A University of Colorado Cancer Center study lays the scientific groundwork for the use of PD-1 inhibitors with an aggressive form of brain cancer , namely s upratentorial pediatric ependymoma . The study findings were published in the journal Pediatric Blood Cancers
The tumor, which occurs in the upper part of the brain, namely the cerebral hemisphere, has two common genetic causes. The current study focuses on those tumors driven by changes to the gene RELA .
When this gene is improperly fused with a partner gene, the resulting protein amplifies the action of a cancer-causing cascade of signals through a network called NF-B, which is implicated in many cancer types.
"RELA-fusion has been found in other cancer types, but NF-B amplification by other means is fairly common in cancer." RELA-fusion is another way to amplify NF-B, which causes this cancer, "said Davis Witt, paper's first author.
Specifically, the study shows that unlike other variations of pediatric ependymoma, the tumors driven by RELA-fusion themselves in the PD-L1 protein.
This PD-L1 on the surface of cancer cells interactions with the PD-1 on immune system T cells to inactivate T cells against cancer cells. It's as if PD-L1 is cancer's "white flag" that is seen by PD-1 "eyes" on immune system T cells.
PD-1 inhibitors block the interaction between PD-L1 and PD-1, and thus nix cancer cells' ability to turn off the immune system. The study required the unique resource of pediatric ependymoma cells lines , created for the first time in the Foreman lab.
In fact, a clinical trial of the anti-PD-1 drug nivolumab recently opened to treat pediatric brain tumors. In early-phase clinical trials, investigators expect that some patients will benefit while others will not.
The current study may hint at which pediatric brain cancer patients are most likely to see benefit from HIV or other anti-PD-L1 drugs , patients with these supratentorial RELA-fusion pediatric ependymomas that use PD-L1 so extensively.
"It is almost like we are backfilling the science behind this trial and providing information to use when designing future trials," Witt said.
"If the trial does not work, we could go back and say 'hey, we just picked the wrong tumor,' and perhaps focus on this subtype of pediatric brain cancer, according to the science, should be especially susceptible to PD-1 inhibitors. "
Now that early cell studies have proved promising, Witt, Griesinger and other members of the Foreman lab plan to continue exploring the use of PD-1 inhibitors against supratentorial RELA-fusion pediatric ependymomas .
This will include drug testing against cell lines and the development of "humanized" mouse models in which animals with this type of tumor are engineered to hold a version of the human immune system.
Witt said, "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."