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

EBioMedicine. 2020 Dec;62:103040. doi: 10.1016/j.ebiom.2020.103040. Epub 2020 Nov 7.


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.

Keywords: Immune checkpoint inhibitors; Immune monitoring; Immunotherapy; Ipilimumab; Malignant pleural mesothelioma; Nivolumab.

MeSH terms

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


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

Associated data

  • ClinicalTrials.gov/NCT03048474