Research progress on PD-1/PD-L1 inhibitors in neoadjuvant therapy for esophageal cancer_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

CHEN Liji ¹ , MA Hongmei ^2,3 , ZHANG Shifa ^2,3 , ZHONG Kaize ^2,3 , YANG Dongbao ¹ , SUN Jiuhe ^2,3 , LIU Hongfeng ^2,3 , SONG Ru ^2,3 , ZHANG Jishan ¹ ,  CAI Haibo ^2,3

1. Jining Medical University, Jining, 272000, Shandong, P. R. China;
2. The Department of Thoracic Surgery, the first People's Hospital of Jining, Jining, 272000, Shandong, P. R. China;
3. Institute of Thoracic Surgery, Jining Institute of Medical Sciences, Jining, 272000, Shandong, P. R. China;

Corresponding author：

CAI Haibo, Email: 13518670801@163.com

Keywords：

Immunotherapy; esophageal cancer; programmed death receptor-1; programmed death ligand-1; inhibitors; neoadjuvant therapy; review

DOI：

10.7507/1007-4848.202409008

Video：

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[Abstract ]Esophageal cancer remains one of the malignant tumors that threaten human health, characterized by a high incidence and significant malignancy. Currently, surgery following neoadjuvant chemoradiotherapy is the standard treatment for locally advanced esophageal cancer. However, long-term prognosis remains unsatisfactory. In recent years, PD-1/PD-L1 inhibitors have made breakthrough progress in other solid tumors, and research on their use in esophageal cancer has gradually been conducted. Given the favorable outcomes of PD-1/PD-L1 inhibitors in first- and second-line treatments for advanced unresectable esophageal cancer, incorporating them into neoadjuvant therapy has become a focus of attention. Therefore, this article provides a review of the mechanisms of action of PD-1/PD-L1 inhibitors and their application in neoadjuvant therapy for esophageal cancer.

