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

## TL;DR

This study compares different CAR-T cell designs targeting CD70 in glioblastoma and finds that a ligand-based design shows the best anti-tumor effects in various models.

## Contribution

The study provides the first comparative evaluation of CD70-directed CAR-T cell designs for glioblastoma treatment.

## Key findings

- CD70-targeting CAR-T cells with CD27z co-stimulatory domains secrete the highest levels of Th1 cytokines.
- The CD27z-based CAR-T cells showed superior survival outcomes in an orthotopic glioblastoma mouse model.
- Murine CD27-based constructs demonstrated potent antitumor activity in vitro and in immunocompetent mouse models.

## 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 CD70 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 in vitro 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.

In this study, Kourtesakis and colleagues present a comprehensive comparative analysis of different CD70-targeting CAR-T cells in glioblastoma. Their work identifies a ligand-based design with superior anti-tumor activity across different platforms, including brain cancer cells, cerebral organoids, and mouse models, highlighting its translational potential for clinical development.