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.

Abstract

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:

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:

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:

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:

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.

• Authors: Joanne M Mankor, Maria J Disselhorst, Myrthe Poncin, Paul Baas, Joachim G J V Aerts, Heleen Vroman
• Journal: EBioMedicine (EBioMedicine) Vol. 62 Pg. 103040 (Dec 2020) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 33166791 (Publication Type: Journal Article)
• Copyright: Copyright © 2020. Published by Elsevier B.V.

Chemical References

• CTLA-4 Antigen
• CTLA4 protein, human
• Immune Checkpoint Inhibitors
• Immune Checkpoint Proteins
• Ipilimumab
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Nivolumab

Topics

• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• 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, etiology, metabolism, mortality)
• Middle Aged
• Molecular Targeted Therapy (adverse effects, methods)
• Nivolumab (administration & dosage)
• Prognosis
• Programmed Cell Death 1 Receptor (antagonists & inhibitors)
• T-Lymphocyte Subsets
• T-Lymphocytes, Cytotoxic (drug effects, immunology, metabolism)
• Translational Research, Biomedical
• Treatment Outcome