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Updated: Jun 30, 2025
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
An engineered TNFR1-selective human lymphotoxin-alpha mutant delivered by an oncolytic adenovirus for tumor
Yan Cheng1, Yu Liu2, Dongge Xu1
1State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, China; Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, China.
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.
Insights
Engineered Lymphotoxin alpha (LTα) selectively targets TNFR1, showing potent antitumor activity. An oncolytic adenovirus delivering this mutant inhibited tumor growth and enhanced anti-tumor immune cell infiltration in preclinical models.
Area of Science:
- Biotechnology
- Immunology
- Oncolytic Virology
Background:
- Lymphotoxin alpha (LTα) is a cytotoxic factor from lymphocytes with therapeutic potential.
- Recombinant LTα faces limitations due to instability and systemic toxicity.
- LTα interacts with multiple receptors, complicating targeted therapy.
Purpose of the Study:
- To engineer a Lymphotoxin alpha (LTα) mutant selective for TNFR1.
- To evaluate the antitumor efficacy of the engineered LTα mutant delivered via an oncolytic adenovirus (oAd).
Main Methods:
- Developed a TNFR1-selective LTα mutant (LTα Q107E) with N-terminal deletions (LTα Q1, Q2).
- Assessed receptor selectivity via binding and NF-κB pathway activation assays.
- Constructed an oncolytic adenovirus (oAdQ2) carrying the LTα Q2 mutant and tested in mouse xenograft models.
Main Results:
- LTα Q1 and Q2 mutants demonstrated selectivity for TNFR1.
- Intratumoral delivery of oAdQ2 significantly inhibited tumor growth in mouse models.
- oAdQ2 treatment increased T cell and IFNγ-positive CD8 T lymphocyte infiltration in human PBMC-reconstituted SCID mice.
Conclusions:
- Reengineering cytokines for receptor selectivity can enhance therapeutic potential.
- The TNFR1-selective LTα mutant delivered by oAdQ2 shows promise for cancer therapy.
- Targeted delivery of engineered cytokines via oncolytic viruses offers a viable strategy for cancer treatment.
