Progress of programmed death-1/programmed death ligand-1 inhibitors for esophageal cancer_West China Medical Journal

Authors：

YAN Min ^1,2 ,  LI Dezhi ³ , BIE Jun ^1,2

1. the Second Clinical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P. R. China;
2. Department of Oncology, Nanchong Central Hospital, Nanchong, Sichuan 637000, P. R. China;
3. Department of Oncology, the Fourth Affiliated Hospital Zhejiang University School of Medicine, Yiwu, Zhejiang 322000, P. R. China;

Corresponding author：

LI Dezhi, Email: mdlidezhi@163.com

Keywords：

Esophageal cancer; Programmed death-1/programmed death ligand-1 inhibitor; Immunotherapy

DOI：

10.7507/1002-0179.201912064

Video：

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Immunotherapy is an important treatment method in tumor therapy. Among them, programmed death-1/programmed death ligand-1 inhibitors are the immune preparations with mature application and great survival benefit at present. Programmed death-1/programmed death ligand-1 inhibitors brought better clinical benefits to patients with esophageal cancer and provided more favorable choice for the treatment of esophageal cancer. This article introduces the mechanism of action, application in esophageal cancer, and efficacy predictors of programmed death protein-1/programmed death protein ligand-1 inhibitors, aiming to provide a theoretical basis for the more rational use of programmed death protein-1/programmed death protein ligand-1 inhibitors in patients with esophageal cancer.

Citation： YAN Min, LI Dezhi, BIE Jun. Progress of programmed death-1/programmed death ligand-1 inhibitors for esophageal cancer. West China Medical Journal, 2020, 35(10): 1267-1272. doi: 10.7507/1002-0179.201912064 Copy

