UCLA researchers have developed a new form of CAR-T cell therapy designed to counteract the immunosuppressive environment that protects solid tumors from immune attack. By engineering CAR-T cells to block vascular endothelial growth factor (VEGF), a protein produced by tumors to support their growth and defense, the scientists aimed to enhance both direct cancer cell targeting and the dismantling of tumor defenses.
The research team tested these "armored" CAR-T cells in mouse models of glioblastoma and ovarian cancer. Results showed that these engineered cells were more effective than standard CAR-T therapies or those combined with systemic anti-VEGF antibodies. The armored CAR-T cells reduced tumor growth and improved survival rates in preclinical studies.
VEGF-blocking drugs such as bevacizumab are already used for several cancers but often provide limited benefits and can cause side effects throughout the body. The UCLA approach differs by having the CAR-T cells secrete a VEGF-blocking antibody fragment, called a single-chain variable fragment (scFv), directly within the tumor environment. This design concentrates treatment where it is most needed, potentially increasing effectiveness while reducing unwanted effects elsewhere in the body.
Sanaz Memarzadeh, MD, PhD, professor at the David Geffen School of Medicine at UCLA and co-author on the study, said: "Ovarian cancer and glioblastoma, for example, are aggressive cancers that often recur despite standard therapies, and at that point, there are very few effective treatment options. In this state, current therapies may slow disease progression but rarely lead to long-term remission, highlighting the urgent need for new approaches that can overcome tumor defenses and improve patient outcomes."
The novel scFv was developed in collaboration with Dr. Han-Chung Wu's group at Academia Sinica in Taiwan. The therapy was tested against conventional CAR-T treatments in animal models by monitoring tumor progression and immune activity.
In ovarian cancer models, armored CAR-T cells slowed tumor growth more effectively than standard therapy and increased long-term survival among mice. When tested on human-derived ovarian tumors from recurrent cases, these modified cells extended survival times and increased levels of interferon-gamma—a protein important for immune response against cancer.
For aggressive glioma models, armored CAR-T cells completely eliminated tumors in 63–88% of mice compared to 0–38% complete responses with standard therapy. Researchers also observed that traditional CAR-T treatments worsened blood vessel abnormalities within tumors; however, armored versions prevented abnormal vessel growth and oxygen deprivation associated with treatment resistance.
According to Chen—a professor at UCLA’s departments of microbiology, immunology, molecular genetics as well as a member of the UCLA Broad Stem Cell Research Center—"This is an exciting step toward making CAR-T therapy effective against solid tumors. By giving CAR-T cells the ability to reshape the tumor environment, we hope to generate a therapy that not only attacks tumor cells directly but also awakens and recruits the endogenous immune system in the fight against cancer."
The study’s first author is Torahito Gao from Chen Laboratory at UCLA; other contributors include Ryan Shih, Justin Clubb, Tanya Singh, Laura James-Allan, Gabriella DiBernardo, Amanda Shafer, Amber Bouren, Melanie Ayala Ceja, Sophie Ong, Andréa Ball and Ajit Divakaruni.
