Researchers at the University of California, Los Angeles (UCLA) have engineered a next-generation CAR-T cell therapy designed to overcome one of the biggest challenges in cancer immunotherapy: the protective microenvironment that shields solid tumors from immune attack.
The approach, reported in Science Translational Medicine, equips CAR-T cells with the ability to block vascular endothelial growth factor (VEGF), a protein that many tumors use to build blood vessels, adapt to low-oxygen conditions, and suppress immune activity. By neutralizing VEGF directly within tumors, the engineered cells can both attack cancer cells and dismantle the defenses that often limit CAR-T effectiveness in solid cancers.
CAR-T therapies have transformed treatment for several blood cancers, but translating the technology to solid tumors has proved difficult, with a major reason being that these tumors create an immunosuppressive microenvironment to protect themselves.
To address this issue, the team engineered CAR-T cells to produce a small antibody fragment known as a single-chain variable fragment (scFv) that blocks VEGF. Instead of delivering an anti-VEGF drug systemically – an approach that can lead to side effects – the modified immune cells release the inhibitor locally within the tumor environment. As CAR-T cells expand at tumor sites, the VEGF-blocking molecule becomes concentrated where it is needed most.
In preclinical mouse models of glioblastoma and ovarian cancer, these “armored” CAR-T cells outperformed conventional CAR-T therapy as well as CAR-T combined with systemic anti-VEGF antibodies. In ovarian cancer models, the engineered cells slowed tumor growth and improved survival, while also boosting levels of interferon-gamma, a key immune signaling molecule.
The results were even more striking in aggressive glioma models. The armored CAR-T therapy completely eliminated tumors in 63–88 percent of mice, compared with complete responses in 0–38 percent of animals treated with standard CAR-T cells.
Researchers also observed that the modified cells helped normalize tumor blood vessels and reduce oxygen deprivation – factors that can otherwise promote tumor survival and suppress immune responses. The therapy appeared to energize CAR-T cells and encourage other immune cells in the tumor microenvironment to adopt cancer-fighting behavior.
The findings highlight a growing trend in immunotherapy development: engineering CAR-T cells not only to recognize cancer cells but also to reshape the tumor environment that enables their survival. And while the research remains at a preclinical stage, the strategy could broaden the potential of CAR-T therapies to treat solid tumors that have historically resisted immunotherapy.
Newsletters
Receive the latest pharmaceutical news, personalities, education, and career development – weekly to your inbox.
