CAR Microglia Clear Glioblastoma Cells in Human Brain Organoid Models
Microglia obtained from human cortical organoids were directed against EGFRvIII. Two-dimensional and three-dimensional experiments followed phagocytosis, tumor-site infiltration and tumor-cell depletion.
Using Microglia as the Effector Cell
A Yale-led research team used microglia obtained from human cortical organoids to explore a myeloid-cell approach to glioblastoma. The cells expressed a chimeric antigen receptor (CAR) directed against EGFRvIII, a tumor-associated EGFR deletion variant. The study evaluated what these engineered microglia did after encountering tumor cells.
In a two-dimensional coculture, the CAR microglia selectively eliminated glioblastoma cells through phagocytosis. A three-dimensional glioblastoma–cortical organoid model then provided a spatial setting for observing tumor-site infiltration and tumor-cell depletion over a longer culture period.
Following the Phagocytic Response
Single-cell RNA sequencing showed increased activity of phagocytosis-associated pathways in the CAR microglia. The analysis also detected internalized tumor-derived transcripts and examined programs associated with resistance to phagocytosis. These molecular observations accompanied the functional and spatial measurements.
The two model formats answer complementary questions about the candidate cell therapy. The simpler coculture tests selective uptake and killing, while the combined tumor–brain organoid setting captures interactions within three-dimensional tissue. The study uses these human-derived systems to investigate CAR microglia as an experimental therapeutic modality for brain tumors.