Cytokine‑Armored CAR T Cells Overcome Antigen Heterogeneity in Glioma Model

Scientists at the UCLA Health Jonsson Comprehensive Cancer Center have developed a cytokine-armored CAR T-cell therapy that helps the immune system better attack aggressive brain tumors in mice. Their study showed that the treatment also reduced dangerous side effects that have long limited immune-based treatments for glioblastoma, which is one of the deadliest and most treatment-resistant brain cancers.

The therapy works by reprogramming CAR T cells to release immune-stimulating proteins, IL-12 and DR-18, which activate the body’s own immune system, strengthening the overall anticancer response. This treatment approach improved tumor control in mouse models, including those carrying cancers made up of mixed cell populations that often escape treatment. Researchers also found that pairing the treatment with a second CAR T strategy targeting VEGF helped reduce side effects while preserving strong anti-tumor activity.

The findings point to a potential new strategy for treating recurrent high-grade gliomas and other solid tumors that historically have been difficult to target with CAR T-cell therapy. Research lead Yvonne Chen, PhD, co-director of the Tumor Immunology and Immunotherapy Program at the UCLA Health Jonsson Comprehensive Cancer Center, is senior author of the study, which is published in Cancer Research, in a paper titled “Armored Chimeric Antigen Receptor-T Cell Therapy Targets Antigen-Heterogeneous Glioma.”

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. “Two features of glioblastoma pose formidable barriers to effective immunotherapy: tumor-antigen heterogeneity and a highly immunosuppressive tumor microenvironment (TME),” the team wrote. While CAR T-cell therapy has transformed treatment for certain blood cancers, success in solid tumors has been limited.

“Early data from clinical evaluation of chimeric-antigen receptor (CAR) T-cell therapies for glioblastoma show a strong safety profile and promising signs of response, but durable efficacy remains elusive,” they continued. Chen added, “A 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.” The researchers further stated, “The glioblastoma TME is characterized by a variety of dysfunctional tumor-associated cell types that support tumor growth and metastasis.” The most abundant of these are tumor-associated macrophages (TAMs), which can directly suppress immune-cell function and promote tumorigenesis.

“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,” Chen noted.

Because brain tumors are considered immunologically cold, meaning they do not naturally trigger a strong immune response, the researchers designed “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.

The team then tested multiple combinations of these “armor” molecules in immunocompetent mouse models of glioblastoma, using head-to-head comparisons to evaluate how each design affected tumor growth and immune activity. The CAR T cells were studied in several orthotopic glioma models, including tumors engineered to vary in antigen expression to better reflect the heterogeneity seen in human disease. After testing multiple combinations, researchers identified one especially potent pairing: IL-12 and decoy-resistant IL-18 (DR-18). “Through head-to-head in vivo comparisons of potentially synergistic armor combinations, we demonstrated that T cells expressing a CAR plus IL-12 and the decoy-resistant form of IL-18 (CAR-12.DR18 T cells) show strong efficacy against antigen-heterogeneous glioma in immunocompetent mice,” the investigators reported.

The team showed that 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. “IL-12 and DR-18 work synergistically to activate the immune system, resulting in a dramatic influx of immune cells into the tumor-bearing brain,” stated Chen, who is also a professor of microbiology, immunology, and molecular genetics at UCLA and a member of the UCLA Broad Stem Cell Research Center. “The diverse immune-cell population recruited into the brain contributes to attacking the tumor, including ones that cannot be directly recognized by the CAR T cells themselves.”

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—a protein that drives abnormal blood vessel growth and contributes to swelling in glioblastoma—helped reduce treatment-related toxicity while maintaining strong tumor control in mice. “Robust anti-tumor efficacy with effective toxicity mitigation was achieved via combined administration of CAR-12.DR18 T cells with CAR T cells that secrete an anti-vascular endothelial growth factor (VEGF-A) single-chain variable fragment. This combination therapy presents a clinically applicable strategy to overcome key barriers to effective treatment of glioblastoma,” the authors stated.

“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.”

The findings point to 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 I clinical trial in patients with the disease.

“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.”

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