机构：[1]Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China[2]Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China[3]Department of Oncology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, Henan, China[4]Department of Respiratory and Critical Care Sleep Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China[5]Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China[6]Department of Oncology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China[7]Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China华中科技大学同济医学院附属协和医院[8]Department of Tumor Immunotherapy, the Fourth Hospital of Hebei Medical University and Hebei Cancer Institute, Shijiazhuang, Hebei, China河北医科大学第四医院[9]Department of Technology, Chengdu ExAb Biotechnology Ltd, Chengdu, Sichuan, China[10]State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou, Henan, China[11]School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China[12]Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China[13]School of Public Health, Zhengzhou University, Zhengzhou, Henan, China
Background Anti-programmed cell death 1 (PD-1) antibody combined with chemotherapy simultaneously is regarded as the standard treatment for patients with advanced non-small cell lung cancer (NSCLC) by current clinical guidelines. Different immune statuses induced by chemotherapy considerably affect the synergistic effects of the chemo-anti-PD-1 combination. Therefore, it is necessary to determine the optimal timing of combination treatment administration.Methods The dynamic immune status induced by chemotherapy was observed in paired peripheral blood samples of patients with NSCLC using flow cytometry and RNA sequencing. Ex vivo studies and metastatic lung carcinoma mouse models were used to evaluate immune activity and explore the optimal combination timing. A multicenter prospective clinical study of 170 patients with advanced NSCLC was performed to assess clinical responses, and systemic immunity was assessed using omics approaches.Results PD-1 expression on CD8+ T cells was downregulated on day 1 (D1) and D2, but recovered on D3 after chemotherapy administration, which is regulated by the calcium influx-P65 signaling pathway. Programmed cell death 1 ligand 1 expression in myeloid-derived suppressor cells was markedly reduced on D3. RNA sequencing analysis showed that T-cell function began to gradually recover on D3 rather than on D1. In addition, ex vivo and in vivo studies have shown that anti-PD-1 treatment on D3 after chemotherapy may enhance the antitumor response and considerably inhibit tumor growth. Finally, in clinical practice, a 3-day-delay sequential combination enhanced the objective response rate (ORR, 68%) and disease control rate (DCR, 98%) compared with the simultaneous combination (ORR=37%; DCR=81%), and prolonged progression-free survival to a greater extent than the simultaneous combination. The new T-cell receptor clones were effectively expanded, and CD8+ T-cell activity was similarly recovered.Conclusions A 3-day-delay sequential combination might increase antitumor responses and clinical benefits compared with the simultaneous combination.
基金：
the National Natural Science Foundation of China [2022YFE0141000]; National Natural Science Foundation of China [82272873, 82473423, 82002564]; Central Government of Henan Province Guides Local Science and Technology Development Fund Projects [Z20221343036]; Science and Technology Project of Henan Province [SBGJ202101010, SBGJ202003021, 232102311067, 222102310052, LHGJ20220050]
第一作者机构：[1]Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
共同第一作者：
通讯作者：
通讯机构：[1]Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China[10]State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou, Henan, China[11]School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China[12]Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China[13]School of Public Health, Zhengzhou University, Zhengzhou, Henan, China
推荐引用方式(GB/T 7714)：
Huo Yachang,Wang Dan,Yang Shuangning,et al.Optimal timing of anti-PD-1 antibody combined with chemotherapy administration in patients with NSCLC[J].JOURNAL FOR IMMUNOTHERAPY OF CANCER.2024,12(12):doi:10.1136/jitc-2024-009627.
APA：
Huo, Yachang,Wang, Dan,Yang, Shuangning,Xu, Yujie,Qin, Guohui...&Zhang, Yi.(2024).Optimal timing of anti-PD-1 antibody combined with chemotherapy administration in patients with NSCLC.JOURNAL FOR IMMUNOTHERAPY OF CANCER,12,(12)
MLA：
Huo, Yachang,et al."Optimal timing of anti-PD-1 antibody combined with chemotherapy administration in patients with NSCLC".JOURNAL FOR IMMUNOTHERAPY OF CANCER 12..12(2024)
医学