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.
Overview
- The study investigated the use of patient-derived tumor organoids to aid in the interpretation of patient treatment responses in clinics.
- The researchers analyzed six sets of glioblastoma organoids treated with autologous CAR-T cell products and correlated the results with patient outcomes.
- The primary objective of the study was to assess the bioactivity of CAR-T cells in real-time and gather insights into immunotherapy efficacy.
Comparative Analysis & Findings
- CAR-T cell treatment led to a reduction in target antigen and cytolysis of tumor cells in glioblastoma organoids, which correlated with CAR-T cell engraftment in patient cerebrospinal fluid.
- The cytokine release patterns in glioblastoma organoids mirrored those in patient cerebrospinal fluid samples over time, suggesting a biological relevance between the two models.
- The study's findings highlight the potential of glioblastoma organoids as a valuable platform for real-time assessment of CAR-T cell bioactivity and insights into immunotherapy efficacy.
Implications and Future Directions
- The study demonstrates the potential of using patient-derived glioblastoma organoids to aid in the interpretation of patient treatment responses in clinics, particularly for CAR-T cell therapies.
- Future studies could explore the use of glioblastoma organoids as a preclinical model for evaluating the efficacy of different CAR-T cell products and optimizing treatment strategies.
- The findings could also inform the development of novel immunotherapies and combination therapies for glioblastoma and other cancers, by providing insights into the biological mechanisms underlying CAR-T cell activity in real-time.