Authors: 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, and Donald M. O’Rourke
Cell Stem Cell - Clinical and Translational Report, 09 December 2024
Scientists describe an innovative phase 1 clinical trial evaluating a bivalent CAR T-cell therapy in patients with recurrent glioblastoma and in patient-derived glioblastoma organoids (GBOs), highlighting the use of Axion’s label-free Maestro Z to assess cell killing and predict clinical outcomes in cancer models.
Glioblastoma brain cancers represent an area of huge unmet need in oncology. Although CAR T-cell therapies have shown promise in preclinical studies, therapeutic efficacy has been limited—in part, according to the authors, due to a lack of biologically relevant cancer models able to accurately represent the tissue heterogeneity and complex tumor microenvironment seen in solid tumors. In this study, scientists describe their first-in-human clinical trial evaluating the efficacy of dual-targeting chimeric antigen receptor T cells (EGFR-IL13Rα2 CAR-T cells) in people with recurrent glioblastoma and highlight how the use of rapidly generated patient-derived glioblastoma organoids (GBOs) from fresh tumor specimens can overcome the limitations of traditional cell culture models and serve “as a valuable platform for real-time assessment of CAR-T cell bioactivity and insights into immunotherapy efficacy.”
To assess CAR T-cell treatment response killing in GBOs co-cultured with patient-matched CAR-T cells, the team used Axion’s real-time, label-free Maestro Z live-cell analysis platform and found that each set of patient-derived GBOs and autologous CAR T cells “demonstrated significant tumor cytolysis over time as assessed by changes in electrical impedance.” The team also used Maestro Z to demonstrate that the magnitude of cytolysis at 24 hours correlated with peak CSF engraftment in patients after receiving CAR T cell therapy, findings supported by magnetic resonance imaging. These exciting ex vivo results “provide direct evidence for the efficacy of the CAR-T cell treatment in tumor killing.”
To gain even deeper insights into the dynamics of T cell activation, the team collected CAR T cell-GBO co-culture media from Axion’s CytoView-Z 96-well plates to detect IFNg, TNFα, and IL-2 levels, and compared the results with cytokine levels found in patients’ CSF. According to lead author Meghan Logun, PhD, in a recent webinar, the results showing a clear correlation between the two were “pretty incredible to see,” and that multiplexed cytokine measurements “could be a good additional real-time assessment to you give more color into what’s happening in the patient.”
Taken together with other findings revealing mechanisms of target antigen reduction and cytokine release, the authors conclude that their proof-of-principle study shows “preliminary success in correlating ex vivo GBO responses with in vivo patient responses,” and suggest that the data “provide a foundation for the future application of GBOs as avatars for testing treatment response in real time to stratify patients for clinical trials and to prioritize potential personalized treatment options.”
