Immunotherapy Strategy Shows Promise for Deadly Brain Cancer 

A new immunotherapy strategy has shown promise in targeting one of the most aggressive and deadly forms of brain cancer, according to a new study published in Nature.

Glioblastoma has long challenged physicians and investigators, with patients typically surviving one to two years from diagnosis, according to National Institutes of Health estimates. Even with intensive treatment including surgery, radiation or chemotherapy, most tumors often return within months.  

One major reason for this therapeutic challenge is differences between the cancer cells within a tumor and the role of non-cancer cells like macrophages in allowing the cancer to hide from the immune system, said Amy Heimberger, MD, PhD, the Jean Malnati Miller Professor of Brain Tumor Research and vice chair for research in the Department of Neurological Surgery, who was a co-author of the new study and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.  

“Glioblastoma includes a network of supporters, including blood vessels, structural cells, and immune cells. Glioblastoma is notable for having a high frequency of tumor-supportive macrophages that promote the tumor vasculature, facilitate brain invasion, mediate drug resistance and suppress the immune response against the glioma,” Heimberger said. “The current study is notable for targeting both the tumor cells and the tumor-supportive macrophages.”   

The investigators, led by Sheila Singh, MD, PhD, joint head of the School of Cancer and Pharmaceutical Sciences and head of the Comprehensive Cancer Center at King’s College London, aimed to develop a therapy that targets both the tumor and the tumor-supportive macrophages simultaneously.

Using a multi-omics discovery platform, the investigators identified a protein called GPNMB that appears on both glioblastoma tumor cells and the immunosuppressive macrophages supporting them. 

Next, by analyzing the immune cells, the investigators found that the macrophages expressing GPNMB are among the most immunosuppressive. In laboratory and animal models, specialized CAR-T cells engineered to target GPNMB demonstrated the ability to attack both tumor cells and the tumor-supporting macrophages. Investigators then tested the therapy in human tumors grafted in mice and fully immune-competent mouse models. Across these, the therapy showed strong anti-tumor activity. 

By eliminating the immunosuppressive macrophages, the therapy may effectively “reset” the tumor environment, allowing the immune system to mount a stronger attack. 

“There have been prior attempts at trying to reprogram tumor-supportive macrophages and those failed in clinical trials because the macrophages can shift between functional states,” Heimberger noted. “This new strategy is different in that it is targeting the tumor-supportive macrophages directly.”

The new approach, she said, may be more effective because it removes those cells altogether rather than trying to change their behavior.

“Rather than viewing glioblastoma purely as a collection of neoplastic cells, we need to think of it as an ecosystem in which tumor cells and tumor-supportive macrophages work together. In this framework, any approach that targets only the tumor or only the macrophages is incomplete,” Singh said. “Durable control of glioblastoma will likely require co-targeting of both compartments of the disease: malignant glioma cells and the immunosuppressive macrophages that sustain them.” 

Moving forward, investigators are now exploring how best to deliver CAR-T cells to the brain safely and effectively. 

The study was supported by the Terry Fox Research Institute Program Project Grant (1065), a translational grant from Brain Canada and the Canadian Research Society, as well as funding from the Canadian Institutes for Health Research, the Brain Tumor Foundation of Canada and Brain Cancer Canada. Additional funding came from National Institute of Health grants R01 CA120813, R01 NS120547 and P50 CA221747.