Cytokine-armored CAR-T cell therapy successfully attacks aggressive brain tumors in mice

Why it matters

Glioblastoma remains extremely difficult to treat because tumors suppress immune responses, contain diverse cancer cells and create abnormal blood vessels that limit the effectiveness of immunotherapy. While CAR-T cell therapy has transformed treatment for certain blood cancers, success in solid tumors has been limited.

Yvonne Chen, PhD, co-director of the Tumor Immunology and Immunotherapy Program at the UCLA Health Jonsson Comprehensive Cancer Center and senior author of the studyA key challenge in treating brain tumors, particularly glioblastoma, is that the tumor cells are often antigen heterogeneous, meaning they do not all express the same proteins that can be recognized by a given targeted therapy. We hypothesized that effective immunotherapy against brain tumors would have to engage naturally occurring immune cells, which can recognize a wide variety of target antigens, in the fight against cancer."

What the study did

Because brain tumors are considered immunologically "cold," meaning they do not naturally trigger a strong immune response, the researchers designed so-called "armored CAR-T cells" to activate immunity against the tumor. These CAR-T cells were built to recognize a tumor antigen called IL-13Rα2, a protein commonly found on glioblastoma cells, while also secreting immune-stimulating proteins that recruit and activate the body's immune cells.

What they found

After testing multiple combinations, researchers identified one especially potent pairing: IL-12 and decoy-resistant IL-18, known as DR-18.

The therapy demonstrated the ability to eliminate tumors containing cancer cells that lacked the target recognized by the CAR-T cells, a major hurdle in glioblastoma treatment because tumors can evolve and escape single-target therapies.

Addressing toxicity 

Because IL-12 can trigger dangerous inflammation, the researchers also explored ways to reduce side effects while maintaining anti-tumor activity.

They found that adding a second engineered CAR-T approach targeting VEGF helped reduce treatment-related toxicity while maintaining strong tumor control in mice.

"When developing novel therapies, we always have to balance considerations for safety and efficacy," Chen said. "Potent cytokines such as IL-12 and DR-18 have toxicity potential, which is why we performed in-depth studies to understand the nature and severity of the toxicity and devised ways to counteract safety concerns while maintaining anti-tumor activity."

What this means for patients

"We are very encouraged by the ability of our cytokine-armored CAR-T cells to kill not only tumor cells that express IL-13Rα2, but also tumor cells that are not directly recognizable to the CAR-T cells," Chen said. "We are excited to have developed a clinical protocol that would allow us to bring this therapy to the clinic while also providing a detailed toxicity management plan to ensure patient safety."

Source:

University of California - Los Angeles Health Sciences

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