Spatiotemporally controllable diphtherin transgene system and neoantigen immunotherapy

Muye He; Yuji Sun; Yi Cheng; Jie Wang; Miao Zhang; Rui Sun; Xinyu Hou; Jiajun Xu; Hai He; Hongtao Wang; Zeting Yuan; Minbo Lan; Yuzheng Zhao; Yi Yang; Xianjun Chen; Feng Gao

doi:10.1016/j.jconrel.2022.08.059

Spatiotemporally controllable diphtherin transgene system and neoantigen immunotherapy

J Control Release. 2023 Mar:355:538-551. doi: 10.1016/j.jconrel.2022.08.059. Epub 2023 Feb 14.

Authors

Muye He¹, Yuji Sun², Yi Cheng², Jie Wang², Miao Zhang², Rui Sun², Xinyu Hou², Jiajun Xu², Hai He², Hongtao Wang², Zeting Yuan³, Minbo Lan⁴, Yuzheng Zhao⁵, Yi Yang⁶, Xianjun Chen⁷, Feng Gao⁸

Affiliations

¹ Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai 200237, China; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Optogenetics and Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China.
² Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
³ Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China.
⁴ Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai 200237, China.
⁵ Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Optogenetics and Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China; Research Unit of New Techniques for Live-cell Metabolic Imaging, Chinese Academy of Medical Sciences, Beijing, China.
⁶ Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Optogenetics and Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China; CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
⁷ Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Optogenetics and Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China; CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: xianjunchen@ecust.edu.cn.
⁸ Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai 200237, China; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Optogenetics and Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China. Electronic address: fgao@ecust.edu.cn.

PMID: 36063962
DOI: 10.1016/j.jconrel.2022.08.059

Abstract

Individualized immunotherapy has attracted great attention due to its high specificity, effectiveness, and safety. We used an exogenous antigen to label tumor cells with MHC I molecules, which allowed neoantigen-specific T cells to recognize and kill tumor cells. A neoantigen vaccine alone cannot achieve complete tumor clearance due to a tumor immunosuppressive microenvironment. The LightOn system was developed to effectively eliminate tumor cells through the spatiotemporally controllable expression of diphtheria toxin A fragment, leading to antigen release in the tumor region. These antigens stimulated and enhanced immunological function and thus, recruited neoantigen-specific T cells to infiltrate tumor tissue. Using the nanoparticle delivery system, neoantigens produced higher delivery efficiency to lymph nodes and improved tumor targeting ability for tumor cell labelling. Good tumor inhibition and prolonged survival were achieved, while eliciting a strong immune response. The combination of a spatiotemporally controllable transgene system with tumor neoantigen labeling has great potential for tumor immunotherapy.

Keywords: Immunotherapy; Light-switchable diphtherin gene expression; Melanoma; Nanoparticle delivery system; Neoantigen.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigens, Neoplasm
Cancer Vaccines* / genetics
Histocompatibility Antigens Class I
Humans
Immunotherapy
Neoplasms* / therapy
T-Lymphocytes
Tumor Microenvironment

Substances

Antigens, Neoplasm
Histocompatibility Antigens Class I
Cancer Vaccines