Biomimetic nanovaccine-mediated multivalent IL-15 self-transpresentation (MIST) for potent and safe cancer immunotherapy

Kaiyuan Wang, Xuanbo Zhang, Hao Ye, Xia Wang, Zhijin Fan, Qi Lu, Songhao Li, Jian Zhao, Shunzhe Zheng, Zhonggui He (), Qianqian Ni (), Xiaoyuan Chen () and Jin Sun ()
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Kaiyuan Wang: Shenyang Pharmaceutical University
Xuanbo Zhang: Shenyang Pharmaceutical University
Hao Ye: Shenyang Pharmaceutical University
Xia Wang: Shenyang Pharmaceutical University
Zhijin Fan: South China University of Technology
Qi Lu: Shenyang Pharmaceutical University
Songhao Li: Shenyang Pharmaceutical University
Jian Zhao: Shenyang Pharmaceutical University
Shunzhe Zheng: Shenyang Pharmaceutical University
Zhonggui He: Shenyang Pharmaceutical University
Qianqian Ni: National University of Singapore
Xiaoyuan Chen: National University of Singapore
Jin Sun: Shenyang Pharmaceutical University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42155-z

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