Meningiomas, tumors of the membranes (meninges) surrounding the brain and spinal cord, are the most common tumors of the central nervous system. Although most meningiomas are low grade and cause few or no symptoms, a subset, called high-grade meningiomas, can cause serious neurologic and cognitive problems and have high mortality rates.
Meningiomas are treated with surgery and in some cases radiation, but there are few other effective therapies, and even with optimal therapy, recurrences are common: About half of all patients with intermediate (grade 2) meningiomas will have a recurrence within 5 years of treatment, and 90% of patients with the most advanced (grade 3) meningiomas will experience recurrences within 5 years.
But as Priscilla Brastianos, MD, from the Mass General Cancer Center and Harvard Medical School (HMS) and colleagues now report, a class of cancer drugs known as immune checkpoint inhibitors can slow disease progression and offer hope for longer survival of patients with high-grade meningiomas.
They report their findings in the open-access journal Nature Communications.
“In the past our understanding of the molecular underpinnings of meningiomas has been limited, and it has only been within the last few years that we have begun to understand the immune microenvironment of meningiomas,” says Brastianos.
Recent studies have suggested that the tumor microenvironment – the environment around a tumor that includes blood vessels, immune cells and chemical signals – may suppress immune responses to meningiomas.
Immune checkpoint inhibitors such as pembrolizumab block PD-1, a protein that prevents the immune system from mounting a defense against tumors. The drug effectively releases the brakes on the immune system, allowing it to accomplish its tumor-identifying and destroying functions.
To see whether immunotherapy could be effective in patients with high-grade meningiomas, Brastianos and colleagues conducted a phase 2 trial in which they treated 25 patients with recurrent and progressive grade 2 or 3 meningiomas with the immune checkpoint inhibitor pembrolizumab (Keytruda).
The trial met its primary goal, with nearly half of all patients alive and without evidence of disease progression for at least 6 months. Half of the patients were still alive 20 months after treatment.
Side effects of therapy were similar to those seen in other studies of pembrolizumab and were manageable.
“Our study shows that it’s both practical to conduct clinical trials for meningiomas – a disease for which there have been very few studies – and that pembrolizumab has promising activity against meningiomas, and needs to be studied further in larger groups of patients,” says Brastianos.
Some studies have shown that PD-L1 was found to be highly expressed in glioblastoma(17, 18), as well as in high-grade meningiomas(19), increasing the possibility of inhibition of the immune checkpoint in central nervous system tumors for which clinical trials are in progress(19, 20).
Immunohistochemistry studies evaluated the PD-L1 expression in tumor cells and concluded that the greater PD-L1 expression in the tumor and in the tumor microenvironment correlates with a worse prognosis and reduced survival time and/or a higher tumor grade(21, 22).
Some recent clinical trials of agents targeting PD-1 or PD-L1 have demonstrated durable tumor regression and prolonged disease stabilization in patients with non-small cell lung cancer, melanoma, clear cell renal cell carcinoma, and Hodgkin’s lymphoma(23-27).
Our study did not detect PD-L1 immunoexpression in any of the 93 cases analyzed.
Wang et al. (2018)(28) studied the PD-L1 immunoexpression in tumors related to neurofibromatosis type 1 and 2, analyzing a total of 10 meningiomas of unspecified grade in patients with neurofibromatosis type 2. This study worked with TMA blocks and performed immunohistochemical reactions with two clones of anti-PD-L1 antibodies (SP142 and E1L3N clones), considered as positive the cases that presented more than 5% of PD-L1 membrane expression in tumor cells.
The results showed PD-L1 immunoexpression in four out of 10 cases for SP142 clone and two of cases for E1L3N clone. These divergences in relation to our study seem to be associated with the difference in clones used and the fact that the sampling of selected meningiomas are all related to patients with neurofibromatosis and have significant populations of tumor infiltrating lymphocytes, which were also accounted for in this work(28).
On the other hand, Du et al. (2014)(29) found high expression of the PD-L1 protein in about 40% grade I, 60% grade II, and 80 grade III. This study detected the presence of messenger ribonucleic acid (mRNA) related to PD-L1 by the of reverse transcription polymerase chain reaction (RT-PCR) technique, with ribonucleic acid (RNA) extraction from a frozen sample of meningiomas of various degrees, in addition to research into the immunoexpression of the PD-L1 protein by the Immunoblot technique.
These differences in the PD-L1 immunoexpression found may reflect the need to use more accurate molecular techniques that reflect the real expression of this protein.
We also point out that the fact that our study used the technique of material representation by TMA, in which some representative areas of the tumor are selected to perform immunohistochemical
reactions, there may be sampling bias in the analysis of the tumors, considering that only one area will be subjected to analysis and not the entire tumor extension.
