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Inhibition of post-surgery tumour recurrence via a hydrogel releasing CAR-T cells and anti-PDL1-conjugated platelets

Abstract

The immunosuppressive microenvironment of solid tumours reduces the antitumour activity of chimeric antigen receptor T cells (CAR-T cells). Here, we show that the release—through the implantation of a hyaluronic acid hydrogel—of CAR-T cells targeting the human chondroitin sulfate proteoglycan 4, polymer nanoparticles encapsulating the cytokine interleukin-15 and platelets conjugated with the checkpoint inhibitor programmed death-ligand 1 into the tumour cavity of mice with a resected subcutaneous melanoma tumour inhibits the local recurrence of the tumour as well as the growth of distant tumours, through the abscopal effect. The hydrogel, which functions as a reservoir, facilitates the enhanced distribution of the CAR-T cells within the surgical bed, and the inflammatory microenvironment triggers platelet activation and the subsequent release of platelet-derived microparticles. The post-surgery local delivery of combination immunotherapy through a biocompatible hydrogel reservoir could represent a translational route for preventing the recurrence of cancers with resectable tumours.

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Fig. 1: Characterization of the engineered hydrogel-based cell delivery.
Fig. 2: CAR-T cells encapsulated in the hydrogel target WM115 melanoma cells in vitro.
Fig. 3: CAR-T cells encapsulated in the hydrogel control WM115 melanoma growth in vivo.
Fig. 4: CAR-T cells encapsulated in the hydrogel persist and expand in vivo.
Fig. 5: Engineered hydrogel cell delivery promotes abscopal antitumour effects.

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. All data generated in this study, including source data and the data used to make the figures, are available from Figshare (https://figshare.com/s/fa6578df11fba2539c13).

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Acknowledgements

This work was supported by grants from the Jonsson Comprehensive Cancer Center at UCLA, the Alfred P. Sloan Foundation (Sloan Research Fellowship), NIH 1R01CA234343-01A1, a pilot grant from the UNC Cancer Center and the start-up package from Zhejiang University to Z.G.

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Contributions

Q.H., G.D. and Z.G. designed the experiments. Q.H., H.L., E.A., Q.C., H.R., S.A., E.D., Y.K. and D.W. performed the experiments and collected the data. All of the authors contributed to writing the manuscript, discussing the results and implications, and editing the manuscript at all stages.

Corresponding authors

Correspondence to Gianpietro Dotti or Zhen Gu.

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Competing interests

Patents describing the drug-delivery system documented in this Article have been filed with the US Patent Office. Q.H. and Z.G. are listed as inventors on the provisional patent application (provisional patent application no. 63/055,738). Z.G. is the co-founder of Zencapsule Inc., and the other authors declare no competing interests.

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Hu, Q., Li, H., Archibong, E. et al. Inhibition of post-surgery tumour recurrence via a hydrogel releasing CAR-T cells and anti-PDL1-conjugated platelets. Nat Biomed Eng (2021). https://doi.org/10.1038/s41551-021-00712-1

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