Smart Immune Cells for Glioblastoma
With an estimated 13,000 new cases each year in the United States, glioblastoma is the most common malignant brain tumor.
Previous immunotherapies like CAR T cells were designed to target glioblastoma cells, but were only effective in killing a portion of the cells – leaving some cancer cells behind, and allowing for tumor recurrence. Traditional CAR T used a single antigen, for example EGFRvIII, to target glioblastoma cells, but only a portion of the cells expresses EGFRvIII.
UCSF researcher Hideho Okada, MD, PhD, Director of the Brain Tumor Immunotherapy Center at UCSF, collaborated with Wendell Lim, PhD, and Kole Roybal, PhD, to develop a new generation of CAR T cells for improved specificity and persistence. The remaining cancer cells could then continue growing. In contrast, other more general antigens, like EphA2, are expressed more widely across glioblastoma cells, but also in normal tissue like liver and kidney – which could create off-target effects.
To address these challenges, Okada and colleagues developed a new CAR T strategy using engineered cells that recognize multi-antigen combinations.
Using a two-stage "prime-and-kill" approach, the SynNotch-CAR T cells are first primed by the presence of tumor- or brain-specific antigens like EGFRvIII, and then programmed to kill cells carrying the more widely expressed antigens like EphA2. Alone, each are imperfect as single-antigen targets, but when used combinatorially, offer a more robust response that can tackle tumor heterogenetity without off-target effects.
Now, after 4 years of development, Okada, Lim and Roybal show that SynNotch-CAR T cells can safely target and kill human patient-derived glioblastoma cells in mouse brain, outperforming traditional CAR T therapies. Their research, featured on the cover of Science Translational Medicine, is ready to move towards clinical trials.