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Targeting Dual Immune Checkpoints PD-L1 and HLA-G by Trispecific T Cell Engager for Treating Heterogeneous Lung
Yu-Chuan Lin1,2, Mei-Chih Chen1, Shi-Wei Huang1,3,4
1Translational Cell Therapy Center, China Medical University Hospital, No. 2, Yude Rd., North Dist., Taichung City, 404, Taiwan.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|September 5, 2024
Summary
A novel trispecific T cell engager (Nb-TriTE) targets both PD-L1 and HLA-G in non-small cell lung cancer (NSCLC). This immunotherapy approach enhances anti-tumor effects and prolongs survival in preclinical models.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Immunotherapy targeting immune checkpoints (ICPs) like programmed death-ligand-1 (PD-L1) shows limited response in advanced non-small cell lung cancer (NSCLC).
- Antigen heterogeneity and the immune-suppressive tumor microenvironment contribute to treatment resistance.
- Human leukocyte antigen-G (HLA-G), an ICP and tumor antigen, is a potential combination target with anti-PD-L1 therapy.
Purpose of the Study:
- To develop and evaluate a novel nanobody-based trispecific T cell engager (Nb-TriTE) for NSCLC treatment.
- To assess the efficacy of Nb-TriTE in overcoming challenges associated with current immunotherapies.
- To investigate the dual targeting of PD-L1 and HLA-G for enhanced anti-tumor activity.
Main Methods:
- Development of a trispecific T cell engager (Nb-TriTE) designed to bind T cells, macrophages, and cancer cells expressing PD-L1 and/or HLA-G.
- In vitro assessment of Nb-TriTE's anti-tumor effects by measuring cytotoxicity mediated by human peripheral blood mononuclear cells (PBMCs).
- In vivo evaluation of Nb-TriTE's anti-cancer potency and safety in a humanized immunodeficient murine NSCLC model.
Main Results:
- Nb-TriTE demonstrated broad-spectrum anti-tumor effects in vitro by augmenting PBMC-mediated cytotoxicity.
- In vivo studies showed superior anti-cancer potency of Nb-TriTE compared to monoclonal antibodies and bispecific T cell engagers.
- Nb-TriTE prolonged mouse survival without inducing significant adverse events or excessive cytokine secretion.
Conclusions:
- Nb-TriTE represents an innovative therapeutic strategy for NSCLC, addressing immunotherapy limitations and the tumor microenvironment.
- Simultaneous targeting of PD-L1 and HLA-G via Nb-TriTE offers a promising approach for enhanced anti-tumor immunity.
- This dual ICP-targeting strategy holds potential for improving treatment outcomes in NSCLC patients.
