New target antigen could make CAR-T possible for glioblastomas

Surgery, radiation and chemotherapy just don’t cut it against glioblastoma, a type of aggressive brain tumor with a dismal five-year survival rate. Survival is highest in younger people, at 19% for those aged 20 to 44, but it drops sharply with age, bottoming out at 5% for patients over 55.

That’s why Gianpietro Dotti, of the University of North Carolina’s Department of Microbiology and Immunology, is working on an immunotherapy for glioblastoma, specifically, a chimeric antigen receptor T (CAR-T) cell therapy.

CAR-T can be an effective form of immunotherapy, the researchers note in their study, which appears in Science Translational Medicine. It has seen success in blood cancers—The FDA approved two such therapies last year—but has been challenging to apply to solid cancers.

And glioblastomas are doubly hard to tackle, as these tumors are heterogeneous, or composed of many different cell types. Some cancer cells may respond to treatment, but others may resist it and continue growing.

Dotti’s team, alongside colleagues from Italy, zeroed in on a new CAR-T target antigen: a protein called CSPG4, which is “highly prevalent” on glioblastoma tumors, according to a press release. The researchers modified immune cells to seek out and destroy CSPG4.

They found that the treatment controlled tumor growth and prolonged survival in mice. In cell models, the CAR-T cells eliminated glioblastoma cells with CSPG4, while the cancer grew unfettered in the presence of normal T cells.

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"While it didn't cure all of the tumors, we think it is very promising as a single agent, and also could be studied in combination with other investigational approaches,” Dotti said in the release.

Other CAR-T targets include IL-13Ra2, which City of Hope researchers are investigating, and EGFRvIII. University of Pennsylvania scientists are studying the latter, which has been shown to promote tumor growth in one-third of glioblastoma patients. While a 10-patient study showed their CAR-T treatment actually made the tumor microenvironment more immunosuppressive, the team suggested this could be counteracted with other drugs, such as checkpoint inhibitors.

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Dotti observed an immunosuppressive response in his study, too, but he hopes to address this in future studies. He will partner with other UNC professors to launch a clinical trial in glioblastoma, focusing on patients with advanced, recurrent disease.

"We are working on a potential new way to try to treat this aggressive tumor," Dotti said. "The experiments in vitro and in vivo were promising, but we need to see what happens in patients."