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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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.
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.
Peer review information Nature Biomedical Engineering thanks the anonymous reviewers for their contribution to the peer review of this work.
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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