期刊
NATURE BIOMEDICAL ENGINEERING
卷 5, 期 9, 页码 1038-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41551-021-00712-1
关键词
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资金
- Jonsson Comprehensive Cancer Center at UCLA
- Alfred P. Sloan Foundation (Sloan Research Fellowship)
- NIH [1R01CA234343-01A1]
- UNC Cancer Center
- Zhejiang University
The use of a hydrogel reservoir for local delivery of combination immunotherapy has shown promise in inhibiting tumor recurrence after surgery.
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. A hydrogel implanted into the cavity of a resected tumour and releasing CAR-T cells and platelets conjugated with a checkpoint inhibitor inhibits local tumour recurrence and the growth of distant tumours in mice.
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