Efficacy of nivolumab and ipilimumab in patients with malignant pleural mesothelioma is related to a subtype of effector memory cytotoxic T cells: Translational evidence from two clinical trials.
Aged
Antineoplastic Combined Chemotherapy Protocols
/ adverse effects
CTLA-4 Antigen
/ antagonists & inhibitors
Clinical Trials as Topic
Female
Humans
Immune Checkpoint Inhibitors
/ administration & dosage
Immune Checkpoint Proteins
/ metabolism
Immunologic Memory
/ drug effects
Ipilimumab
/ administration & dosage
Male
Mesothelioma, Malignant
/ drug therapy
Middle Aged
Molecular Targeted Therapy
/ adverse effects
Nivolumab
/ administration & dosage
Prognosis
Programmed Cell Death 1 Receptor
/ antagonists & inhibitors
T-Lymphocyte Subsets
T-Lymphocytes, Cytotoxic
/ drug effects
Translational Research, Biomedical
Treatment Outcome
Immune checkpoint inhibitors
Immune monitoring
Immunotherapy
Ipilimumab
Malignant pleural mesothelioma
Nivolumab
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Dec 2020
Dec 2020
Historique:
received:
23
07
2020
revised:
14
09
2020
accepted:
15
09
2020
pubmed:
10
11
2020
medline:
25
8
2021
entrez:
9
11
2020
Statut:
ppublish
Résumé
Combined immune checkpoint inhibitor (ICI) treatment targeting PD-1 and CTLA-4 was suggested to yield clinical benefit over chemotherapy in malignant pleural mesothelioma (MPM), whereas aPD-1 monotherapy failed to provide benefit in phase-III trials. Success of ICI depends on the presence and activation of tumor-specific T cells. Therefore, we investigated whether T-cell characteristics are underlying clinical efficacy of ICI treatment in MPM. Comprehensive immune cell profiling was performed on screening and on treatment peripheral blood samples of mesothelioma patients treated with nivolumab (aPD-1) monotherapy (NCT02497508), or a combination of nivolumab and ipilimumab (aCTLA-4) (NCT03048474). aPD-1/aCTLA-4 combination treatment induced a profound increase in proliferation and activation of T cells, which was not observed upon aPD-1 monotherapy. Moreover, patients that responded to combination treatment had low frequencies of naive CD8 T cells and high frequencies of effector memory CD8 T cells that re-expressed RA (TEMRA) at screening. The frequency of Granzyme-B and Interferon-γ producing TEMRAs was also higher in responding patients. High proportions of TEMRAs and cytokine production by TEMRAs before treatment, was associated with a better clinical outcome. TEMRAs, which likely comprise tumor-specific T cells, tend to require blockage of both aPD-1 and aCTLA-4 to be reactivated. In conclusion, peripheral blood TEMRAs can play a key role in explaining and predicting clinical benefit upon aPD-1/aCTLA-4 combination treatment. Bristol-Myers Squibb sponsored NivoMes and INITIATE clinical trials and provided study drugs. No external funding was applicable for the flow cytometric analyses of peripheral blood samples described in this manuscript.
Sections du résumé
BACKGROUND
BACKGROUND
Combined immune checkpoint inhibitor (ICI) treatment targeting PD-1 and CTLA-4 was suggested to yield clinical benefit over chemotherapy in malignant pleural mesothelioma (MPM), whereas aPD-1 monotherapy failed to provide benefit in phase-III trials. Success of ICI depends on the presence and activation of tumor-specific T cells. Therefore, we investigated whether T-cell characteristics are underlying clinical efficacy of ICI treatment in MPM.
METHODS
METHODS
Comprehensive immune cell profiling was performed on screening and on treatment peripheral blood samples of mesothelioma patients treated with nivolumab (aPD-1) monotherapy (NCT02497508), or a combination of nivolumab and ipilimumab (aCTLA-4) (NCT03048474).
FINDINGS
RESULTS
aPD-1/aCTLA-4 combination treatment induced a profound increase in proliferation and activation of T cells, which was not observed upon aPD-1 monotherapy. Moreover, patients that responded to combination treatment had low frequencies of naive CD8 T cells and high frequencies of effector memory CD8 T cells that re-expressed RA (TEMRA) at screening. The frequency of Granzyme-B and Interferon-γ producing TEMRAs was also higher in responding patients.
INTERPRETATION
CONCLUSIONS
High proportions of TEMRAs and cytokine production by TEMRAs before treatment, was associated with a better clinical outcome. TEMRAs, which likely comprise tumor-specific T cells, tend to require blockage of both aPD-1 and aCTLA-4 to be reactivated. In conclusion, peripheral blood TEMRAs can play a key role in explaining and predicting clinical benefit upon aPD-1/aCTLA-4 combination treatment.
FUNDING
BACKGROUND
Bristol-Myers Squibb sponsored NivoMes and INITIATE clinical trials and provided study drugs. No external funding was applicable for the flow cytometric analyses of peripheral blood samples described in this manuscript.
Identifiants
pubmed: 33166791
pii: S2352-3964(20)30416-3
doi: 10.1016/j.ebiom.2020.103040
pmc: PMC7658658
pii:
doi:
Substances chimiques
CTLA-4 Antigen
0
CTLA4 protein, human
0
Immune Checkpoint Inhibitors
0
Immune Checkpoint Proteins
0
Ipilimumab
0
PDCD1 protein, human
0
Programmed Cell Death 1 Receptor
0
Nivolumab
31YO63LBSN
Banques de données
ClinicalTrials.gov
['NCT03048474']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
103040Informations de copyright
Copyright © 2020. Published by Elsevier B.V.
Déclaration de conflit d'intérêts
Declaration of Competing Interest Prof. dr. Aerts reports personal fees from Eli Lilly, Roche, Boehringer Ingelheim, BMS, MSD, Amphera and AstraZeneca. Furthermore, prof. dr. Aerts has a patent pending on tumour lysate antigen (EP2938354A1) and is stock owner at Amphera B.V. Immunotherapy. Prof. dr. Baas reports grants from BMS, during the conduct of this study. Furthermore, he receives grants from MSD, outside the submitted work. All other authors do not have any financial relationships to disclose.
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