1. Exploration of Immune-Modulatory Effects of Amivantamab in Combination with Pembrolizumab in Lung and Head and Neck Squamous Cell Carcinoma.
- Author
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Lim SM, Kang SS, Kim DK, Lee SH, Synn CB, Baek S, Yang SM, Han YJ, Kim MH, Han H, Na K, Kim YT, Yun MR, Kim JH, Byeon Y, Kim YS, Lee JB, Hong MH, Curtin JC, Patel B, Bergiers I, Pyo KH, and Cho BC
- Subjects
- Humans, Animals, Mice, Head and Neck Neoplasms drug therapy, Head and Neck Neoplasms pathology, Head and Neck Neoplasms immunology, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, B7-H1 Antigen metabolism, Cell Line, Tumor, Antibodies, Monoclonal, Humanized pharmacology, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized administration & dosage, Squamous Cell Carcinoma of Head and Neck drug therapy, Squamous Cell Carcinoma of Head and Neck immunology, Squamous Cell Carcinoma of Head and Neck pathology, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Lung Neoplasms immunology, Tumor Microenvironment drug effects, Tumor Microenvironment immunology
- Abstract
Immune checkpoint inhibitors are effective first-line therapy for solid cancers. However, low response rate and acquired resistance over time has led to the need for additional therapeutic options. Here, we evaluated synergistic antitumor efficacy of EGFR × MET targeting bispecific antibody, amivantamab with PD-L1 immunotherapy, pembrolizumab in head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma tumor-bearing humanized patient-derived xenograft (PDX) models. We demonstrated that pembrolizumab or amivantamab alone was ineffective and that combination treatment induced a significant reduction of tumor growth in both models (P < 0.0001 and P < 0.01, respectively). It appeared that combination of amivantamab and pembrolizumab significantly enhanced infiltration of granzyme B-producing CD8 T cells was in the TME of HNSCC PDX (P < 0.01) and enhanced neoantigen-associated central memory CD8 T cells in circulating immune cells. Analysis of single-cell RNA transcriptomics suggested that the tumor cells dramatically upregulated EGFR and MET in response to PD-L1 immunotherapy, potentially creating a metabolic state fit for tumor persistence in the tumor microenvironment (TME) and rendered pembrolizumab ineffective. We demonstrated that EGFRHIGHMETHIGH subcluster displayed an increased expression of genes implicated in production of lactate [SLC16A3 and lactate dehydrogenase A (LDHA)] compared to the EGFRLOWMETLOW cluster. Accumulation of lactate in the TME has been associated with immunosuppression by hindering the infiltration of tumor killing CD8 T and NK cells. This study proved that amivantamab reduced glycolytic markers in the EGFRHIGHMETHIGH subcluster including SLC16A3 and LDHA and highlighted remodeling of the TME by combination treatment, providing rationale for additional therapy of amivantamab with PD-1 immunotherapy., Significance: Amivantamab in synergy with pembrolizumab effectively eradicated EGFRHIGHMETHIGH tumor subcluster in the tumor microenvironment of head and neck squamous cell carcinoma and overcame resistance against anti-PD-1 immunotherapy., (©2024 The Authors, Published by the American Association for Cancer Research.)
- Published
- 2024
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