An engineered TNFR1-selective human lymphotoxin-alpha mutant delivered by an oncolytic adenovirus for tumor immunotherapy

Yan Cheng; Yu Liu; Dongge Xu; Dan Zhang; Yang Yang; Yuqing Miao; Susu He; Qing Xu; Erguang Li

doi:10.1016/j.bbadis.2024.167122

An engineered TNFR1-selective human lymphotoxin-alpha mutant delivered by an oncolytic adenovirus for tumor immunotherapy

Biochim Biophys Acta Mol Basis Dis. 2024 Mar 16;1870(5):167122. doi: 10.1016/j.bbadis.2024.167122. Online ahead of print.

Authors

Yan Cheng¹, Yu Liu², Dongge Xu¹, Dan Zhang³, Yang Yang⁴, Yuqing Miao⁵, Susu He⁶, Qing Xu⁷, Erguang Li⁸

Affiliations

¹ State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, China; Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, China.
² Department of Oncology, Shanghai Tenth People's Hospital, Shanghai, China.
³ Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, China.
⁴ Shanghai Baoyuan Pharmaceutical Co., Ltd, Shanghai, China.
⁵ The Affiliated Yancheng First People's Hospital, Medical School, Nanjing University, Yancheng, China.
⁶ State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, China; Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, China; The Affiliated Yancheng First People's Hospital, Medical School, Nanjing University, Yancheng, China.
⁷ Department of Oncology, Shanghai Tenth People's Hospital, Shanghai, China; Department of Medical Oncology, Shanghai Tenth People's Hospital, Tongji University Cancer Center, School of Medicine, Tongji University, Shanghai, China. Electronic address: xuqingmd@aliyun.com.
⁸ State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, China; Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, China; Department of Oncology, Shanghai Tenth People's Hospital, Shanghai, China. Electronic address: erguang@nju.edu.cn.

PMID: 38492783
DOI: 10.1016/j.bbadis.2024.167122

Abstract

Lymphotoxin α (LTα) is a soluble factor produced by activated lymphocytes which is cytotoxic to tumor cells. Although a promising candidate in cancer therapy, the application of recombinant LTα has been limited by its instability and toxicity by systemic administration. Secreted LTα interacts with several distinct receptors for its biological activities. Here, we report a TNFR1-selective human LTα mutant (LTα Q107E) with potent antitumor activity. Recombinant LTα Q107E with N-terminal 23 and 27 aa deletion (named LTα Q1 and Q2, respectively) showed selectivity to TNFR1 in both binding and NF-κB pathway activation assays. To test the therapeutic potential, we constructed an oncolytic adenovirus (oAd) harboring LTα Q107E Q2 mutant (named oAdQ2) and assessed the antitumor effect in mouse xenograft models. Intratumoral delivery of oAdQ2 inhibited tumor growth. In addition, oAdQ2 treatment enhanced T cell and IFNγ-positive CD8 T lymphocyte infiltration in a human PBMC reconstituted-SCID mouse xenograft model. This study provides evidence that reengineering of bioactive cytokines with tissue or cell specific properties may potentiate their therapeutic potential of cytokines with multiple receptors.