Dmello tested hundreds of kinases to find the one that most affected immune activity in gliomas.
Olivia Dimmer
IImmunotherapy has become a weapon of choice in the cancer-fighting arsenals of many oncologists. But even the hordes of immune cells that rally are no match for brain cancers such as glioma. Powerful immunotherapies, including immune checkpoint inhibition, end up being sidelined during the treatment of these tricky tumors that often claim patients’ lives in just over a year.1
Recent work suggests a way to help immune cells penetrate the defenses of gliomas. “It was the hardest cancer to treat,” said Crismita Dmello, a neuroscientist at Northwestern University and lead author of the study. “But we decided to go.” In a study published in Nature Communicationhis team reported that blocking a signaling molecule called Chek2 may make immune checkpoint inhibition more effective in destroying gliomas.2
Previous work by the team has shown that the level of signaling molecules called kinases is linked to how patients respond to immune checkpoint inhibition.3 But with over 700 kinases in the human body, they didn’t know which were the most crucial.
To figure this out, Dmello and his colleagues reduced the levels of each kinase, one at a time, using CRISPR gene editing in mouse gliomas. They measured whether CD8+ T cells, the main immune cells invoked by immunotherapies, could kill tumor cells even in the absence of immunotherapy. After testing all 713 kinases, the researchers found that the greatest increase in tumor destruction occurred when they reduced Chek2.
“This suggests that the presence of Chek2 suppresses the immune system, and when we deplete or inhibit it, we do [the tumor] more recognized,” Dmello said.
Next, the team combined inactivation of Chek2 with immunotherapy. They genetically reduced Chek2 levels in lab-grown tumor cells that typically do not respond to anti-PD-1 immune checkpoint inhibition and injected the cells into mice, which then received anti-inflammatory immunotherapy. -PD-1 a few days later. These mice survived longer than mice with intact Chek2 who received the same immunotherapy.
To easily turn this into therapy, the researchers needed a way to reduce Chek2 without genetic modification. Fortunately, a solution already existed: Prexasertib, a drug that blocks the activity of Chek2 and can enter the brain. When they treated mice with gliomas with prexasertib and anti-PD-1 immunotherapy, the mice lived longer and 30% were cured of their cancer.
“The fact that there are Chek2 inhibitors already available in the clinic really maximizes the translational relevance of the work,” said Stephen Bagley, a neuro-oncologist at the University of Pennsylvania who was not involved in this study.
But after years of seeing glioma drugs fail in human clinical trials, Bagley is wary. Mouse models like those used in this study are known to demonstrate better immune responses than humans, he said. Bagley wants to see the drug work in human patients before he gets too optimistic.
Dmello and his collaborators are setting up a clinical trial of Chek2 inhibitors combined with radiation and immune checkpoint inhibition for maximum cancer-fighting potency. At the same time, she’s trying to better understand exactly how reducing Chek2 makes a tumor more hospitable to immune cells and exploring whether it could help treat other types of cancer, such as breast cancer.
“Most of the work we do on the bench just goes into the books and papers and nothing beyond that,” Dmello said. “My intention is that at some point my research will go to patients.”
The references
- Glioblastoma Research Organization. “What is the average survival rate for glioblastoma? Accessed May 2023. https://www.gbmresearch.org/blog/glioblastoma-survival-rate
- Dmello, C., et al. Inhibition of checkpoint kinase 1/2 potentiates the anti-tumor immune response and sensitizes gliomas to immune checkpoint blockade. Nat Common. 14(1), 1566 (2023). do I: 10.1038/s41467-023-36878-2
- Zhao, J., et al. Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma. NatMed. 25(3), 462-9 (2019). do I: 10.1038/s41591-019-0349-y
