Solid tumor-on-chip model for efficacy and safety assessment of CAR-T cell therapy

Maulana, T. I.; Teufel, C.; Cipriano, M.; Lazarevski, L.; van den Hil, F. E.; Orlova, V.; Koch, A.; Alb, M.; Hudecek, M.; Loskill, P.

doi:10.1101/2023.07.13.548856

bioRxiv · 10.1101/2023.07.13.548856

Solid tumor-on-chip model for efficacy and safety assessment of CAR-T cell therapy

Maulana, T. I.·Teufel, C.·Cipriano, M.·Lazarevski, L.·van den Hil, F. E.·Orlova, V.·Koch, A.·Alb, M.·Hudecek, M.·Loskill, P.

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Abstract

The non-clinical assessment of CAR-T cells demands innovative models that are capable of predicting safety and efficacy in the clinical setting. Here, we present a novel solid tumor-on-chip model that allows CAR-T cell perfusion and integrates the vasculature and tumor lesions to recapitulate key events of CAR-T cell performance including extravasation, tumor infiltration and cytokine release. We assessed CAR-T cells targeting the ROR1 antigen against tumor aggregates that were derived from a breast cancer cell line and primary breast cancer organoids. The data show the temporal kinetic of ROR1 CAR-T cell migration and expansion, lytic activity and cytokine production over the course of 8 days, and reveal a correlation between anti-tumor efficacy and ROR1 antigen density on tumor cells. CAR-modified T cells extravasated faster, infiltrated tumor lesions stronger, persisted longer and in higher numbers than non-CAR modified T cells. Intriguingly, we detected cytokine release levels and kinetics typically observed in patients who developed cytokine release syndrome, and administered dasatinib as a pharmacologic OFF switch to control this inflammatory response. The data illustrate the ability of this tumor-on-chip platform to assess parameters associated withherapeutic outcome and the potential to aid in patient stratification and monitoring of CAR-T cell therapy.

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Maulana, T. I., Teufel, C., Cipriano, M., Lazarevski, L., van den Hil, F. E., Orlova, V., Koch, A., Alb, M., Hudecek, M., Loskill, P.. 2023-07-15. Solid tumor-on-chip model for efficacy and safety assessment of CAR-T cell therapy. https://doi.org/10.1101/2023.07.13.548856

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