Patient-derived glioblastoma organoids as real-time avatars for assessing responses to clinical CAR-T cell therapy

SUMMARY Patient-derived tumor organoids have been leveraged for disease modeling and preclinical studies, but rarely applied in real-time to aid with interpretation of patient treatment responses in clinics. We recently demonstrated early efficacy signals in a first-in-human, phase 1 study of dual-targeting chimeric antigen receptor T cells (EGFR-IL13Rα2 CAR-T cells) in patients with recurrent glioblastoma. Here we analyzed six sets of patient-derived glioblastoma organoids (GBOs) treated concurrently with the same autologous CAR-T cell products as patients in our phase 1 study. We found that CAR-T cell treatment led to target antigen reduction and cytolysis of tumor cells in GBOs, the degree of which correlated with CAR-T cell engraftment detected in patients’ cerebrospinal fluid (CSF). Furthermore, cytokine release patterns in GBOs mirrored patient CSF samples over time. Our findings highlight a unique trial design and GBOs as a valuable platform for real-time assessment of CAR-T cell bioactivity and insights into immunotherapy efficacy.