Bispecific T-cell Engager (CD3 × EGFR)-Based Triplet Therapy Unlocks CD40/CD40L Crosstalk to Revert Immunosuppression in Third-Generation EGFR-Tyrosine Kinase Inhibitor-Refractory NSCLC.
[INTRODUCTION] Acquired resistance to third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) is a major challenge in NSCLC, with approximately 50% of cases lacking precise resistance mechanisms.
- p-value p < 0.001
APA
Guo H, Wang Y, et al. (2026). Bispecific T-cell Engager (CD3 × EGFR)-Based Triplet Therapy Unlocks CD40/CD40L Crosstalk to Revert Immunosuppression in Third-Generation EGFR-Tyrosine Kinase Inhibitor-Refractory NSCLC.. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 103607. https://doi.org/10.1016/j.jtho.2026.103607
MLA
Guo H, et al.. "Bispecific T-cell Engager (CD3 × EGFR)-Based Triplet Therapy Unlocks CD40/CD40L Crosstalk to Revert Immunosuppression in Third-Generation EGFR-Tyrosine Kinase Inhibitor-Refractory NSCLC.." Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2026, pp. 103607.
PMID
41672197
Abstract
[INTRODUCTION] Acquired resistance to third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) is a major challenge in NSCLC, with approximately 50% of cases lacking precise resistance mechanisms. This study investigates the immunosuppressive tumor microenvironment (TME) driving resistance and develops a novel triple-combination therapy to restore T-cell antitumor activity.
[METHODS] Single-cell RNA sequencing and multicolor fluorescence staining were performed on NSCLC patient samples to analyze TME changes post-EGFR-TKI resistance. A triple therapy combining BC3448 (EGFR and CD3 bispecific T-cell engager), tucidinostat (histone deacetylase inhibitor), and WBP3425 (4-1BB agonist) was tested using in vitro co-culture assays, syngeneic cell-derived xenograft models in humanized NOG-EXL mice, and multi-omics analyses.
[RESULTS] Single-cell RNA sequencing revealed reduced T-cell infiltration or activation and increased immunosuppressive myeloid cells in resistant NSCLC. BC3448 monotherapy activated T cells and induced tumor cell apoptosis in vitro but was limited in vivo because of myeloid-driven immunosuppression. The triple therapy significantly enhanced tumor regression in osimertinib-resistant models (tumor growth inhibition >70%, p < 0.001), promoted CD8+ effector T-cell differentiation, and suppressed Tregs and M2 macrophages. CD40-CD40L axis activation between T cells and monocyte-derived macrophages was critical for TME remodeling, with spatial profiling revealing increased CD40L+ T-cell and CD40+ macrophage proximity, correlating with higher IFN-γ and reduced angiogenesis. A durable response to BC3448 monotherapy was observed in an immunotherapy-resistant patient with NSCLC (>2 y of stable disease), presenting a translational potential of this approach.
[CONCLUSIONS] This study establishes a novel triple therapy that overcomes the limitations of bispecific T-cell engagers in cold and immunosuppressive TMEs and provides an immunomodulatory approach to addressing third-generation EGFR-TKI resistance.
[METHODS] Single-cell RNA sequencing and multicolor fluorescence staining were performed on NSCLC patient samples to analyze TME changes post-EGFR-TKI resistance. A triple therapy combining BC3448 (EGFR and CD3 bispecific T-cell engager), tucidinostat (histone deacetylase inhibitor), and WBP3425 (4-1BB agonist) was tested using in vitro co-culture assays, syngeneic cell-derived xenograft models in humanized NOG-EXL mice, and multi-omics analyses.
[RESULTS] Single-cell RNA sequencing revealed reduced T-cell infiltration or activation and increased immunosuppressive myeloid cells in resistant NSCLC. BC3448 monotherapy activated T cells and induced tumor cell apoptosis in vitro but was limited in vivo because of myeloid-driven immunosuppression. The triple therapy significantly enhanced tumor regression in osimertinib-resistant models (tumor growth inhibition >70%, p < 0.001), promoted CD8+ effector T-cell differentiation, and suppressed Tregs and M2 macrophages. CD40-CD40L axis activation between T cells and monocyte-derived macrophages was critical for TME remodeling, with spatial profiling revealing increased CD40L+ T-cell and CD40+ macrophage proximity, correlating with higher IFN-γ and reduced angiogenesis. A durable response to BC3448 monotherapy was observed in an immunotherapy-resistant patient with NSCLC (>2 y of stable disease), presenting a translational potential of this approach.
[CONCLUSIONS] This study establishes a novel triple therapy that overcomes the limitations of bispecific T-cell engagers in cold and immunosuppressive TMEs and provides an immunomodulatory approach to addressing third-generation EGFR-TKI resistance.
같은 제1저자의 인용 많은 논문 (5)
- Neuroglia and immune cells play different roles in neuroinflammation and neuroimmune response in post-stroke neural injury and repair.
- Global trends in psychosexual and emotional health challenges among breast cancer survivors (1999-2024): Implications for public health and survivorship care.
- Global trends in gastric cancer and nutrition, 2000-2023: A bibliometric and visualization analysis.
- ALK-negative inflammatory myofibroblastic tumor with an undetermined differentiation direction: A case report and review of the literature.
- Unraveling Multi-target Mechanisms of Codonopsis pilosula in Breast Cancer: A Synergistic Approach Combining Network Pharmacology, Molecular Docking, and Machine Learning Techniques.