A recently published report showed the case of a patient with metastatic pulmonary adenocarcinoma who was also diagnosed with meningioma, he was treated with the anti-PD-L1 monoclonal antibody Nivolumabe, for the former. There was a decrease in the size of the meningioma(30).
The treatment of meningiomas with the monoclonal anti- PD-L1 antibody showed a significant decrease in tumor size according to Gelerstein et al. (2017)(30). PD-L1 was also found expressed in infiltrating macrophages in meningiomas, in addition to tumor cells(31, 32). This may indicate that the populations of immune cells in the tumor microenvironment interfere with the immunoexpression of PD-L1.
In a recent study, Hao S et al. (2019)(33) evaluated 92 cases of skull base meningiomas, performing gene sequencing to check for mutations that could be associated with immunological checkpoint inhibition pathways. They concluded that meningiomas that showed the TRAF7 mutation had higher levels of PD-L1 expression, which was measured by immunohistochemistry and Western blot techniques, further affirming the crucial role of mutagenic pathways in suppressing the immune response in the tumor microenvironment.
This study provides us with a reflection on the role of several mutagenic pathways that are related to tumor immune escape mechanisms and that influence the PD-L1 expression and that are not yet fully elucidated.
However, other previous studies have shown results similar to ours(28, 34), revealing low PD-L1 expression, even suggesting that the expression of this biomarker is uncommon in meningiomas.
Some authors even question the applicability of immunotherapy in meningiomas and argue that this treatment becomes an exceptional option in recurrent meningiomas cases that have a rich inflammatory T-cell infiltrate(35, 36).
The PD-L1 expression in meningioma cells and its potential role in local immunosuppression are not fully established and its indication as an alternative treatment for meningiomas is still controversial(30-32).
IFN-alpha (IFN-α) treatment has been found to inhibit the growth of human meningioma cell lines cultured in vitro(15). Studies also show that it is an alternative therapy for recurrent and refractory meningiomas. Evidence suggests its antiproliferative, immunomodulatory and antiangiogenic action on these tumors(37, 38).
In a clinical trial conducted with recurrent and refractory WHO grade 1 meningiomas which underwent surgery and radiation therapy, IFN-α treatment demonstrated progression-free survival at six and 12 months of 52% and 29%, respectively(39).
Current treatment of high-grade meningioma uses cytoreductive surgery with the intent of complete resection, often involving more than one surgery, as well as radiation therapy. Chamberlain and Glantz (2008)(39) studied the use of IFN-α in the treatment of high-grade meningiomas, but concluded that there was no impact on survival. The results of six patients with a non-resectable and recurrent condition who received IFN-α for five days a week showed that one patient presented less tumor reduction and four patients showed stable disease that lasted up to 14 months(39).
A larger and longer study with 12 patients reported that nine patients had stable disease after treatment with IFN-α, which lasted up to eight years(40). A more recent study published with 35 patients with grade I meningioma, who received subcutaneous INF-γ daily(39), showed that ten patients presented mild toxicity, requiring a reduction on the drug dose of the, but, in general, the drug was safe. Twenty-five patients (74%) had stable disease with a median time to tumor progression of seven months and only nine patients (26%) had disease progression(39, 41).
Our study showed interesting results in relation to IFN-γ immunoexpression, pointing out that it is a possible variable that reduces the risk of recurrence and improves disease-free survival.
It was observed that patients with IFN-γ immunoexpression had lower rates of tumor recurrence and longer progression-free survival time, although we did not find statistical significance in some results, which can be attributed to a matter of sampling and studied population.
Considering IFN-γ as a forcing input variable, we found that the absence of expression of this marker reduces the mean time to progression-free survival by 3.46 times.
There was also a difference in immunoexpression in relation to the patient’s gender, women showed a higher IFN-γ expression than men. Our study showed that most tumors with IFN-γ immunoexpression were in brain lobes, 42.3%.
Our study also found that IFN-γ immunoexpression was related to the absence of pleomorphism in tumor cells, showing that the marker confers better differentiation and less tumor grade, in addition to higher disease-free survival rates (71 months versus 65 months of those which did not present marker immunoexpression) it was inversely related to recurrence rates (85% of recurrence cases that did not show IFN-γ immunoexpression).
reference link : https://www.scielo.br/j/jbpml/a/mX9597gLcPvKNsDHyRpMqPQ/?format=html&lang=en#
More information: Priscilla K. Brastianos et al, Phase 2 study of pembrolizumab in patients with recurrent and residual high-grade meningiomas, Nature Communications (2022). DOI: 10.1038/s41467-022-29052-7