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

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.

Emerging avenues in immunotherapy for the management of malignant pleural mesothelioma

“…Given the data from Checkpoint-743 it would seem that nivolumab/ipilimumab should be used in the first line setting, however, cost reimbursement may limit their uptake [ 194 ]. The issue of whether or not to give it to all comers irrespective of histology and PD-L1 status has however yet to be resolved given the data that suggests PD-L1 negative tumors have better responses to chemotherapy, and that patients with the sarcomatoid histology may be better candidates for checkpoint inhibitors [ 53 , 153 , 195 ]. Indeed it may be that PD-L1 negative non-sarcomatoid patients should initially be treated with a chemotherapy regimen and then proceed to a checkpoint inhibitor in the salvage setting upon progression, whilst PD-L1 positive patients should be offered first-line nivolumab/ipilimumab.…”

Matter of TIME: the tumor-immune microenvironment of mesothelioma and implications for checkpoint blockade efficacy

“…Additionally, there is evidence that the ratio of CTLs to malignant cells is higher in sarcomatoid MPM. 24 Furthermore, by examining paired biopsies, Pasello and coworkers detected that the CD8 + cell proportion increased following administration of platinum plus pemetrexed. 25 Finally, our own group has recently demonstrated via multiregional sequencing that CTL infiltration can be influenced by the tumor's clonal architecture.…”

The efficacy of immune checkpoint inhibitors in thoracic malignancies

“…UJIIE et al [114] showed that a high CD163+ tumour-associated macrophages/CD8+ T lymphocytes ratio and a low CD163+/CD20+ B lymphocytes ratios were independent prognostic factors of worse and better survival outcomes, respectively. Non-epithelioid histologies have been more frequently characterised by higher CD8+ density and CD45RO+ memory cells, while epithelioid one has higher amounts of peritumoural CD4+ T and CD20+ B lymphocytes [115,116]. PD-L1 expression has been shown to correlate with the presence of CD68+ macrophages [117], CD45+ immune cells, activated CD3+ T cells, proliferating CD8+ T cells and FOXP3+/CD4+ Treg lymphocytes [118].…”

“…Nevertheless, due the immune-pathological features (described in the previous Section), sarcomatoid and biphasic histologies were supposed being the more prone to immunotherapy action. Albeit some data sustained this hypothesis [116,126,127], non-epithelioid MPM cases included in clinical trials or retrospective series were too scant to drive any conclusion. Of major relevance, the combination of nivolumab and ipilimumab in MPM has been recently proven superior to first-line chemotherapy in terms of OS benefit.…”