Scientists at the UCLA Health Jonsson Comprehensive Cancer Centre have developed a new cytokine-armoured CAR-T cell therapy that helps the immune system better attack aggressive brain tumours in mice while reducing dangerous side effects that have long limited immune-based treatments for glioblastoma, one of the deadliest and most treatment-resistant brain cancers.

The therapy works by reprogramming CAR-T cells to release immune-stimulating proteins, called IL-12 and DR-18, that activate the body’s own immune system, strengthening the overall anti-cancer response.

In mouse models, the approach improved tumour control, including against cancers made up of mixed cell populations that often escape therapies.

Researchers also found that pairing the treatment with a second CAR-T strategy targeting VEGF, a protein that drives abnormal blood vessel growth and contributes to swelling in glioblastoma, helped reduce side effects while preserving strong anti-tumour activity.

The findings, published in Cancer Research, a journal of the American Association for Cancer Research, suggest a potential new strategy for treating recurrent high-grade gliomas and other solid tumours that historically have been difficult to target with CAR-T cell therapy.

Why it matters

Glioblastoma remains extremely difficult to treat because tumours 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 tumours has been limited.

“A key challenge in treating brain tumours, particularly glioblastoma, is that the tumour cells are often antigen heterogeneous, meaning they do not all express the same proteins that can be recognised by a given targeted therapy,” said Yvonne Chen, PhD, co-director of the Tumour Immunology and Immunotherapy Programme at the UCLA Health Jonsson Comprehensive Cancer Centre and senior author of the study.

“We hypothesised that effective immunotherapy against brain tumours would have to engage naturally occurring immune cells, which can recognise a wide variety of target antigens, in the fight against cancer.”

What the study did

Because brain tumours are considered immunologically “cold,” meaning they do not naturally trigger a strong immune response, the researchers designed so-called “armoured CAR-T cells” to activate immunity against the tumour.

These CAR-T cells were built to recognise a tumour 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.

The team then tested multiple combinations of these “armour” molecules in immunocompetent mouse models of glioblastoma, using head-to-head comparisons to evaluate how each design affected tumour growth and immune activity.

The CAR-T cells were studied in several orthotopic glioma models, including tumours engineered to vary in antigen expression to better reflect the heterogeneity seen in human disease.

What they found

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

“IL-12 and DR-18 work synergistically to activate the immune system, resulting in a dramatic influx of immune cells into the tumour-bearing brain,” said Chen, who is also a professor of microbiology, immunology, and molecular genetics at UCLA and a member of the UCLA Broad Stem Cell Research Centre.

“The diverse immune-cell population recruited into the brain contributes to attacking the tumour, including ones that cannot be directly recognised by the CAR-T cells themselves.”

The therapy demonstrated the ability to eliminate tumours containing cancer cells that lacked the target recognised by the CAR-T cells, a major hurdle in glioblastoma treatment because tumours 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-tumour activity.

They found that adding a second engineered CAR-T approach targeting VEGF helped reduce treatment-related toxicity while maintaining strong tumour 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-tumour activity.”

What this means for patients

The findings suggest a potential new strategy for treating recurrent high-grade gliomas.

The researchers are now completing the necessary preclinical studies and raising funds to launch a Phase 1 clinical trial in patients with the disease.

“We are very encouraged by the ability of our cytokine-armoured CAR-T cells to kill not only tumour cells that express IL-13Rα2, but also tumour cells that are not directly recognisable 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.”

About the research team

The study’s first author is Justin Clubb, a doctoral student in the department of Chemical & Biomolecular Engineering at UCLA.

Other UCLA authors include Ryan Shih, Torahito Gao, Amanda Shafer, Shreya Vajragiri, Katrina Lam, Sohan Talluri, Amber Bouren and Robert Prins.

Source: University of California - Los Angeles Health Sciences