Abstract

BACKGROUND: In vitro models have demonstrated immune-modulating effects of bevacizumab. Combinations of EGFR tyrosine kinase inhibitor (TKI) with bevacizumab improve progression free survival (PFS) in patients with EGFR mutated lung adenocarcinoma. How bevacizumab confers this clinical effect and underlying mechanisms are not clear.

PATIENT AND METHODS: Fifty-five patients with stage 4 EGFR mutated lung adenocarcinoma were enrolled. Myeloid derived suppressor cells (MDSCs), T helper cells (Th1/Th2) and cytotoxic T lymphocytes (CTLs) were analyzed by flow cytometry. Clinical data were collected for analysis.

RESULT: Twenty-five patients received EGFR-TKI and BEV combination therapy (BEV/TKI group) and thirty patients received EGFR-TKI (TKI group) monotherapy. BEV/TKI group had longer PFS (23.0 vs. 8.6 months, p=0.001) and, particularly, better intracranial control rates (80.0% vs. 43.0%, p=0.03), longer time to intracranial progression (49.1 vs. 12.9 months, p=0.002) and fewer new brain metastases (38.0% vs. 71.0%, p=0.03) than TKI group. BEV/TKI group had lower circulating MDSCs (20.4±6.5% vs. 12.8±6.6%, pre- vs. post-treatment, respectively, p=0.02) and higher Th1 (22.9±15.3% vs. 33.2±15.6%, p<0.01) and CTLs (15.5±7.2% vs. 21.2±5.6%, p<0.01) after treatment, changes which were not seen in the TKI only group. Pretreatment MDSC was correlated with PFS, which correlation was attenuated after Bev/TKI treatment. MDSC was also associated with shorter time to intracranial progression.

CONCLUSION: Combining EGFR-TKI with bevacizumab extended PFS and protected from brain metastasis. Those effects were probably due to bevacizumab reduction of circulating S100A9+ MDSCs, leading to restoration of effective anti-tumor immunity. Our data also support the rationale for BEV-immune checkpoint inhibitors combination.

Original languageEnglish
JournalJournal of Thoracic Oncology
DOIs
Publication statusE-pub ahead of print - Apr 20 2018

Fingerprint

Protein-Tyrosine Kinases
Disease-Free Survival
Cytotoxic T-Lymphocytes
Bevacizumab
Myeloid-Derived Suppressor Cells
Adenocarcinoma of lung
Neoplasm Metastasis
Brain
Therapeutics
Helper-Inducer T-Lymphocytes
Immunity
Flow Cytometry

Cite this

@article{43abc48fabfc4dbabb0ee8529bf82470,
title = "Bevacizumab Reduces S100A9 MDSC Linked to Intracranial Control in Patients with EGFR Mutant Lung Adenocarcinoma",
abstract = "BACKGROUND: In vitro models have demonstrated immune-modulating effects of bevacizumab. Combinations of EGFR tyrosine kinase inhibitor (TKI) with bevacizumab improve progression free survival (PFS) in patients with EGFR mutated lung adenocarcinoma. How bevacizumab confers this clinical effect and underlying mechanisms are not clear.PATIENT AND METHODS: Fifty-five patients with stage 4 EGFR mutated lung adenocarcinoma were enrolled. Myeloid derived suppressor cells (MDSCs), T helper cells (Th1/Th2) and cytotoxic T lymphocytes (CTLs) were analyzed by flow cytometry. Clinical data were collected for analysis.RESULT: Twenty-five patients received EGFR-TKI and BEV combination therapy (BEV/TKI group) and thirty patients received EGFR-TKI (TKI group) monotherapy. BEV/TKI group had longer PFS (23.0 vs. 8.6 months, p=0.001) and, particularly, better intracranial control rates (80.0{\%} vs. 43.0{\%}, p=0.03), longer time to intracranial progression (49.1 vs. 12.9 months, p=0.002) and fewer new brain metastases (38.0{\%} vs. 71.0{\%}, p=0.03) than TKI group. BEV/TKI group had lower circulating MDSCs (20.4±6.5{\%} vs. 12.8±6.6{\%}, pre- vs. post-treatment, respectively, p=0.02) and higher Th1 (22.9±15.3{\%} vs. 33.2±15.6{\%}, p<0.01) and CTLs (15.5±7.2{\%} vs. 21.2±5.6{\%}, p<0.01) after treatment, changes which were not seen in the TKI only group. Pretreatment MDSC was correlated with PFS, which correlation was attenuated after Bev/TKI treatment. MDSC was also associated with shorter time to intracranial progression.CONCLUSION: Combining EGFR-TKI with bevacizumab extended PFS and protected from brain metastasis. Those effects were probably due to bevacizumab reduction of circulating S100A9+ MDSCs, leading to restoration of effective anti-tumor immunity. Our data also support the rationale for BEV-immune checkpoint inhibitors combination.",
keywords = "EGFR, Angiogenesis, Myeloid-derived suppressor cells, Lung cancer",
author = "Po-Hao Feng and Kuan-Yuan Chen and Yu-Chen Huang and Ching-Shan Luo and Wu, {Shen Ming} and Tzu-Tao Chen and Chun-Nin Lee and Chi-Tai Yeh and Hsiao-Chi Chuang and Chia-Li Han and Chiou-Feng Lin and Wei-Hwa Lee and Chih-Hsi Kuo and Kang-Yun Lee",
note = "Copyright {\circledC} 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.",
year = "2018",
month = "4",
day = "20",
doi = "10.1016/j.jtho.2018.03.032",
language = "English",
journal = "Journal of Thoracic Oncology",
issn = "1556-0864",
publisher = "International Association for the Study of Lung Cancer",

