The activity and immune dynamics of PD-1 inhibition on high-risk pulmonary ground glass opacity lesions: insights from a single-arm, phase II trial

Bo Cheng; Caichen Li; Jianfu Li; Longlong Gong; Peng Liang; Ying Chen; Shuting Zhan; Shan Xiong; Ran Zhong; Hengrui Liang; Yi Feng; Runchen Wang; Haixuan Wang; Hongbo Zheng; Jun Liu; Chengzhi Zhou; Wenlong Shao; Yuan Qiu; Jiancong Sun; Zhanhong Xie; Zhu Liang; Chenglin Yang; Xiuyu Cai; Chunxia Su; Wei Wang; Jianxing He; Wenhua Liang

doi:10.1038/s41392-024-01799-z

Signal Transduction and Targeted Therapy (Apr 2024)

The activity and immune dynamics of PD-1 inhibition on high-risk pulmonary ground glass opacity lesions: insights from a single-arm, phase II trial

Bo Cheng,
Caichen Li,
Jianfu Li,
Longlong Gong,
Peng Liang,
Ying Chen,
Shuting Zhan,
Shan Xiong,
Ran Zhong,
Hengrui Liang,
Yi Feng,
Runchen Wang,
Haixuan Wang,
Hongbo Zheng,
Jun Liu,
Chengzhi Zhou,
Wenlong Shao,
Yuan Qiu,
Jiancong Sun,
Zhanhong Xie,
Zhu Liang,
Chenglin Yang,
Xiuyu Cai,
Chunxia Su,
Wei Wang,
Jianxing He,
Wenhua Liang

Affiliations

Bo Cheng: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease
Caichen Li: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease
Jianfu Li: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease
Longlong Gong: Medical Department, Genecast Biotechnology Co., Ltd
Peng Liang: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease
Ying Chen: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease
Shuting Zhan: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease
Shan Xiong: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease
Ran Zhong: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease
Hengrui Liang: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease
Yi Feng: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease
Runchen Wang: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease
Haixuan Wang: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease
Hongbo Zheng: Medical Department, Genecast Biotechnology Co., Ltd
Jun Liu: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease
Chengzhi Zhou: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease
Wenlong Shao: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease
Yuan Qiu: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease
Jiancong Sun: Department of Radiation Oncology, the First Affiliated Hospital of Guangzhou Medical University
Zhanhong Xie: Department of Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease
Zhu Liang: Department of Cardiothoracic Surgery, Affiliated Hospital of Guangdong Medical University
Chenglin Yang: Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
Xiuyu Cai: Department of VIP Inpatient, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Sun Yat-sen University
Chunxia Su: Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University
Wei Wang: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease
Jianxing He: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease
Wenhua Liang: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease

DOI: https://doi.org/10.1038/s41392-024-01799-z
Journal volume & issue: Vol. 9, no. 1
pp. 1 – 13

Abstract

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Abstract Immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1) protein significantly improve survival in patients with advanced non-small-cell lung cancer (NSCLC), but its impact on early-stage ground-glass opacity (GGO) lesions remains unclear. This is a single-arm, phase II trial (NCT04026841) using Simon’s optimal two-stage design, of which 4 doses of sintilimab (200 mg per 3 weeks) were administrated in 36 enrolled multiple primary lung cancer (MPLC) patients with persistent high-risk (Lung-RADS category 4 or had progressed within 6 months) GGOs. The primary endpoint was objective response rate (ORR). T/B/NK-cell subpopulations, TCR-seq, cytokines, exosomal RNA, and multiplexed immunohistochemistry (mIHC) were monitored and compared between responders and non-responders. Finally, two intent-to-treat (ITT) lesions (pure-GGO or GGO-predominant) showed responses (ORR: 5.6%, 2/36), and no patients had progressive disease (PD). No grade 3–5 TRAEs occurred. The total response rate considering two ITT lesions and three non-intent-to-treat (NITT) lesions (pure-solid or solid-predominant) was 13.9% (5/36). The proportion of CD8+ T cells, the ratio of CD8+/CD4+, and the TCR clonality value were significantly higher in the peripheral blood of responders before treatment and decreased over time. Correspondingly, the mIHC analysis showed more CD8+ T cells infiltrated in responders. Besides, responders’ cytokine concentrations of EGF and CTLA-4 increased during treatment. The exosomal expression of fatty acid metabolism and oxidative phosphorylation gene signatures were down-regulated among responders. Collectively, PD-1 inhibitor showed certain activity on high-risk pulmonary GGO lesions without safety concerns. Such effects were associated with specific T-cell re-distribution, EGF/CTLA-4 cytokine compensation, and regulation of metabolism pathways.

Published in Signal Transduction and Targeted Therapy

ISSN: 2059-3635 (Online)
Publisher: Nature Publishing Group
Country of publisher: United Kingdom
LCC subjects: Medicine; Science: Biology (General)
Website: http://www.nature.com/sigtrans/

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