The critical role of the endogenous immune compartment after CAR T cell therapy in recurrent GBM
Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with a median survival of under 15 months and no effective treatment after recurrence. A recent phase 1 trial of intracerebroventricular bivalent chimeric antigen receptor (CAR) T cells in recurrent GBM, registered at ClinicalTrials.gov (NCT05168423), showed promising responses, including tumor reduction and prolonged survival. However, relapse remains common. We performed in-depth profiling of longitudinal cerebrospinal fluid (CSF) and tumor samples from responders and non-responders to characterize immune dynamics following infusion. Our study reveals that, although CAR T cells activate post infusion across all patients, outcomes were defined by divergent remodeling of the endogenous immune landscape. Cytotoxic natural killer cell expansion characterized responders, whereas regulatory T cell expansion and abundant baseline immunosuppressive scavenger myeloid cells characterized non-responders. These findings indicate that host immune cells play a critical role in CAR T cell therapy for GBM, suggesting that combinatorial strategies modulating the endogenous immune compartment could improve next-generation treatments.
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BibTeX
@article{freeburg2026critical,
title = {{The critical role of the endogenous immune compartment after CAR T cell therapy in recurrent GBM}},
author = {Nelson F Freeburg and Daniel Chafamo and Gayathri Konanur Gopikrishna and Regan M Murphy and Jacqueline J Peng and Shridhar Parthasarathy and Sydney Dumont and Edward G Estrada and Meghan T Logun and Yusha Sun and Xin Wang and Payal Grover and Jesse L Rodriguez and Daniel L Zhang and Kristen Park and Yao Fu and Nadine Ben Hamouda and Isaias Hernandez-Verdin and Lamia Lamrani and Kelly A Hicks and Natalie A Cooper and Christina Ekwegbara and Emma Grace Bawden and Joshua J Waterfall and Jaime Fuentealba and Marion Alcantara and John T Seykora and Stephen M Prouty and David Barrett and Esha Banerjee and Arin Cox and Charles-Antoine Assenmacher and Camilla Macia and Melinda Yin and Erica L Carpenter and Guo-Li Ming and Catherine Sautès-Fridman and Wolf H Fridman and Eric Tartour and E John Wherry and Sebastian Amigorena and Joseph A Fraietta and Maclean P Nasrallah and Hongjun Song and Tyler E Miller and Stephen J Bagley and Donald M O’rourke and Zev A Binder and Cécile Alanio and Dana Silverbush},
journal = {Cell},
year = {2026},
month = oct,
doi = {10.1016/j.cell.2026.05.026},
url = {https://cnrs.hal.science/hal-05829062v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The critical role of the endogenous immune compartment after CAR T cell therapy in recurrent GBM
AU - Nelson F Freeburg
AU - Daniel Chafamo
AU - Gayathri Konanur Gopikrishna
AU - Regan M Murphy
AU - Jacqueline J Peng
AU - Shridhar Parthasarathy
AU - Sydney Dumont
AU - Edward G Estrada
AU - Meghan T Logun
AU - Yusha Sun
AU - Xin Wang
AU - Payal Grover
AU - Jesse L Rodriguez
AU - Daniel L Zhang
AU - Kristen Park
AU - Yao Fu
AU - Nadine Ben Hamouda
AU - Isaias Hernandez-Verdin
AU - Lamia Lamrani
AU - Kelly A Hicks
AU - Natalie A Cooper
AU - Christina Ekwegbara
AU - Emma Grace Bawden
AU - Joshua J Waterfall
AU - Jaime Fuentealba
AU - Marion Alcantara
AU - John T Seykora
AU - Stephen M Prouty
AU - David Barrett
AU - Esha Banerjee
AU - Arin Cox
AU - Charles-Antoine Assenmacher
AU - Camilla Macia
AU - Melinda Yin
AU - Erica L Carpenter
AU - Guo-Li Ming
AU - Catherine Sautès-Fridman
AU - Wolf H Fridman
AU - Eric Tartour
AU - E John Wherry
AU - Sebastian Amigorena
AU - Joseph A Fraietta
AU - Maclean P Nasrallah
AU - Hongjun Song
AU - Tyler E Miller
AU - Stephen J Bagley
AU - Donald M O’rourke
AU - Zev A Binder
AU - Cécile Alanio
AU - Dana Silverbush
PY - 2026
DA - 2026/10/21
JO - Cell
DO - 10.1016/j.cell.2026.05.026
UR - https://cnrs.hal.science/hal-05829062v1
AB - Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with a median survival of under 15 months and no effective treatment after recurrence. A recent phase 1 trial of intracerebroventricular bivalent chimeric antigen receptor (CAR) T cells in recurrent GBM, registered at ClinicalTrials.gov (NCT05168423), showed promising responses, including tumor reduction and prolonged survival. However, relapse remains common. We performed in-depth profiling of longitudinal cerebrospinal fluid (CSF) and tumor samples from responders and non-responders to characterize immune dynamics following infusion. Our study reveals that, although CAR T cells activate post infusion across all patients, outcomes were defined by divergent remodeling of the endogenous immune landscape. Cytotoxic natural killer cell expansion characterized responders, whereas regulatory T cell expansion and abundant baseline immunosuppressive scavenger myeloid cells characterized non-responders. These findings indicate that host immune cells play a critical role in CAR T cell therapy for GBM, suggesting that combinatorial strategies modulating the endogenous immune compartment could improve next-generation treatments.
SN - 0092-8674
SN - 1097-4172
ER -