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37.	Yang P, Zhou X, Yang X, et al. Neoadjuvant camrelizumab plus chemotherapy in treating locally advanced esophageal squamous cell carcinoma patients: A pilot study. World J Surg Oncol, 2021, 19(1): 333.
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1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
2. Cao W, Chen HD, Yu YW, et al. Changing profiles of cancer burden worldwide and in China: A secondary analysis of the global cancer statistics 2020. Chin Med J (Engl), 2021, 134(7): 783-791.
3. Lin Y, Totsuka Y, He Y, et al. Epidemiology of esophageal cancer in Japan and China. J Epidemiol, 2013, 23(4): 233-242.
4. He Y, Li D, Shan B, et al. Incidence and mortality of esophagus cancer in China, 2008—2012. Chin J Cancer Res, 2019, 31(3): 426-434.
5. Guo X, Mao T, Gu Z, et al. Clinical study on postoperative recurrence in patients with pN1 esophageal squamous cell carcinoma. Thorac Cancer, 2015, 6(2): 146-150.
6. Eyck BM, van Lanschot JJB, Hulshof MCCM, et al. Ten-year outcome of neoadjuvant chemoradiotherapy plus surgery for esophageal cancer: The randomized controlled CROSS trial. J Clin Oncol, 2021, 39(18): 1995-2004.
7. Yang H, Liu H, Chen Y, et al. Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): A phase Ⅲ multicenter, randomized, open-label clinical trial. J Clin Oncol, 2018, 36(27): 2796-2803.
8. Yang H, Liu H, Chen Y, et al. Long-term efficacy of neoadjuvant chemoradiotherapy plus surgery for the treatment of locally advanced esophageal squamous cell carcinoma: The NEOCRTEC5010 randomized clinical trial. JAMA Surg, 2021, 156(8): 721-729.
9. Zhao X, Ren Y, Hu Y, et al. Neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the esophagus or the gastroesophageal junction: A meta-analysis based on clinical trials. PLoS One, 2018, 13(8): e0202185.
10. Moujaess E, Haddad FG, Eid R, et al. The emerging use of immune checkpoint blockade in the adjuvant setting for solid tumors: A review. Immunotherapy, 2019, 11(16): 1409-1422.
11. Kato K, Cho BC, Takahashi M, et al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol, 2019, 20(11): 1506-1517.
12. Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): A randomised, placebo-controlled, phase 3 study. Lancet, 2021, 398(10302): 759-771.
13. Huang J, Xu J, Chen Y, et al. Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): A multicentre, randomised, open-label, phase 3 study. Lancet Oncol, 2020, 21(6): 832-842.
14. Zak KM, Kitel R, Przetocka S, et al. Structure of the complex of human programmed death 1, PD-1, and its ligand PD-L1. Structure, 2015, 23(12): 2341-2348.
15. Zhang X, Schwartz JC, Guo X, et al. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity, 2004, 20(3): 337-347.
16. Chen X, Fosco D, Kline DE, et al. PD-1 regulates extrathymic regulatory T-cell differentiation. Eur J Immunol, 2014, 44(9): 2603-2616.
17. Zak KM, Grudnik P, Guzik K, et al. Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1). Oncotarget, 2016, 7(21): 30323-30335.
18. Lee JY, Lee HT, Shin W, et al. Structural basis of checkpoint blockade by monoclonal antibodies in cancer immunotherapy. Nat Commun, 2016, 7: 13354.
19. Tang Q, Chen Y, Li X, et al. The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers. Front Immunol, 2022, 13: 964442.
20. Ai L, Xu A, Xu J. Roles of PD-1/PD-L1 pathway: Signaling, cancer, and beyond. Adv Exp Med Biol, 2020, 1248: 33-59.
21. Galluzzi L, Humeau J, Buqué A, et al. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol, 2020, 17(12): 725-741.
22. Kroemer G, Galluzzi L, Kepp O, et al. Immunogenic cell death in cancer therapy. Annu Rev Immunol, 2013, 31: 51-72.
23. Meric-Bernstam F, Larkin J, Tabernero J, et al. Enhancing anti-tumour efficacy with immunotherapy combinations. Lancet, 2021, 397(10278): 1010-1022.
24. Topalian SL, Taube JM, Pardoll DM. Neoadjuvant checkpoint blockade for cancer immunotherapy. Science, 2020, 367(6477): eaax0182.
25. Grigg C, Rizvi NA. PD-L1 biomarker testing for non-small cell lung cancer: Truth or fiction? J Immunother Cancer, 2016, 4: 48.
26. Liu P, Zhao L, Pol J, et al. Crizotinib-induced immunogenic cell death in non-small cell lung cancer. Nat Commun, 2019, 10(1): 1486.
27. Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest, 2014, 124(2): 687-695.
28. Galluzzi L, Humeau J, Buqué A, et al. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol, 2020, 17(12): 725-741.
29. Kelly RJ, Landon BV, Zaidi AH, et al. Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: A phase Ⅰb trial and ctDNA analyses. Nat Med, 2024, 30(4): 1023-1034.
30. Yamamoto S, Kato K, Daiko H, et al. Feasibility study of nivolumab as neoadjuvant chemotherapy for locally esophageal carcinoma: FRONTiER (JCOG1804E). Future Oncol, 2020, 16(19): 1351-1357.
31. Park S, Lee Y, Lee J, et al. Neoadjuvant nivolumab therapy for esophageal squamous cell carcinoma: A single-arm, phase Ⅱ study. Cancer Res Treat, 2024, 56(2): 567-579.
32. Li C, Zhao S, Zheng Y, et al. Preoperative pembrolizumab combined with chemoradiotherapy for oesophageal squamous cell carcinoma (PALACE-1). Eur J Cancer, 2021, 144: 232-241.
33. Zheng Y, Li C, Yu B, et al. Preoperative pembrolizumab combined with chemoradiotherapy for esophageal squamous cell carcinoma: Trial design. JTCVS Open, 2021, 9: 293-299.
