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

Our plain-English summary of 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, by J.M. Mankor, M.J. Disselhorst, M. Poncin, et al (EBioMedicine, 2020).

The study

• Authors: J.M. Mankor, M.J. Disselhorst, M. Poncin, P. Baas, J.G.J.V. Aerts, H. Vroman
• Journal: EBioMedicine
• Published: 2020;62:103040
• Cited by: 38 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

Copyright © 2020. Published by Elsevier B.V.

In plain English

This study analyzed blood samples from patients with malignant pleural mesothelioma (MPM) in two phase II drug trials. It did not examine asbestos exposure. In NivoMes, 34 patients who had progressed after platinum-based chemotherapy received nivolumab alone. In INITIATE, 35 such patients received nivolumab plus ipilimumab. Blood was sampled on the first treatment day and after six weeks. Nivolumab alone showed no increase in T-cell proliferation at six weeks; the authors said this was likely too late to assess its effects. The combination increased proliferation of several T-cell subsets, but this was independent of clinical response. Before treatment, responders to the combination had fewer naive and central memory CD8 T cells and more EMRA CD8 T cells. Patients with a high EMRA CD8 proportion had longer median progression-free survival (13.1 vs 3.5 months, p = 0.045). The overall survival difference (25.9 vs 10.2 months) was not statistically significant. The authors concluded that high pre-treatment proportions of cytokine-expressing EMRA cells were associated with better outcomes on combination therapy. They noted small patient and responder numbers and called for validation in a larger, independent cohort.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Translational laboratory analysis (flow cytometry immune profiling) of blood samples collected within two phase II clinical trials, planned in advance as part of those trials
• Who was studied: Patients with malignant pleural mesothelioma whose disease progressed after at least one cycle of platinum-based chemotherapy. There were 34 treated in the NivoMes trial and 35 in the INITIATE trial, with the trials approved by the Netherlands Cancer Institute review board. Blood samples at screening plus a response evaluation were available for 23 NivoMes and 32 INITIATE patients. 'Responders' were defined as complete response, partial response or stable disease at six months.
• Exposure: Not asbestos. The exposures studied were immune checkpoint drugs: nivolumab (anti-PD-1) alone at 3 mg/kg every 2 weeks (NivoMes), or nivolumab 240 mg flat dose every 2 weeks plus ipilimumab (anti-CTLA-4) 1 mg/kg every 6 weeks up to four times (INITIATE).
• Main results:
  • In patients given nivolumab alone, no increase in T-cell proliferation was observed between screening and six weeks of treatment. The authors noted that other studies found such increases peaked at 3 weeks, so the six-week sampling was most likely too late to assess the effects.
  • In patients given nivolumab plus ipilimumab, proliferation of several CD4 and CD8 T-cell subsets increased, but this increase was independent of clinical response.
  • Before treatment, patients who responded to the combination had significantly lower frequencies of naive and central memory CD8 T cells and a higher frequency of EMRA CD8 T cells than non-responders.
  • In the combination group, patients with a high (above-median) EMRA CD8 T-cell proportion at screening had a significantly longer median progression-free survival than those with a low proportion: 13.1 vs 3.5 months, p = 0.045.
  • In the combination group, median overall survival was 10.2 months for the low EMRA CD8 group and 25.9 months for the high group. This difference was not statistically significant (p = 0.086).
  • In responders to the combination, the frequency of cytokine-expressing memory CD8 T cells (including Granzyme-B and interferon-gamma expressing EMRA cells) was increased.
  • When combination patients were split by high vs low Granzyme-B positive EMRA CD8 T cells, median progression-free survival was 10.8 vs 3.5 months and median overall survival was 32.6 vs 10.2 months. Neither difference was statistically significant (p = 0.14 and p = 0.051).
• The authors' conclusion: The authors concluded that high pre-treatment proportions of cytokine-expressing EMRA CD8 T cells (TEMRAs) were associated with better clinical outcome on nivolumab plus ipilimumab. They suggested this was likely because these cells include tumor-specific T cells.
• Limitations the authors state:
  • Small numbers of patients and of responders, especially in the nivolumab-alone study. The authors said the findings need validation in a larger, independent cohort.
  • The differences found could be phenomenological, and the results do not support general conclusions for tumor types other than MPM.
  • It is unknown whether blood T-cell changes reflect changes within the tumor.
  • Sampling at six weeks may have been too late to detect effects of nivolumab alone.
  • Nivolumab dosing differed between the two trials. The authors believed this most likely did not cause the immune differences.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Nivolumab (Opdivo), Ipilimumab (Yervoy), Pleural Mesothelioma, Clinical Trial, checkpoint inhibitors, CTLA-4, Chemotherapy, Mesothelioma.

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