plan describing the methodology and work to be performed To reach the primary and secondary objectives the proposal is divided into three main WPs
WP1 To decipher how certolizumab and infliximab influence the ICI-dependent systemic immune responses in advanced melanoma patients
WP2 To analyse the impact TNFi have on ICI-dependent anti-melanoma immune responses in tumors in advanced melanoma patients The investigators already performed immunohistochemistry IHC on formalin-fixed paraffin-embedded FFPE melanoma biopsies from patients enrolled in the first part of TICIMEL to evaluate the tumor-infiltrating leukocytes before and along therapy CD3 CD8 CD4 FOXP3 CD68
WP3 To analyse the impact TNFi have on ICI-dependent anti-melanoma immune responses in co-culture experiments and in mice
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None