Nature Communications | mRNA-encoded TCE targeting GPC3 for liver cancer therapy

This study developed an mRNA-encoded bispecific T cell engager, MTS105, targeting hepatocellular carcinoma antigen GPC3. By utilizing liver-targeting lipid nanoparticle (LNP) delivery, the drug exposure in the liver was significantly increased, enabling efficient and sustained antitumor immune responses. The study validated the efficacy and safety in multiple preclinical models, offering a novel strategy for liver cancer immunotherapy.

Literature Overview
This article, titled 'Organ-specific delivery of an mRNA-encoded bispecific T cell engager targeting glypican-3 in hepatocellular carcinoma', published in the journal Nature Communications, reviews and summarizes the clinical validation of T cell engager (TCE)-based immunotherapies in hematologic malignancies and explores the challenges of their application in solid tumors.

Background Knowledge
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Although early-stage HCC can be treated surgically, most patients are diagnosed at an advanced stage, resulting in poor prognosis. Currently, TCE drugs have demonstrated clinical efficacy in hematologic cancers but still face challenges in solid tumors, such as insufficient tumor infiltration, immunosuppressive tumor microenvironment, and systemic toxicity. This study leverages an mRNA-LNP delivery system for liver-specific targeting, enhancing mRNA translational efficiency in the liver to achieve sustained, high-level TCE expression, thereby overcoming the limitations of conventional TCEs in solid tumor applications. This work provides a novel strategic framework for immunotherapy in liver cancer and other solid tumors.

Research Methods and Experiments
The research team designed an mRNA-encoded TCE, MTS105, targeting GPC3, and achieved liver-specific delivery using the MLX0473-LNP system. The pharmacokinetics, targeting efficiency, and antitumor activity of MTS105 were evaluated in mouse, rat, and cynomolgus monkey models. The study also analyzed T cell activation, proliferation, and changes in the tumor microenvironment using flow cytometry, ELISA, and single-cell RNA sequencing.

Key Conclusions and Perspectives

• MLX0473-LNP significantly enhanced mRNA expression in the liver, with luciferase activity in the liver being sevenfold higher compared to conventional Lipid5-LNP.
• MTS105 demonstrated potent T cell activation and tumor cell killing both in vitro and in vivo, with its activity dependent on the co-expression of CD3 and GPC3.
• In both immunocompetent and humanized mouse models, MTS105 induced tumor-specific T cell infiltration, cytokine release, and expansion of effector memory T cells, without notable toxicity.
• In cynomolgus monkeys, MTS105 exhibited favorable pharmacokinetics, with a significantly longer half-life compared to conventional BiTE molecules, and no evident systemic inflammation or organ damage was observed.
• Combination with PD-1 blockade further enhanced the antitumor efficacy of MTS105, indicating its potential for synergistic application with immune checkpoint inhibitors.

Conclusion
This study successfully developed a liver-targeted mRNA-LNP delivery system encoding the bispecific T cell engager MTS105, which targets the hepatocellular carcinoma antigen GPC3. In multiple animal models, MTS105 demonstrated superior antitumor activity, achieving complete tumor regression and promoting the formation of effector memory T cells to enhance antitumor immune memory. Additionally, in non-human primate models, MTS105 showed favorable pharmacokinetics and safety profiles without significant toxicity. The research team has initiated the first-in-human clinical trial to evaluate the safety and preliminary efficacy of MTS105 in liver cancer patients. This platform provides a new direction for immunotherapy in solid tumors and holds broad translational potential.

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