Po-Hao Feng1, Kuan-Yuan Chen2, Yu-Chen Huang3, Ching-Shan Luo4, Shen Ming Wu4, Tzu-Tao Chen4, Chun-Nin Lee4, Chi-Tai Yeh5, Hsiao-Chi Chuang6, Chia-Li Han7, Chiou-Feng Lin8, Wei-Hwa Lee9, Chih-Hsi Kuo3, Kang-Yun Lee10. 1. Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Republic of China; Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Republic of China; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD. 2. Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Republic of China; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Republic of China. 3. Division of Pulmonary Medicine, Department of Internal Medicine, Chang Gung Medical Foundation, Linko Branch, Taoyuan, Republic of China. 4. Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Republic of China. 5. Department of Medical Research and Education, Shuang Ho Hospital, Taipei Medical University, Taipei, Republic of China. 6. School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Republic of China. 7. Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, College of Pharmacy, Taipei Medical University, Taipei, Republic of China. 8. Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Republic of China. 9. Department of Pathology, Shuang Ho Hospital, Taipei Medical University, Taipei, Republic of China. 10. Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Republic of China; Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Republic of China. Electronic address: lee4949@ms41.hinet.net.
Abstract
INTRODUCTION: In vitro models have demonstrated immune-modulating effects of bevacizumab (BEV). Combinations of an EGFR tyrosine kinase inhibitor (TKI) with BEV improve progression-free survival (PFS) in patients with EGFR-mutated lung adenocarcinoma. How BEV confers this clinical effect and the underlying mechanisms of its effect are not clear. METHODS: A total of 55 patients with stage 4 EGFR-mutated lung adenocarcinoma were enrolled. Myeloid-derived suppressor cells (MDSCs), type 1 and type 2 helper T cells, and cytotoxic T lymphocytes were analyzed by flow cytometry. Clinical data were collected for analysis. RESULT: In all, 25 patients received EGFR TKI and BEV combination therapy (the BEV/TKI group) and 30 patients received EGFR TKI monotherapy (the TKI-only group). The BEV/TKI group had longer PFS (23.0 versus 8.6 months [p = 0.001]) and, in particular, better intracranial control rates (80.0% versus 43.0% [p = 0.03]), a longer time to intracranial progression (49.1 versus 12.9 months [p = 0.002]), and fewer new brain metastases (38.0% versus 71.0% [p = 0.03]) than the TKI-only group did. The BEV/TKI group had a lower percentage of circulating MDSCs (20.4% ± 6.5% before treatment versus 12.8% ± 6.6% after treatment, respectively [p = 0.02]), and higher percentages of type 1 helper T cells (22.9% ± 15.3% versus 33.2% ± 15.6% [p < 0.01]) and cytotoxic T lymphocytes (15.5% ± 7.2% versus 21.2% ± 5.6% [p < 0.01]) after treatment, changes that were not seen in the TKI-only group. Pretreatment percentage of MDSCs was correlated with PFS, with this correlation attenuated after BEV/TKI treatment. Percentage of MDSCs was also associated with shorter time to intracranial progression. CONCLUSION: Combining a EGFR TKI with BEV extended PFS and protected against brain metastasis. Those effects were probably due to the reduction of circulating S100A9-positive MDSCs by BEV, which leads to restoration of effective antitumor immunity. Our data also support the rationale for a BEV-immune checkpoint inhibitor combination.
INTRODUCTION: In vitro models have demonstrated immune-modulating effects of bevacizumab (BEV). Combinations of an EGFR tyrosine kinase inhibitor (TKI) with BEV improve progression-free survival (PFS) in patients with EGFR-mutated lung adenocarcinoma. How BEV confers this clinical effect and the underlying mechanisms of its effect are not clear. METHODS: A total of 55 patients with stage 4 EGFR-mutated lung adenocarcinoma were enrolled. Myeloid-derived suppressor cells (MDSCs), type 1 and type 2 helper T cells, and cytotoxic T lymphocytes were analyzed by flow cytometry. Clinical data were collected for analysis. RESULT: In all, 25 patients received EGFR TKI and BEV combination therapy (the BEV/TKI group) and 30 patients received EGFR TKI monotherapy (the TKI-only group). The BEV/TKI group had longer PFS (23.0 versus 8.6 months [p = 0.001]) and, in particular, better intracranial control rates (80.0% versus 43.0% [p = 0.03]), a longer time to intracranial progression (49.1 versus 12.9 months [p = 0.002]), and fewer new brain metastases (38.0% versus 71.0% [p = 0.03]) than the TKI-only group did. The BEV/TKI group had a lower percentage of circulating MDSCs (20.4% ± 6.5% before treatment versus 12.8% ± 6.6% after treatment, respectively [p = 0.02]), and higher percentages of type 1 helper T cells (22.9% ± 15.3% versus 33.2% ± 15.6% [p < 0.01]) and cytotoxic T lymphocytes (15.5% ± 7.2% versus 21.2% ± 5.6% [p < 0.01]) after treatment, changes that were not seen in the TKI-only group. Pretreatment percentage of MDSCs was correlated with PFS, with this correlation attenuated after BEV/TKI treatment. Percentage of MDSCs was also associated with shorter time to intracranial progression. CONCLUSION: Combining a EGFR TKI with BEV extended PFS and protected against brain metastasis. Those effects were probably due to the reduction of circulating S100A9-positive MDSCs by BEV, which leads to restoration of effective antitumor immunity. Our data also support the rationale for a BEV-immune checkpoint inhibitor combination.