Preliminary study highlights the potential of immune checkpoint inhibitors in sarcomatoid mesothelioma

Our plain-English summary of Preliminary study highlights the potential of immune checkpoint inhibitors in sarcomatoid mesothelioma, by N.K. Brockwell, M. Alamgeer, B. Kumar, et al (Translational Lung Cancer Research, 2020).

The study

• Authors: N.K. Brockwell, M. Alamgeer, B. Kumar, G. Rivalland, T. John, B.S. Parker
• Journal: Translational Lung Cancer Research
• Published: 2020;9(3):639-645
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is well known as an aggressive disease with poor survival. This has sparked trials of alternate immune-based therapies in MPM. While up to a quarter of MPM patients respond to immune checkpoint inhibitors (ICIs), predicting response remains challenging and PD-L1 expression alone has been deemed insufficient. Additionally, patients with sarcomatoid MPM are often excluded from trials utilizing ICIs due to their rapid progression. Here, we analyze the association of T lymphocytes with response to ICI-based immunotherapy to uncover predictive immune markers across subtypes.

Methods: Retrospective analysis of immunotherapy treated mesothelioma patient cohorts from two sites were pooled. Patient characteristics, including age, sex, subtype and previous treatment were captured. Multiplex immunohistochemistry was used to assess proportions of CD4, CD8, CD45RO and FOXP3 positive infiltrates in MPM and their association with progression free (PFS) and overall (OS) survival post immunotherapy.

Results: Samples derived from 22 patients were analyzed; 13 (59%) had epithelioid MPM, 6 (27%) sarcomatoid and 3 (14%) biphasic. The overall ICI response rate was 40%, with a median PFS (mPFS) and OS (mOS) of 3.8 and 11.17 months, respectively. Of the subtypes, sarcomatoid patients displayed the greatest median PFS and OS (>28 months) post ICI compared to the epithelioid subtype (3 and 11 months respectively), which correlated with higher proportions of infiltrating CD8+, CD45RO+ and CD8+CD45RO+ cells. Patients who received ICIs as first-line therapy had greater PFS than those who received it as second or third line post-chemotherapy.

Conclusions: High proportions of T lymphocytes and CD45RO+ cells were associated with prolonged mPFS and mOS in sarcomatoid patients treated with ICI immunotherapy. These data support the expansion of trials utilizing single and combination ICIs as first-line therapy in sarcomatoid MPM and warrants further studies testing the impact or detriment of chemotherapy pre-ICI.

2020 Translational Lung Cancer Research. All rights reserved.

In plain English

This was a small retrospective study of 22 patients with malignant pleural mesothelioma treated with immune checkpoint inhibitor drugs (a type of immunotherapy). The patients had biopsies taken before treatment between 2012 and 2017 at Monash Hospital and the Austin Hospital in Australia. The article did not discuss asbestos exposure. Thirteen patients had epithelioid, six sarcomatoid and three biphasic tumors. The researchers stained the biopsies to measure immune cells, including CD8+ T cells and CD45RO+ memory cells, and compared these with how long patients lived, and lived without the cancer worsening, after starting immunotherapy. Sarcomatoid tumors had up to twice the proportion of CD8+ and CD8+CD45RO+ cells seen in epithelioid tumors. Sarcomatoid patients also had longer survival: four of the six were alive without progression beyond 15 months. Patients with no previous chemotherapy had a median of 19.5 months without progression, compared with 2.5 months for those who had chemotherapy first. The authors concluded that immunotherapy may be a potent first-line therapy for sarcomatoid mesothelioma, and they called for larger trials. They noted that the small number of biopsies and the use of different drugs limited firm conclusions.

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: Small retrospective cohort study of patient records and stored tumor tissue, with multiplex immune staining of biopsies
• Who was studied: 22 patients with malignant pleural mesothelioma (13 epithelioid, 6 sarcomatoid, 3 biphasic) who had pre-treatment biopsies between 2012 and 2017 at Monash Hospital and the Austin Hospital (Victoria, Australia), received immune checkpoint inhibitors, and had tissue and follow-up data available
• Exposure: Asbestos exposure was not addressed. The treatment studied was immune checkpoint inhibitor immunotherapy (the figure lists pembrolizumab, nivolumab/ipilimumab and avelumab), alongside tumor immune cell levels measured before treatment (CD4, CD8, CD45RO, FOXP3)
• Main results:
  • For all 22 patients, the main text reports an overall response rate to immune checkpoint inhibitors of over 30%, median progression-free survival of 3.8 months and median overall survival of 11.1 months
  • CD8+ T cells and CD8+CD45RO+ cells were up to 2 times higher in sarcomatoid tumors than in epithelioid tumors
  • Patients with sarcomatoid mesothelioma had longer progression-free and overall survival after immunotherapy than patients with epithelioid mesothelioma. In Table S1, the p value for median progression-free survival by subtype was 0.052
  • Sarcomatoid patients whose CD8+ and CD45RO+ cell levels were above the median had progression-free and overall survival of more than 28 months
  • In the epithelioid and biphasic groups, survival did not differ between patients with immune cell levels above and below the median
  • Four of the 6 sarcomatoid patients (67%) were alive and progression free for over 15 months, compared with 2 of the 13 epithelioid patients (15%) progression free at 10 months
  • Median progression-free survival was 2.5 months in the 15 patients who had previous chemotherapy and 19.5 months in the 7 who had not (p = 0.035)
  • Median progression-free survival was 10.97 months in the 9 patients with a partial response, 6.07 months in the 6 with stable disease and 1.37 months in the 7 with progressive disease (p = 0.02)
• The authors' conclusion: The authors concluded that immune checkpoint inhibitors may be a potent first-line therapy for sarcomatoid mesothelioma and that high levels of memory and T cells are candidate predictors of benefit in this subtype. They said sarcomatoid patients should be a focus of future trials
• Limitations the authors state:
  • The small number of available biopsies from treated patients made it difficult to develop predictive immune markers
  • Patients received different immune checkpoint inhibitors, which made definitive conclusions difficult
  • The study could not show whether sarcomatoid patients would do as well on single drugs as on combinations

Topics

Medical terms in this study, explained in our Lexicon: checkpoint inhibitors, Sarcomatoid, Mesothelioma, Pleural Mesothelioma, PD-L1, Immunotherapy, Immunohistochemistry, Epithelioid.

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• LAG3 is an independent prognostic biomarker and potential target for immune checkpoint inhibitors in malignant pleural mesothelioma: a retrospective study — K. Arimura, K. Hiroshima, et al. (2023)
• Potential of fluoropyrimidine to be an immunologically optimal partner of immune checkpoint inhibitors through inducing immunogenic cell death for thoracic malignancies — H. Kozai, H. Ogino, et al. (2024)
• In-depth profiling of tumor tissue derived from malignant pleural mesothelioma patients identifies potential biomarkers predicting response to immune-checkpoint inhibitor therapy — D. Shek, B. Gao, et al. (2024)
• Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors — A. Vogrig, M. Fouret, et al. (2019)
• Immune checkpoint inhibitors in non-small cell lung cancer (NSCLC): Approaches on special subgroups and unresolved burning questions — J. Remon, N. Vilariño, et al. (2018)

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