Lyophilized lymph nodes for improved delivery of chimeric antigen receptor T cells

Jiaqi Shi; Wei Wu; Dong Chen; Ziyan Liao; Tao Sheng; Yanfang Wang; Yuejun Yao; Qing Wu; Feng Liu; Ruyi Zhou; Chaojie Zhu; Xinyuan Shen; Zhengwei Mao; Yuan Ding; Weilin Wang; Gianpietro Dotti; Jie Sun; Xiao Liang; Weijia Fang; Peng Zhao; Hongjun Li; Zhen Gu

doi:10.1038/s41563-024-01825-z

Lyophilized lymph nodes for improved delivery of chimeric antigen receptor T cells

Nat Mater. 2024 Mar 6. doi: 10.1038/s41563-024-01825-z. Online ahead of print.

Authors

Jiaqi Shi^#^{1

2}, Wei Wu^#³, Dong Chen^#⁴, Ziyan Liao^{1

2}, Tao Sheng¹, Yanfang Wang¹, Yuejun Yao¹, Qing Wu^{1

2}, Feng Liu^{1

2}, Ruyi Zhou¹, Chaojie Zhu^{1

5}, Xinyuan Shen¹, Zhengwei Mao⁶, Yuan Ding⁵, Weilin Wang⁵, Gianpietro Dotti⁷, Jie Sun², Xiao Liang⁸, Weijia Fang³, Peng Zhao⁹, Hongjun Li^{10

11

12

13

14}, Zhen Gu^{15

16

17

18

19

20}

Affiliations

¹ National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
² Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
³ Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
⁴ Department of Colorectal Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
⁵ Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
⁶ MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China.
⁷ Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
⁸ Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
⁹ Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. zhaop@zju.edu.cn.
¹⁰ National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. hongjun@zju.edu.cn.
¹¹ Liangzhu Laboratory, Zhejiang University, Hangzhou, China. hongjun@zju.edu.cn.
¹² Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. hongjun@zju.edu.cn.
¹³ Jinhua Institute, Zhejiang University, Jinhua, China. hongjun@zju.edu.cn.
¹⁴ Key Laboratory for Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. hongjun@zju.edu.cn.
¹⁵ National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. guzhen@zju.edu.cn.
¹⁶ Liangzhu Laboratory, Zhejiang University, Hangzhou, China. guzhen@zju.edu.cn.
¹⁷ MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China. guzhen@zju.edu.cn.
¹⁸ Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. guzhen@zju.edu.cn.
¹⁹ Jinhua Institute, Zhejiang University, Jinhua, China. guzhen@zju.edu.cn.
²⁰ Key Laboratory for Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. guzhen@zju.edu.cn.

^# Contributed equally.

PMID: 38448658
DOI: 10.1038/s41563-024-01825-z

Abstract

Lymph nodes are crucial organs of the adaptive immune system, orchestrating T cell priming, activation and tolerance. T cell activity and function are highly regulated by lymph nodes, which have a unique structure harbouring distinct cells that work together to detect and respond to pathogen-derived antigens. Here we show that implanted patient-derived freeze-dried lymph nodes loaded with chimeric antigen receptor T cells improve delivery to solid tumours and inhibit tumour recurrence after surgery. Chimeric antigen receptor T cells can be effectively loaded into lyophilized lymph nodes, whose unaltered meshwork and cytokine and chemokine contents promote chimeric antigen receptor T cell viability and activation. In mouse models of cell-line-derived human cervical cancer and patient-derived pancreatic cancer, delivery of chimeric antigen receptor T cells targeting mesothelin via the freeze-dried lymph nodes is more effective in preventing tumour recurrence when compared to hydrogels containing T-cell-supporting cytokines. This tissue-mediated cell delivery strategy holds promise for controlled release of various cells and therapeutics with long-term activity and augmented function.