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

Logun, M.; Wang, X.; Sun, Y. Y.; Bagley, S.; Li, N.; Desai, A.; Zhang, D. Y.; Nasrallah, M.; Pai, E. L.-L.; Oner, B. S.; Plesa, G.; Siegel, D.; Binder, Z. A.; Ming, G.-L.; Song, H.; O'Rourke, D.

doi:10.1101/2024.10.03.616503

bioRxiv · 10.1101/2024.10.03.616503

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

Logun, M.·Wang, X.·Sun, Y. Y.·Bagley, S.·Li, N.·Desai, A.·Zhang, D. Y.·Nasrallah, M.·Pai, E. L.-L.·Oner, B. S.·Plesa, G.·Siegel, D.·Binder, Z. A.·Ming, G.-L.·Song, H.·O'Rourke, D.

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Abstract

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-IL13R2 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.

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Logun, M., Wang, X., Sun, Y. Y., Bagley, S., Li, N., Desai, A., Zhang, D. Y., Nasrallah, M., Pai, E. L.-L., Oner, B. S., Plesa, G., Siegel, D., Binder, Z. A., Ming, G.-L., Song, H., O'Rourke, D.. 2024-10-04. Patient-derived glioblastoma organoids as real-time avatars for assessing responses to clinical CAR-T cell therapy. https://doi.org/10.1101/2024.10.03.616503

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