Chek-Mate for Gliomas

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Scientist pipetting at the bench with white coat and purple gloves

Dmello tested hundreds of kinases to find the one that affected immune activity in gliomas the most.

Olivia Dimmer

Immunotherapy has become a go-to weapon in many oncologists’ cancer-fighting arsenals. But even rallying hordes of immune cells are no match for brain cancers such as glioma. Potent immunotherapies, including immune checkpoint inhibition, end up sidelined during the treatment of these wily tumors that often claim patients’ lives in just over one year.1

Recent work proposes a way to help immune cells penetrate gliomas’ defenses. “This was the most challenging cancer to work with,” said Crismita Dmello, a neuroscientist at Northwestern University and lead author of the study. “But we decided to go for it.” In a study published in Nature Communications, her team reported that blocking a signaling molecule called Chek2 may make immune checkpoint inhibition better at destroying gliomas.2

Previous work from the team showed that the level of signaling molecules called kinases is linked to how well patients respond to immune checkpoint inhibition.3 But with over 700 kinases in the human body, they weren’t sure which ones were most crucial.

To figure this out, Dmello and 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 summoned by immunotherapies, could kill tumor cells even in the absence of immunotherapy. After testing all 713 kinases, the researchers found the largest increase in tumor-killing was when they reduced Chek2.

“This suggested that the presence of Chek2 is suppressing the immune system, and when we deplete or inhibit it, we make [the tumor] more recognized,” Dmello said.

Then, the team combined Chek2 inactivation with immunotherapy. They genetically reduced Chek2 levels in laboratory-grown tumor cells that do not usually respond to anti-PD-1 immune checkpoint inhibition and injected the cells into mice, who then received anti-PD-1 immunotherapy a few days later. These mice survived longer than mice with intact Chek2 that received the same immunotherapy. 

To easily turn this into a therapy, the researchers needed a way to reduce Chek2 without gene editing. Fortunately, a solution already existed: Prexasertib, a drug that blocks Chek2 activity and can penetrate the brain. When they treated mice with gliomas with Prexasertib and anti-PD-1 immunotherapy, the mice lived longer—and 30 percent were cured of their cancer.

“The fact that there are Chek2 inhibitors that are already clinically available 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 the ones used in this study are notorious for demonstrating better immune responses than humans, he said. Bagley wants to see the drug work in human patients before getting too optimistic.

Dmello and her collaborators are setting up a clinical trial of Chek2 inhibitors combined with radiation and immune checkpoint inhibition for maximum cancer-fighting power. At the same time, she is trying to better understand exactly how reducing Chek2 makes a tumor more welcoming to immune cells, and exploring whether it might help treat other types of cancer, such as breast cancer.

“Most of the work we do at the bench just goes in the books and papers and nothing beyond that,” Dmello said. “My intention is that, at some point, my research should go to patients.”

References

  1. Glioblastoma Research Organization. “What Is the Average Glioblastoma Survival Rate?” Accessed May 2023. https://www.gbmresearch.org/blog/glioblastoma-survival-rate 
  2. Dmello, C., et al. Checkpoint kinase 1/2 inhibition potentiates anti-tumoral immune response and sensitizes gliomas to immune checkpoint blockade. Nat Commun. 14(1), 1566 (2023). doi: 10.1038/s41467-023-36878-2
  3. Zhao, J., et al. Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma. Nat Med. 25(3), 462-9 (2019). doi: 10.1038/s41591-019-0349-y
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