Examining the presence of PD-L1 molecules in a tumor as a test to predict if therapy with immune checkpoint inhibitors will work is a highly controversial area in this field of research, according to an editorial that accompanied a recently published study exploring PD-L1 in mesothelioma.
The research looked at how the presence of PD-L1 and gene mutations were linked to survival in mesothelioma.
But measuring PD-L1 with immunohistochemistry — a method where pathologists use dyes to highlight tissue structures viewed under the microscope — is an unreliable predictor of treatment response, the editorial, “PD-L1 Testing for Immune Checkpoint Inhibitors in Mesothelioma: For Want of Anything Better?” pointed out.
The fact that the study did not address treatment responses was not mentioned in the editorial.
With the recent surge of successful immunotherapies in several cancer types, the idea of harnessing the immune system to combat cancer is now mainstay. But, as was the case in the pre-immunotherapy era, mesothelioma is a cancer not able to reap the benefits of the new treatments.
Checkpoint inhibitors make use of molecules that are found on tumor and immune cell surfaces and make sure the immune system does not attack a tumor. When these factors — including the pair PD-1 and PD-L1 — are blocked or inhibited, the immune system is revitalized, seeing the cancer for the threat it is. At least, that’s the theory.
In real life, people respond very differently to immune checkpoint inhibitors. And the search for markers that could tell a physician which patients are likely to respond well to the treatment is a holy grail of checkpoint research.
Researchers examining other cancer types initially suggested that the response to immune checkpoint blockers was linked to the amount of checkpoint molecules in a patient — reasoning that makes intuitive sense. A drug works better if there are more molecules to target.
Numerous clinical trials have also explored checkpoint inhibitors in mesothelioma, with improvements in survival rates. But so far, the effects are not as impressive as in other cancers, and no drug has been approved to treat this aggressive cancer.
In an attempt to examine if the presence of PD-L1 could impact mesothelioma, the study titled “The Immune Microenvironment, Genome-wide Copy Number Aberrations, and Survival in Mesothelioma” looked at the levels of PD-L1 in samples from 329 mesothelioma patients. Its researchers also looked at gene mutations in the tumor tissue. (Both articles were published in the Journal of Thoracic Oncology.)
But the team from the University of Melbourne and Olivia Newton-John Cancer Research Institute — both in Australia — did not correlate their molecular findings with response to checkpoint treatment. The patients were not treated with this type of drug. Instead, they looked at survival rates.
They found that the presence of PD-L1 was more common in patients with non-epithelioid mesothelioma. Those with higher levels of the molecule had worse outcomes and more immune cells within the tumor tissue. More gene mutations was also linked to poorer survival, but did not impact levels of PD-L1.
Still, the article spurred a group of researchers from the Cancer Center of Léon Bérard and other French research institutions to write an editorial in which they pointed out the shortcomings of PD-L1 measurements.
The editorial tackled research investigating PD-L1 analyses for use as predictors of checkpoint treatment effectiveness. This, its writers stated, was a highly controversial area, and they illustrated their view with examples of patients with no detectable PD-L1 who responded as well to treatment with checkpoint inhibitors as those who had high levels of the factor.
So far, they maintained, researchers have not been able to explain this puzzling response.
The French editorial — although it did not address the fact that the Australian study did not use PD-L1 to predict treatment response — highlighted the difficulties in obtaining robust measurements of PD-L1, citing studies that show that the levels of the molecule change with time and treatment, and may even differ between locations in the same tumor.
In addition, examinations of the assays used to detect PD-L1 show high variability.
Despite their criticism, the writers agreed that the original study’s findings were similar to those found by others, including the proportion of patients testing positive for PD-L1, and the link between the molecule and the presence of immune cells in the tumor.
They did, however, point out that as the search for biomarkers of response to checkpoint inhibitors continues, neither PD-L1 testing nor mutational burden in mesothelioma are likely to be sensitive enough to advance research into checkpoint immunotherapy for mesothelioma.