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ResearchIn-Press PreviewImmunologyOncology Open Access | 10.1172/jci.insight.196296

Locoregionally delivered PD-1 blockade augments B7-H3 targeting CAR T cell efficacy in models of glioblastoma

Jonathan F. Khan,1 Parwiz Abrahimi,1 Winson Cai,2 Lauren Dong,1 Kenny Kwok-Hei Yu,3 Svena Verma,1 Yacine Marouf,1 Sadna Budhu,1 Tara Pal Chaudhuri,1 Valeria Estrada Navarro,1 Mamadou A. Bah,1 Kelsey Hopland,4 Yanhong Yang,3 Terence J. Purdon,5 Ileana C. Miranda,6 Viviane Tabar,3 Jedd D. Wolchok,1 Taha Merghoub,1 and Renier J. Brentjens5

1Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New York, United States of America

2Department of Pharmacology, Weill Cornell Medicine, New York, United States of America

3Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Neuroscience, Weill Cornell Medicine, New York, United States of America

5Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Laboratory of Comparative Pathology, Weill Cornell Medicine, New York, United States of America

7Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New york, United States of America

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1Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New York, United States of America

2Department of Pharmacology, Weill Cornell Medicine, New York, United States of America

3Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Neuroscience, Weill Cornell Medicine, New York, United States of America

5Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Laboratory of Comparative Pathology, Weill Cornell Medicine, New York, United States of America

7Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New york, United States of America

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1Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New York, United States of America

2Department of Pharmacology, Weill Cornell Medicine, New York, United States of America

3Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Neuroscience, Weill Cornell Medicine, New York, United States of America

5Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Laboratory of Comparative Pathology, Weill Cornell Medicine, New York, United States of America

7Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New york, United States of America

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1Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New York, United States of America

2Department of Pharmacology, Weill Cornell Medicine, New York, United States of America

3Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Neuroscience, Weill Cornell Medicine, New York, United States of America

5Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Laboratory of Comparative Pathology, Weill Cornell Medicine, New York, United States of America

7Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New york, United States of America

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1Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New York, United States of America

2Department of Pharmacology, Weill Cornell Medicine, New York, United States of America

3Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Neuroscience, Weill Cornell Medicine, New York, United States of America

5Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Laboratory of Comparative Pathology, Weill Cornell Medicine, New York, United States of America

7Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New york, United States of America

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1Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New York, United States of America

2Department of Pharmacology, Weill Cornell Medicine, New York, United States of America

3Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Neuroscience, Weill Cornell Medicine, New York, United States of America

5Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Laboratory of Comparative Pathology, Weill Cornell Medicine, New York, United States of America

7Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New york, United States of America

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1Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New York, United States of America

2Department of Pharmacology, Weill Cornell Medicine, New York, United States of America

3Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Neuroscience, Weill Cornell Medicine, New York, United States of America

5Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Laboratory of Comparative Pathology, Weill Cornell Medicine, New York, United States of America

7Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New york, United States of America

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1Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New York, United States of America

2Department of Pharmacology, Weill Cornell Medicine, New York, United States of America

3Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Neuroscience, Weill Cornell Medicine, New York, United States of America

5Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Laboratory of Comparative Pathology, Weill Cornell Medicine, New York, United States of America

7Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New york, United States of America

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1Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New York, United States of America

2Department of Pharmacology, Weill Cornell Medicine, New York, United States of America

3Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Neuroscience, Weill Cornell Medicine, New York, United States of America

5Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Laboratory of Comparative Pathology, Weill Cornell Medicine, New York, United States of America

7Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New york, United States of America

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1Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New York, United States of America

2Department of Pharmacology, Weill Cornell Medicine, New York, United States of America

3Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Neuroscience, Weill Cornell Medicine, New York, United States of America

5Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Laboratory of Comparative Pathology, Weill Cornell Medicine, New York, United States of America

7Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New york, United States of America

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1Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New York, United States of America

2Department of Pharmacology, Weill Cornell Medicine, New York, United States of America

3Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Neuroscience, Weill Cornell Medicine, New York, United States of America

5Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Laboratory of Comparative Pathology, Weill Cornell Medicine, New York, United States of America

7Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New york, United States of America

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1Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New York, United States of America

2Department of Pharmacology, Weill Cornell Medicine, New York, United States of America

3Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Neuroscience, Weill Cornell Medicine, New York, United States of America

5Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Laboratory of Comparative Pathology, Weill Cornell Medicine, New York, United States of America

7Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New york, United States of America

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1Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New York, United States of America

2Department of Pharmacology, Weill Cornell Medicine, New York, United States of America

3Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Neuroscience, Weill Cornell Medicine, New York, United States of America

5Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Laboratory of Comparative Pathology, Weill Cornell Medicine, New York, United States of America

7Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New york, United States of America

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1Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New York, United States of America

2Department of Pharmacology, Weill Cornell Medicine, New York, United States of America

3Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Neuroscience, Weill Cornell Medicine, New York, United States of America

5Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Laboratory of Comparative Pathology, Weill Cornell Medicine, New York, United States of America

7Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New york, United States of America

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1Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New York, United States of America

2Department of Pharmacology, Weill Cornell Medicine, New York, United States of America

3Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Neuroscience, Weill Cornell Medicine, New York, United States of America

5Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Laboratory of Comparative Pathology, Weill Cornell Medicine, New York, United States of America

7Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New york, United States of America

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1Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New York, United States of America

2Department of Pharmacology, Weill Cornell Medicine, New York, United States of America

3Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Neuroscience, Weill Cornell Medicine, New York, United States of America

5Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Laboratory of Comparative Pathology, Weill Cornell Medicine, New York, United States of America

7Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New york, United States of America

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1Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New York, United States of America

2Department of Pharmacology, Weill Cornell Medicine, New York, United States of America

3Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Neuroscience, Weill Cornell Medicine, New York, United States of America

5Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Laboratory of Comparative Pathology, Weill Cornell Medicine, New York, United States of America

7Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New york, United States of America

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1Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New York, United States of America

2Department of Pharmacology, Weill Cornell Medicine, New York, United States of America

3Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Neuroscience, Weill Cornell Medicine, New York, United States of America

5Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Laboratory of Comparative Pathology, Weill Cornell Medicine, New York, United States of America

7Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New york, United States of America

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1Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New York, United States of America

2Department of Pharmacology, Weill Cornell Medicine, New York, United States of America

3Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Neuroscience, Weill Cornell Medicine, New York, United States of America

5Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

6Laboratory of Comparative Pathology, Weill Cornell Medicine, New York, United States of America

7Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cance, Weill Cornell Medicine, New york, United States of America

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Published October 13, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.196296.
Copyright © 2026, Khan et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 13, 2026 - Version history
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Abstract

Glioblastoma (GBM) is a lethal brain tumor with a 95% five-year mortality rate, and remains a major unmet clinical need. An innovative approach to target GBM is administration of chimeric antigen receptor (CAR) T cells. In this study we identified B7-H3 as a favorable target antigen for CAR T cell therapy of GBM and developed a B7-H3 targeting CAR T cell. This CAR demonstrates robust, antigen-specific cytolysis and cytokine production, low tonic signaling, and preservation of a stem/naïve cell phenotype. Using orthotopic xenograft models of GBM we show that a single intravenous administration of this B7-H3 targeted CAR confers tumor control, and long-term survival. We identified upregulation of T cell inhibitory ligands PD-L1 and PD-L2 as a mechanism of resistance, and modified our B7-H3 targeting CAR vector to include a secreted a PD-1 blocking scFv. We further demonstrate that concomitant PD-1 blockade by the secreted PD-1 blocking scFv augments the antitumor capabilities of B7-H3-targeting CAR T cells through increased intratumoral infiltration by the CAR T cells and improved effector function. These data demonstrate B7-H3 targeting CAR T cells with concomitant PD-1 blockade is a safe and efficient method for improving the antitumor capacity of CAR T cells for GBM.

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