Abstract

Cytokine therapy, involving interleukin-15 (IL-15), is a promising strategy for cancer immunotherapy. However, clinical application has been limited due to severe toxicity and the relatively low immune response rate, caused by wide distribution of cytokine receptors, systemic immune activation and short half-life of IL-15. Here we show that a biomimetic nanovaccine, developed to co-deliver IL-15 and an antigen/major histocompatibility complex (MHC) selectively targets IL-15 to antigen-specific cytotoxic T lymphocytes (CTL), thereby reducing off-target toxicity. The biomimetic nanovaccine is composed of cytomembrane vesicles, derived from genetically engineered dendritic cells (DC), onto which IL-15/IL-15 receptor α (IL-15Rα), tumor-associated antigenic (TAA) peptide/MHC-I, and relevant costimulatory molecules are simultaneously anchored. We demonstrate that, in contrast to conventional IL-15 therapy, the biomimetic nanovaccine with multivalent IL-15 self-transpresentation (biNV-IL-15) prolonged blood circulation of the cytokine with an 8.2-fold longer half-life than free IL-15 and improved the therapeutic window. This dual targeting strategy allows for spatiotemporal manipulation of therapeutic T cells, elicits broad spectrum antigen-specific T cell responses, and promotes cures in multiple syngeneic tumor models with minimal systemic side effects.

Cancer immune therapy utilizing interleukin 15 (Il-15) is hampered by the short half-life and systemic toxic effects of the cytokine. Here authors introduce a biomimetic nanovaccine, in which Il-15 and tumor-associated antigenic peptide/MHC-I complexes are co-anchored to cell membrane vesicles of dendritic cell origin, which elicits antigen-specific T cell response leading to superior anti-tumour effect in syngeneic mouse tumour models.

Details

Title
Biomimetic nanovaccine-mediated multivalent IL-15 self-transpresentation (MIST) for potent and safe cancer immunotherapy
Author
Wang, Kaiyuan 1   VIAFID ORCID Logo  ; Zhang, Xuanbo 1 ; Ye, Hao 2   VIAFID ORCID Logo  ; Wang, Xia 3 ; Fan, Zhijin 4   VIAFID ORCID Logo  ; Lu, Qi 5 ; Li, Songhao 5 ; Zhao, Jian 5 ; Zheng, Shunzhe 5 ; He, Zhonggui 5   VIAFID ORCID Logo  ; Ni, Qianqian 6 ; Chen, Xiaoyuan 7   VIAFID ORCID Logo  ; Sun, Jin 5   VIAFID ORCID Logo 

 Shenyang Pharmaceutical University, Department of Pharmaceutics, Wuya College of Innovation, Shenyang, P. R. China (GRID:grid.412561.5) (ISNI:0000 0000 8645 4345); National University of Singapore, Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431) 
 Shenyang Pharmaceutical University, Department of Pharmaceutics, Wuya College of Innovation, Shenyang, P. R. China (GRID:grid.412561.5) (ISNI:0000 0000 8645 4345); Institute of Robotics & Intelligent Systems (IRIS), ETH Zurich, Multi-Scale Robotics Lab (MSRL), Zurich, Switzerland (GRID:grid.5801.c) (ISNI:0000 0001 2156 2780) 
 Shenyang Pharmaceutical University, School of Pharmacy, Shenyang, China (GRID:grid.412561.5) (ISNI:0000 0000 8645 4345) 
 South China University of Technology, School of Medicine, Guangzhou, P.R. China (GRID:grid.79703.3a) (ISNI:0000 0004 1764 3838) 
 Shenyang Pharmaceutical University, Department of Pharmaceutics, Wuya College of Innovation, Shenyang, P. R. China (GRID:grid.412561.5) (ISNI:0000 0000 8645 4345) 
 National University of Singapore, Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431); National University of Singapore, Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431); National University of Singapore, Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431) 
 National University of Singapore, Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431); National University of Singapore, Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431); National University of Singapore, Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431); Agency for Science, Technology, and Research (A*STAR), Institute of Molecular and Cell Biology, Singapore, Singapore (GRID:grid.418812.6) (ISNI:0000 0004 0620 9243) 
Pages
6748
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2881060505
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.