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bioRxiv · 10.1101/2025.01.10.632392

Highly potent novel multi-armoured IL13Rα2 CAR-T subverts the immunosuppressive microenvironment of Glioblastoma

Mangolini, M.·Srivastava, S.·Souster, E.·Yang, Y.·Wang, H.·Karattil, R.·Schultz, L.·Ma, B.·Pombal, D.·Greenig, M.·Ramon, A.·Sormanni, P.·Cordoba, S.·Onuoha, S.
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Abstract

Glioblastoma remains one of the most challenging and lethal brain cancers, with limited treatment options. While CAR-T cells have shown promise in some patients, sustaining T-cell activity and overcoming the immunosuppressive tumour microenvironment remain significant hurdles. Here, we present an armoured CAR-T cell design to address these challenges and enhance persistence in GBM tumours. We developed a highly specific humanised single-domain antibody targeting IL13R2 and included it alongside four additional modular elements in a single retroviral vector for CAR-T generation. Our results demonstrate that this single-cassette CAR-T cell design possesses high resilience against TGF-{beta}-mediated immunosuppression, enhanced tumour-killing capacity through IL-12 secretion while maintaining a favourable safety profile, extended persistence in the host, and an additional layer of safety control through the incorporation of a suicide switch. Importantly, despite its complexity, the construct can still be manufactured efficiently. These advancements represent a significant step forward in addressing key challenges associated with CAR-T cell therapy in solid tumours.

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Mangolini, M., Srivastava, S., Souster, E., Yang, Y., Wang, H., Karattil, R., Schultz, L., Ma, B., Pombal, D., Greenig, M., Ramon, A., Sormanni, P., Cordoba, S., Onuoha, S.. 2025-01-14. Highly potent novel multi-armoured IL13Rα2 CAR-T subverts the immunosuppressive microenvironment of Glioblastoma. https://doi.org/10.1101/2025.01.10.632392

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