This study reveals the prevalence of EGFR and MET co-expression in mesothelioma and its predictive value for amivantamab sensitivity, providing direct experimental evidence for developing immunotherapeutic strategies targeting c-MET and EGFR, particularly beneficial for patient populations such as epithelioid subtypes who respond poorly to immune checkpoint inhibitors.
Literature Overview
This article, 'Amivantamab induces immune-mediated cytotoxicity in mesothelioma via EGFR and MET engagement,' published in the 'Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer,' systematically investigates the antitumor mechanism of the bispecific antibody amivantamab in diffuse pleural mesothelioma (DPM). By integrating transcriptomic analysis, single-cell RNA sequencing, immunohistochemistry, and in vitro and in vivo functional experiments, the study demonstrates that amivantamab achieves significant tumor suppression by simultaneously binding EGFR and c-MET, thereby activating natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC). This work offers a novel therapeutic strategy for DPM, a lethal malignancy lacking effective targeted therapies.Background Knowledge
Diffuse pleural mesothelioma (DPM) is a highly aggressive malignant tumor with extremely limited treatment options. Although immune checkpoint inhibitors have improved survival in some patients, the epithelioid subtype—the most common form—shows low response rates to current immunotherapies and lacks effective targeted treatments. Tyrosine kinase inhibitors (TKIs) targeting EGFR and c-MET have shown limited efficacy in mesothelioma, either as monotherapy or in combination, possibly due to signaling pathway redundancy and lack of immune system involvement. This study introduces the bispecific antibody amivantamab to simultaneously target EGFR and c-MET, aiming not only to block downstream oncogenic signaling but also to recruit immune effector cells via its IgG1 Fc domain, thereby overcoming the limitations of conventional targeted therapies. Furthermore, single-cell RNA-seq analysis confirms specific co-expression of these targets on tumor cells, establishing a molecular basis for precise patient selection. This strategy holds promise for filling the current gap in targeted therapy for epithelioid mesothelioma.
Research Methods and Experiments
The research team first systematically evaluated the co-expression patterns of EGFR and c-MET in DPM patient samples by analyzing public RNA-seq datasets from TCGA and Bueno et al., combined with single-cell RNA sequencing (scRNA-seq). Subsequently, co-expression at the protein level was validated using immunohistochemistry (IHC) in 27 clinical specimens. In vitro, multiple mesothelioma cell lines (e.g., H2373, H2461) and immortalized mesothelial cells (MET-5A) were used to confirm the specific binding of amivantamab to EGFR and c-MET on tumor cell surfaces via flow cytometry and confocal microscopy. Western blot analysis assessed amivantamab’s inhibition of ligand-induced phosphorylation of EGFR and c-MET and downstream PI3K/AKT and MAPK/ERK pathways. Receptor internalization was monitored in real time using a pH-dependent fluorescent probe. To investigate immune mechanisms, co-culture systems with PBMCs or purified NK cells were established to quantitatively evaluate amivantamab-induced cytotoxicity, with FcγR activation confirmed using an ADCC reporter gene assay.
In vivo, patient-derived xenograft (PDX) models were established in immunodeficient NSG mice, with in vitro-expanded human NK cells engrafted to reconstruct innate immune effector function. The experimental design included control, NK cell monotherapy, amivantamab monotherapy, and combination groups to systematically assess tumor growth inhibition (TGI) and animal toxicity. The combination of amivantamab with the IL-15 superagonist N-803 was further evaluated to enhance NK cell activity.Key Conclusions and Perspectives
Research Significance and Prospects
This study opens a new avenue for drug development in mesothelioma. As a bispecific antibody, amivantamab overcomes the limitations of traditional single-target TKIs and enables synergistic tumor killing by activating the innate immune system, representing a paradigm of 'targeted + immune' dual-function therapy. Its efficacy is independent of PD-L1 expression, offering a potential treatment option for patients with epithelioid mesothelioma.
For clinical monitoring, the study suggests that EGFR and c-MET co-expression levels detected by IHC or RNA-seq could serve as biomarkers for patient selection, while monitoring NK cell status in peripheral blood or the tumor microenvironment may help predict treatment response. Additionally, the mechanistic findings support combining amivantamab with immune enhancers such as IL-15 agonists in clinical trials to maximize therapeutic outcomes.
In the field of disease modeling, the PDX-NK humanized model established in this study provides a reliable platform for evaluating the ADCC activity of other antibody drugs, particularly for assessing novel therapeutics targeting c-MET or EGFR. This model can be widely applied in personalized drug efficacy evaluation and combination screening.
Conclusion
This study systematically elucidates the dual mechanism of action of amivantamab in mesothelioma: inhibiting tumor growth by blocking EGFR and c-MET signaling pathways and enabling immune clearance through NK cell-mediated ADCC. These findings not only provide strong preclinical evidence for mesothelioma—especially the epithelioid subtype that responds poorly to existing immunotherapies—but also highlight the unique advantages of bispecific antibodies in solid tumor therapy. From bench to bedside, this research advances precision immunotherapeutic strategies targeting c-MET and EGFR, supporting the progression of amivantamab into clinical trials, particularly for mesothelioma patients with EGFR/MET co-expression. Moreover, the PDX-NK humanized model established in this study serves as a valuable tool for future drug screening and mechanistic research, potentially accelerating the translation of novel antibody therapies and ultimately improving the clinical care system for this recalcitrant malignancy.
