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

Meghan Logun; Xin Wang; Yusha Sun; Stephen J Bagley; Nannan Li; Arati Desai; Daniel Y Zhang; MacLean P Nasrallah; Emily Ling-Lin Pai; Bike Su Oner; Gabriela Plesa; Donald Siegel; Zev A Binder; Guo-Li Ming; Hongjun Song; Donald M O'Rourke

doi:10.1016/j.stem.2024.11.010

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

Cell Stem Cell. 2024 Dec 4:S1934-5909(24)00409-0. doi: 10.1016/j.stem.2024.11.010. Online ahead of print.

Authors

Meghan Logun¹, Xin Wang², Yusha Sun³, Stephen J Bagley⁴, Nannan Li¹, Arati Desai⁴, Daniel Y Zhang⁵, MacLean P Nasrallah⁶, Emily Ling-Lin Pai⁷, Bike Su Oner⁷, Gabriela Plesa⁷, Donald Siegel⁸, Zev A Binder⁹, Guo-Li Ming¹⁰, Hongjun Song¹¹, Donald M O'Rourke¹²

Affiliations

¹ Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
² Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
³ Neuroscience Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁴ Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁵ Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁶ Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁷ Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁸ Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁹ Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Electronic address: binderz@pennmedicine.upenn.edu.
¹⁰ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Electronic address: gming@pennmedicine.upenn.edu.
¹¹ Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Electronic address: shongjun@pennmedicine.upenn.edu.
¹² Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Electronic address: donald.orourke@pennmedicine.upenn.edu.

PMID: 39657679
DOI: 10.1016/j.stem.2024.11.010

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 (CAR)-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 those in 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.

Keywords: CAR-T cell therapy; clinical trial; cytokine; ex vivo; glioblastoma; organoid; patient-derived tumor organoid; real-time correlative.