}

TY - JOUR

T1 - Bevacizumab Reduces S100A9 MDSC Linked to Intracranial Control in Patients with EGFR Mutant Lung Adenocarcinoma

AU - Feng, Po-Hao

AU - Chen, Kuan-Yuan

AU - Huang, Yu-Chen

AU - Luo, Ching-Shan

AU - Wu, Shen Ming

AU - Chen, Tzu-Tao

AU - Lee, Chun-Nin

AU - Yeh, Chi-Tai

AU - Chuang, Hsiao-Chi

AU - Han, Chia-Li

AU - Lin, Chiou-Feng

AU - Lee, Wei-Hwa

AU - Kuo, Chih-Hsi

AU - Lee, Kang-Yun

N1 - Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

PY - 2018/4/20

Y1 - 2018/4/20

N2 - BACKGROUND: In vitro models have demonstrated immune-modulating effects of bevacizumab. Combinations of EGFR tyrosine kinase inhibitor (TKI) with bevacizumab improve progression free survival (PFS) in patients with EGFR mutated lung adenocarcinoma. How bevacizumab confers this clinical effect and underlying mechanisms are not clear.PATIENT AND METHODS: Fifty-five patients with stage 4 EGFR mutated lung adenocarcinoma were enrolled. Myeloid derived suppressor cells (MDSCs), T helper cells (Th1/Th2) and cytotoxic T lymphocytes (CTLs) were analyzed by flow cytometry. Clinical data were collected for analysis.RESULT: Twenty-five patients received EGFR-TKI and BEV combination therapy (BEV/TKI group) and thirty patients received EGFR-TKI (TKI group) monotherapy. BEV/TKI group had longer PFS (23.0 vs. 8.6 months, p=0.001) and, particularly, better intracranial control rates (80.0% vs. 43.0%, p=0.03), longer time to intracranial progression (49.1 vs. 12.9 months, p=0.002) and fewer new brain metastases (38.0% vs. 71.0%, p=0.03) than TKI group. BEV/TKI group had lower circulating MDSCs (20.4±6.5% vs. 12.8±6.6%, pre- vs. post-treatment, respectively, p=0.02) and higher Th1 (22.9±15.3% vs. 33.2±15.6%, p<0.01) and CTLs (15.5±7.2% vs. 21.2±5.6%, p<0.01) after treatment, changes which were not seen in the TKI only group. Pretreatment MDSC was correlated with PFS, which correlation was attenuated after Bev/TKI treatment. MDSC was also associated with shorter time to intracranial progression.CONCLUSION: Combining EGFR-TKI with bevacizumab extended PFS and protected from brain metastasis. Those effects were probably due to bevacizumab reduction of circulating S100A9+ MDSCs, leading to restoration of effective anti-tumor immunity. Our data also support the rationale for BEV-immune checkpoint inhibitors combination.

AB - BACKGROUND: In vitro models have demonstrated immune-modulating effects of bevacizumab. Combinations of EGFR tyrosine kinase inhibitor (TKI) with bevacizumab improve progression free survival (PFS) in patients with EGFR mutated lung adenocarcinoma. How bevacizumab confers this clinical effect and underlying mechanisms are not clear.PATIENT AND METHODS: Fifty-five patients with stage 4 EGFR mutated lung adenocarcinoma were enrolled. Myeloid derived suppressor cells (MDSCs), T helper cells (Th1/Th2) and cytotoxic T lymphocytes (CTLs) were analyzed by flow cytometry. Clinical data were collected for analysis.RESULT: Twenty-five patients received EGFR-TKI and BEV combination therapy (BEV/TKI group) and thirty patients received EGFR-TKI (TKI group) monotherapy. BEV/TKI group had longer PFS (23.0 vs. 8.6 months, p=0.001) and, particularly, better intracranial control rates (80.0% vs. 43.0%, p=0.03), longer time to intracranial progression (49.1 vs. 12.9 months, p=0.002) and fewer new brain metastases (38.0% vs. 71.0%, p=0.03) than TKI group. BEV/TKI group had lower circulating MDSCs (20.4±6.5% vs. 12.8±6.6%, pre- vs. post-treatment, respectively, p=0.02) and higher Th1 (22.9±15.3% vs. 33.2±15.6%, p<0.01) and CTLs (15.5±7.2% vs. 21.2±5.6%, p<0.01) after treatment, changes which were not seen in the TKI only group. Pretreatment MDSC was correlated with PFS, which correlation was attenuated after Bev/TKI treatment. MDSC was also associated with shorter time to intracranial progression.CONCLUSION: Combining EGFR-TKI with bevacizumab extended PFS and protected from brain metastasis. Those effects were probably due to bevacizumab reduction of circulating S100A9+ MDSCs, leading to restoration of effective anti-tumor immunity. Our data also support the rationale for BEV-immune checkpoint inhibitors combination.

KW - EGFR

KW - Angiogenesis

KW - Myeloid-derived suppressor cells

KW - Lung cancer

U2 - 10.1016/j.jtho.2018.03.032

DO - 10.1016/j.jtho.2018.03.032

M3 - Article

JO - Journal of Thoracic Oncology

JF - Journal of Thoracic Oncology

SN - 1556-0864

ER -