Trial Title:
Blocking TNF to Potentiate the ICI-dependent Immune Awakening in Melanoma
NCT ID:
NCT05867004
Condition:
Melanoma
Immune Defect
Tumor Skin
Conditions: Official terms:
Melanoma
Conditions: Keywords:
Melanoma
Immune checkpoint inhibitors
TNF
Resistance
Study type:
Observational
Overall status:
Recruiting
Study design:
Time perspective:
Retrospective
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.
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 IIIc/IV) 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 (i.e., 92) have been enrolled between 2018
and 2021. TICIMEL (n=32) 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 (n=60) is a
pilot study aiming at discovering predictive biomarkers of response/resistance to ICI. It
notably shows high TNF levels are detected upon ipi/nivo 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 ipi/nivo one. Accordingly, the investigators observed increased IFN-gamma
plasma concentrations in the certolizumab cohort. Proportions of Th2, Th17 and Th1/17 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 central/effector 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 ipi/nivo. Moreover, the investigators show
in a mouse melanoma model (B16Ova) whereby treatment conditions mimic that of TICIMEL and
MELANFalpha (alphaPD-1+alphaCTLA-4+/- TNFi [anti-mouse TNF, clone XT3.11]), 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 objective(s) and endpoint(s) 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 (ipi+nivo+certo or inflix) and MELANFalpha (ipi+nivo,
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.
Criteria for eligibility:
Study pop:
Patients with melanoma included in TICIMEL and MELANFalpha trials.
Sampling method:
Non-Probability Sample
Criteria:
Inclusion Criteria:
- Inclusion in TICIMEL clinical trial (NCT03293784),
- Inclusion in MELANFα trial (NCT03348891)
Exclusion Criteria:
- NA
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Institut Claudius Regaud
Address:
City:
Toulouse
Zip:
31059
Country:
France
Status:
Recruiting
Contact:
Last name:
Bruno SEGUI, Pr
Phone:
+33 (0)5 82 74 16 21
Email:
bruno.segui@inserm.fr
Start date:
January 1, 2023
Completion date:
December 31, 2026
Lead sponsor:
Agency:
Institut Claudius Regaud
Agency class:
Other
Collaborator:
Agency:
Institut National de la Santé Et de la Recherche Médicale, France
Agency class:
Other
Source:
Institut Claudius Regaud
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05867004