34. Duan H, Shao C, Pan M, et al. Neoadjuvant pembrolizumab and chemotherapy in resectable esophageal cancer: An open-label, single-arm study (PEN-ICE). Front Immunol, 2022, 13: 849984.
35. Shang X, Zhao G, Liang F, et al. Safety and effectiveness of pembrolizumab combined with paclitaxel and cisplatin as neoadjuvant therapy followed by surgery for locally advanced resectable (stage Ⅲ) esophageal squamous cell carcinoma: A study protocol for a prospective, single-arm, single-center, open-label, phase-Ⅱ trial (Keystone-001). Ann Transl Med, 2022, 10(4): 229.
36. Shang X, Zhang W, Zhao G, et al. Pembrolizumab combined with neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy followed by surgery for locally advanced oesophageal squamous cell carcinoma: Protocol for a multicentre, prospective, randomized-controlled, phase Ⅲ clinical study (Keystone-002). Front Oncol, 2022, 12: 831345.
37. Yang P, Zhou X, Yang X, et al. Neoadjuvant camrelizumab plus chemotherapy in treating locally advanced esophageal squamous cell carcinoma patients: A pilot study. World J Surg Oncol, 2021, 19(1): 333.
38. Liu J, Yang Y, Liu Z, et al. Multicenter, single-arm, phase Ⅱ trial of camrelizumab and chemotherapy as neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma. J Immunother Cancer, 2022, 10(3): e004291.
39. Yang Y, Liu J, Liu Z, et al. Two-year outcomes of clinical N2-3 esophageal squamous cell carcinoma after neoadjuvant chemotherapy and immunotherapy from the phase 2 NICE study. J Thorac Cardiovasc Surg, 2024, 167(3): 838-847.
40. Yang Y, Zhu L, Cheng Y, et al. Three-arm phase Ⅱ trial comparing camrelizumab plus chemotherapy versus camrelizumab plus chemoradiation versus chemoradiation as preoperative treatment for locally advanced esophageal squamous cell carcinoma (NICE-2 Study). BMC Cancer, 2022, 22(1): 506.
41. Liu J, Li J, Lin W, et al. Neoadjuvant camrelizumab plus chemotherapy for resectable, locally advanced esophageal squamous cell carcinoma (NIC-ESCC2019): A multicenter, phase 2 study. Int J Cancer, 2022, 151(1): 128-137.
42. Yang W, Xing X, Yeung SJ, et al. Neoadjuvant programmed cell death 1 blockade combined with chemotherapy for resectable esophageal squamous cell carcinoma. J Immunother Cancer, 2022, 10(1): e003497.
43. Yang G, Su X, Huang Y, et al. Intensive cycles of neoadjuvant camrelizumab combined with chemotherapy in locally advanced esophageal squamous cell carcinoma: A single-arm, phase Ⅱ trial. J Transl Med, 2023, 21(1): 411.
44. Yang Y, Zhang J, Meng H, et al. Neoadjuvant camrelizumab combined with paclitaxel and nedaplatin for locally advanced esophageal squamous cell carcinoma: A single-arm phase 2 study (cohort study). Int J Surg, 2024, 110(3): 1430-1440.
45. Zhang W, Yan C, Gao X, et al. Safety and feasibility of radiotherapy plus camrelizumab for locally advanced esophageal squamous cell carcinoma. Oncologist, 2021, 26(7): e1110-e1124.
46. Duan H, Wang T, Luo Z, et al. A multicenter single-arm trial of sintilimab in combination with chemotherapy for neoadjuvant treatment of resectable esophageal cancer (SIN-ICE study). Ann Transl Med, 2021, 9(22): 1700.
47. Zhang Z, Hong ZN, Xie S, et al. Neoadjuvant sintilimab plus chemotherapy for locally advanced esophageal squamous cell carcinoma: A single-arm, single-center, phase 2 trial (ESONICT-1). Ann Transl Med, 2021, 9(21): 1623.
48. Chen X, Xu X, Wang D, et al. Neoadjuvant sintilimab and chemotherapy in patients with potentially resectable esophageal squamous cell carcinoma (KEEP-G 03): An open-label, single-arm, phase 2 trial. J Immunother Cancer, 2023, 11(2): e005830.
49. Zhang Z, Ye J, Li H, et al. Neoadjuvant sintilimab and chemotherapy in patients with resectable esophageal squamous cell carcinoma: A prospective, single-arm, phase 2 trial. Front Immunol, 2022, 13: 1031171.
50. Chen Y, Ren M, Li B, et al. Neoadjuvant sintilimab plus chemotherapy for locally advanced resectable esophageal squamous cell carcinoma: A prospective, single-arm, phase Ⅱ clinical trial (CY-NICE). J Thorac Dis, 2023, 15(12): 6761-6775.
51. Jiang N, Zhang J, Guo Z, et al. Short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab for locally advanced esophageal squamous cell carcinoma (SCALE-1): A single-arm phase Ib clinical trial. J Immunother Cancer, 2024, 12(1): e008229.
52. Xu X, Sun Z, Liu Q, et al. Neoadjuvant chemoradiotherapy combined with sequential perioperative toripalimab in locally advanced esophageal squamous cell cancer. J Immunother Cancer, 2024, 12(3): e008631.
53. Gao L, Lu J, Zhang P, et al. Toripalimab combined with docetaxel and cisplatin neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma: A single-center, single-arm clinical trial (ESONICT-2). J Gastrointest Oncol, 2022, 13(2): 478-487.
54. He W, Leng X, Mao T, et al. Toripalimab plus paclitaxel and carboplatin as neoadjuvant therapy in locally advanced resectable esophageal squamous cell carcinoma. Oncologist, 2022, 27(1): e18-e28.
55. Xing W, Zhao L, Zheng Y, et al. The sequence of chemotherapy and toripalimab might influence the efficacy of neoadjuvant chemoimmunotherapy in locally advanced esophageal squamous cell cancer-A phase Ⅱ study. Front Immunol, 2021, 12: 772450.
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Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Latest ArticlesResearch progress on PD-1/PD-L1 inhibitors in neoadjuvant therapy for esophageal cancer

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