Immune checkpoint inhibitors targeting the PD-1 pathway could be a promising approach in treating certain children with an aggressive form of brain cancer known as supratentorial pediatric ependymoma, researchers suggest.
Their study, “Specific expression of PD-L1 in RELA-fusion supratentorial ependymoma: Implications for PD-1-targeted therapy,” was published in the journal Pediatric Blood & Cancer.
Pediatric ependymoma (EPN) is the third most common cancer of the central nervous system. It occurs in the upper region on the brain, and subtypes of the tumor have been associated with two main genetic causes.
One of these is related to the gene RELA, which incorrectly fuses with a gene called C11orf95. The resulting fusion, called ST-RELA, functions to amplify signaling pathways that lead to cancer formation.
Immune checkpoint inhibitors, which work to strengthen the immune system’s response to cancer cells, are garnering interest for the treatment of brain tumors. One particular class of these drugs, which include Keytruda (pembroluzimab) and Opdivo (nivolumab), targets the interaction between the protein PD-L1 and its receptor PD-1.
In many cancers, PD-L1 is present on a tumor cell’s surface and PD-1 on the surface of immune cells. When PD-L1 and PD-1 interact, the immune cell is silenced, or turned off, instead of killing the cancer cell. Blocking, or inhibiting, this interaction could re-activate immune cells so that they might destroy cancer cells.
Since PD-L1 expression on the surface of cancer cells can predict whether the cancer would respond to PD-1 inhibitors, researchers at the University of Colorado, Denver, set out to determine the messenger RNA (mRNA) and protein levels of PD-L1 across EPN subtypes.
“This is a tumor with poor prognosis. Overall, pediatric cancers have a nearly 90 percent survival rate. But only 60 percent of patients with the most common form of supratentorial ependymoma will be alive five years after diagnosis,” Andrea Griesinger said a press release. Griesinger is a research assistant in the lab of Nick Foreman, chair of pediatric neuro-oncology at Children’s Hospital Colorado.
Results showed that ST-RELA tumors had significantly higher levels of PD-L1 mRNA, which was also confirmed by high PD-L1 protein levels. Other subtypes of EPN had little PD-L1 on their cancer cells.
PD-1 levels on immune cells around the tumors were also high, suggesting that these tumors could potentially be treated with anti-PD-1 drugs.
“Any PD-1 inhibitor therapy trial, if conducted in EPN should be enriched for relapsed ST-RELA tumors. Alternative immunotherapies should be developed for the other subtypes of EPN,” the researchers concluded.
Since this study showed some promising results, researchers are now continuing to explore PD-1 inhibitors against ST-RELA EPNs. They plan studies testing existing PD-1 inhibitors against ST-RELA cell lines and against mouse models of this tumor.
“This RELA-fusion subgroup is uniquely expressing high levels of PD-1. At this point, we’re all very hopeful this means these tumors will be susceptible to anti-PD-1 drugs,” said David Witt, the study’s first author.
