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

Quanyin Hu; Hongjun Li; Edikan Archibong; Qian Chen; Huitong Ruan; Sarah Ahn; Elena Dukhovlinova; Yang Kang; Di Wen; Gianpietro Dotti; Zhen Gu

doi:10.1038/s41551-021-00712-1

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

Nat Biomed Eng. 2021 Sep;5(9):1038-1047. doi: 10.1038/s41551-021-00712-1. Epub 2021 Apr 26.

Authors

Quanyin Hu^#^{1

2

3

4}, Hongjun Li^#^{1

2

5

6}, Edikan Archibong^{3

7}, Qian Chen^{1

2

3}, Huitong Ruan^{1

2}, Sarah Ahn⁷, Elena Dukhovlinova⁷, Yang Kang^{1

2}, Di Wen^{1

2}, Gianpietro Dotti⁸, Zhen Gu^{9

10

11

12

13

14}

Affiliations

¹ Department of Bioengineering, University of California, Los Angeles, CA, USA.
² California NanoSystems Institute, University of California, Los Angeles, CA, USA.
³ Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, USA.
⁴ Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA.
⁵ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.
⁶ College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
⁷ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
⁸ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. gdotti@med.unc.edu.
⁹ Department of Bioengineering, University of California, Los Angeles, CA, USA. guzhen@zju.edu.cn.
¹⁰ California NanoSystems Institute, University of California, Los Angeles, CA, USA. guzhen@zju.edu.cn.
¹¹ Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, USA. guzhen@zju.edu.cn.
¹² Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA. guzhen@zju.edu.cn.
¹³ College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. guzhen@zju.edu.cn.
¹⁴ Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA, USA. guzhen@zju.edu.cn.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Monoclonal, Humanized
Blood Platelets
Cell-Derived Microparticles*
Hydrogels
Immunotherapy, Adoptive*
Mice
Neoplasm Recurrence, Local / prevention & control
T-Lymphocytes
Tumor Microenvironment

Substances

Antibodies, Monoclonal, Humanized
Hydrogels
atezolizumab

Abstract

Publication types

MeSH terms

Substances

Grants and funding