A comparative analysis of CD70-directed CAR-T cells for glioblastoma treatment demonstrates a superior efficacy of the ligand-based construct

CD70, a member of the tumor necrosis factor receptor superfamily, is expressed in glioblastoma (GB), where it promotes tumor growth, migration, and immunosuppression. Accordingly, it has emerged as a target for chimeric antigen receptor (CAR)-T cell therapy. Despite the influence of CAR structure on therapeutic efficacy, no comparative studies have evaluated different CD70-directed CAR designs in GB. Our study addressed this gap. We first validated <i>CD70</i> expression in transcriptomic datasets, patient tissue, and GB cell lines. We then generated CD70-specific CAR-T cells featuring distinct target recognition and co-stimulatory domains (CD27z, LF28z, and LFBBz) and performed phenotypic characterization. Using co-culture systems and 3D cerebral organoids, we showed that all constructs eliminated target cells in a CD70-dependent manner, with CD27z secreting the highest levels of Th1 cytokines. This functional advantage translated into superior survival in an orthotopic GB mouse model. Based on these findings, we developed a panel of murine CD27-based constructs, all of which demonstrated potent antitumor activity <i>in vitro</i> and in immunocompetent GB mouse models, further underscoring the therapeutic promise of CD27 integration into the CAR design. Collectively, our comparative analysis highlights the superior efficacy of the ligand-based construct, supporting its incorporation into a clinical trial targeting CD70 in recurrent GB.

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Publication Details

Journal
Molecular Therapy Oncology
Published
2026-01-20
DOI
https://doi.org/10.1016/j.omton.2026.201134
Primary Topic
CAR-T cell therapy research
Type
article
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article

A comparative analysis of CD70-directed CAR-T cells for glioblastoma treatment demonstrates a superior efficacy of the ligand-based construct

Rainer Will, Alexandros Kourtesakis, Abigail K. Suwala, Lukas Bunse et al.
Molecular Therapy Oncology
CAR-T cell therapy research
article

A comparative analysis of CD70-directed CAR-T cells for glioblastoma treatment demonstrates a superior efficacy of the ligand-based construct

Rainer Will, Alexandros Kourtesakis, Abigail K. Suwala, Lukas Bunse, Michael O. Breckwoldt, Carsten Müller‐Tidow, Leon D. Kaulen, Denise Reibold, Dirk Carsten Frieder Hoffmann, Ammar Jabali, Ralph Sinn, Robin J. Wagener, Dennis A. Agardy, Sandra Horschitz, S Pusch, Melissa Hahn, Christoph Schifflers, Tim Sauer, Michael Plattén, Hiu Nam Hannah Chow, Eileen Bailey, H. Rohdjeß, M. Dominik Fischer, Yu-Chan Chih, Andreas von Deimling, Michael Schmitt, Wolfgang Wick, Ling Hai, Tobias Kessler, Felix Sahm, Philipp Koch
article en

Abstract

CD70, a member of the tumor necrosis factor receptor superfamily, is expressed in glioblastoma (GB), where it promotes tumor growth, migration, and immunosuppression. Accordingly, it has emerged as a target for chimeric antigen receptor (CAR)-T cell therapy. Despite the influence of CAR structure on therapeutic efficacy, no comparative studies have evaluated different CD70-directed CAR designs in GB. Our study addressed this gap. We first validated <i>CD70</i> expression in transcriptomic datasets, patient tissue, and GB cell lines. We then generated CD70-specific CAR-T cells featuring distinct target recognition and co-stimulatory domains (CD27z, LF28z, and LFBBz) and performed phenotypic characterization. Using co-culture systems and 3D cerebral organoids, we showed that all constructs eliminated target cells in a CD70-dependent manner, with CD27z secreting the highest levels of Th1 cytokines. This functional advantage translated into superior survival in an orthotopic GB mouse model. Based on these findings, we developed a panel of murine CD27-based constructs, all of which demonstrated potent antitumor activity <i>in vitro</i> and in immunocompetent GB mouse models, further underscoring the therapeutic promise of CD27 integration into the CAR design. Collectively, our comparative analysis highlights the superior efficacy of the ligand-based construct, supporting its incorporation into a clinical trial targeting CD70 in recurrent GB.

Molecular Therapy OncologyVol. 34(1)
University of Namur (BE), University of Mannheim (DE), German Cancer Research Center (DE), Heidelberg University (DE), University Hospital Heidelberg (DE), Central Institute of Mental Health (DE), Bernstein Center for Computational Neuroscience Heidelberg-Mannheim (DE), University Medical Centre Mannheim (DE)
Openalex Percentile: Top 84%
CAR-T cell therapy research
DOIOpen Access PDFOpenAlex
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