1.	贺宇彤, 李道娟, 梁迪, 等. 2013年中国食管癌发病和死亡估计. 中华肿瘤杂志, 2017, 39(4): 315-320.
2.	Ferlay J, Colombet M, Soerjomataram I, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer, 2019, 144(8): 1941-1953.
3.	Hou H, Meng Z, Zhao X, et al. Survival of esophageal cancer in China: a pooled analysis on hospital-based studies from 2000 to 2018. Front Oncol, 2019, 9: 548.
4.	Zhao Q, Yu J, Meng X. A good start of immunotherapy in esophageal cancer. Cancer Med, 2019, 8(10): 4519-4526.
5.	Leitner J, Grabmeier-Pfistershammer K, Steinberger P. Receptors and ligands implicated in human T cell costimulatory processes. Immunol Lett, 2010, 128(2): 89-97.
6.	Sharma P, Allison JP. The future of immune checkpoint therapy. Science, 2015, 348(6230): 56-61.
7.	Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol, 2008, 26: 677-704.
8.	Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther, 2015, 14(4): 847-856.
9.	Jiang Y, Chen M, Nie H, et al. PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations. Hum Vaccin Immunother, 2019, 15(5): 1111-1122.
10.	Efremova M, Rieder D, Klepsch V, et al. Targeting immune checkpoints potentiates immunoediting and changes the dynamics of tumor evolution. Nat Commun, 2018, 9(1): 32.
11.	Sanmamed MF, Chen L. A paradigm shift in cancer immunotherapy: from enhancement to normalization. Cell, 2018, 175(2): 313-326.
12.	Doi T, Piha-Paul SA, Jalal SI, et al. Safety and antitumor activity of the anti-programmed death-1 antibody pembrolizumab in patients with advanced esophageal carcinoma. J Clin Oncol, 2018, 36(1): 61-67.
13.	Shah MA, Kojima T, Hochhauser D, et al. Efficacy and safety of pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: the phase 2 KEYNOTE-180 study. JAMA Oncol, 2019, 5(4): 546-550.
14.	Kojima T, Muro K, Francois E, et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase Ⅲ KEYNOTE-181 study. J Clin Oncol, 2019, 37: 2.
15.	Kudo T, Hamamoto Y, Kato K, et al. Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. Lancet Oncol, 2017, 18(5): 631-639.
16.	Huang J, Xu B, Mo H, et al. Safety, activity, and biomarkers of SHR-1210, an anti-PD-1 antibody, for patients with advanced esophageal carcinoma. Clin Cancer Res, 2018, 24(6): 1296-1304.
17.	Zitvogel L, Galluzzi L, Smyth MJ, et al. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity, 2013, 39(1): 74-88.
18.	Ramakrishnan R, Huang C, Cho HI, et al. Autophagy induced by conventional chemotherapy mediates tumor cell sensitivity to immunotherapy. Cancer Res, 2012, 72(21): 5483-5493.
19.	Pol J, Vacchelli E, Aranda F, et al. Trial watch: immunogenic cell death inducers for anticancer chemotherapy. Oncoimmunology, 2015, 4(4): e1008866.
20.	Pasquier E, Kavallaris M, André N. Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol, 2010, 7(8): 455-465.
21.	Bang YJ, Kang YK, Catenacci DV, et al. Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase Ⅱ nonrandomized KEYNOTE-059 study. Gastric Cancer, 2019, 22(4): 828-837.
22.	Xu N, Shen L, Jiang H, et al. Efficacy and safety of sintilimab in combination with XELOX in first-line gastric or gastroesophageal junction carcinoma (GC/GEJC). J Clin Oncol, 2019, 37(15 suppl): 4042-4042.
23.	Kato K, Shah MA, Enzinger P, et al. KEYNOTE-590: phase Ⅲ studyof first-line chemotherapy with or without pembrolizumab for advanced esophageal cancer. Future Oncol, 2019, 15(10): 1057-1066.
24.	Terme M, Pernot S, Marcheteau E, et al. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res, 2013, 73(2): 539-549.
25.	Zhang B, Qi L, Wang X, et al. Phase 2 study of camrelizumab (anti-PD-1 antibody) combined with apatinib and chemotherapy for the first-line treatment of advanced esophageal squamous cell carcinoma. J Clin Oncol, 2019, 37(15 suppl): 4033.
26.	Shen L, Peng Z, Zhang Y, et al. Camrelizumab combined with capecitabine and oxaliplatin followed by camrelizumab and apatinib as first-line therapy for advanced or metastatic gastric or gastroesophageal junction cancer: updated results from a multicenter, open label phase Ⅱ trial. J Clin Oncol, 2019, 37 (15 suppl): 4031.
27.	Herbst RS, Arkenau HT, Santana-Davila R, et al. Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial. Lancet Oncol, 2019, 20(8): 1109-1123.
28.	Janjigian YY, Maron SB, Chatila WK, et al. First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial. Lancet Oncol, 2020, 21(6): 821-831.
29.	Gameiro SR, Jammeh ML, Wattenberg MM, et al. Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. Oncotarget, 2014, 5(2): 403-416.
30.	de la Cruz-Merino L, Illescas-Vacas A, Grueso-López A, et al. Radiation for awakening the dormant immune system, a promising challenge to be explored. Front Immunol, 2014, 5: 102.
31.	Walle T, Martinez Monge R, Cerwenka A, et al. Radiation effects on antitumor immune responses: current perspectives and challenges. Ther Adv Med Oncol, 2018, 10: 1758834017742575.
32.	Shapiro J, van Lanschot JJB, Hulshof MCCM, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results ofa randomised controlled trial. Lancet Oncol, 2015, 16(9): 1090-1098.
33.	de Clercq NC, van den Ende T, van Berge Henegouwen MI, et al. A phase Ⅱ feasibility trial of neoadjuvant chemoradiotherapy combined with atezolizumab for resectable esophageal adenocarcinoma: the PERFECT trial. J Clin Oncol, 2019, 37 (15 suppl): 4045.
34.	Hong MH, Kim H, Park SY, et al. A phase Ⅱ trial of preoperative chemoradiotherapy and pembrolizumab for locally advanced esophageal squamous cell carcinoma (ESCC). J Clin Oncol, 2019, 37(15 suppl): 4027.
35.	Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet, 2016, 387(10027): 1540-1550.
36.	Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet, 2017, 389(10066): 255-265.
37.	Ma J, Li J, Qian M, et al. PD-L1 expression and the prognostic significance in gastric cancer: a retrospective comparison of three PD-L1 antibody clones (SP142, 28-8 and E1L3N). Diagn Pathol, 2018, 13(1): 91.
38.	Dong J, Zhu D, Tang X, et al. Circulating tumor cells in pulmonary vein and peripheral arterial provide a metric for PD-L1 diagnosis and prognosis of patients with non-small cell lung cancer. PLoS One, 2019, 14(7): e0220306.
39.	Yue C, Jiang Y, Li P, et al. Dynamic change of PD-L1 expression on circulating tumor cells in advanced solid tumor patients undergoing PD-1 blockade therapy. Oncoimmunology, 2018, 7(7): e1438111.
40.	Strati A, Koutsodontis G, Papaxoinis G, et al. Prognostic significance of PD-L1 expression on circulating tumor cells in patients with head and neck squamous cell carcinoma. Ann Oncol, 2017, 28(8): 1923-1933.
41.	Guo W, Wang P, Li N, et al. Prognostic value of PD-L1 in esophageal squamous cell carcinoma: a meta-analysis. Oncotarget, 2017, 9(17): 13920-13933.
42.	Ajani JA, D’Amico TA, Bentrem DJ, et al. Esophageal and Esophagogastric junction cancers, version 2. 2019, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw, 2019, 17(7): 855-883.
43.	Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N EnglJ Med, 2015, 373(2): 123-135.
44.	O’Donnell JS, Long GV, Scolyer RA, et al. Resistance to PD-1/PD-L1 checkpoint inhibition. Cancer Treat Rev, 2017, 52: 71-81.
45.	Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science, 2017, 357(6349): 409-413.
46.	Kong P, Wang J, Song Z, et al. Circulating lymphocytes, PD-L1 expression on tumor-infiltrating lymphocytes, and survival of colorectal cancer patients with different mismatch repair gene status. J Cancer, 2019, 10(7): 1745-1754.
47.	Dudley JC, Lin MT, Le DT, et al. Microsatellite instability asa biomarker for PD-1 blockade. Clin Cancer Res, 2016, 22(4): 813-820.
48.	Mills AM, Dill EA, Moskaluk CA, et al. The relationship between mismatch repair deficiency and PD-L1 expression in breast carcinoma. Am J Surg Pathol, 2018, 42(2): 183-191.
49.	Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med, 2017, 377(25): 2500-2501.

1. 贺宇彤, 李道娟, 梁迪, 等. 2013年中国食管癌发病和死亡估计. 中华肿瘤杂志, 2017, 39(4): 315-320.
2. Ferlay J, Colombet M, Soerjomataram I, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer, 2019, 144(8): 1941-1953.
3. Hou H, Meng Z, Zhao X, et al. Survival of esophageal cancer in China: a pooled analysis on hospital-based studies from 2000 to 2018. Front Oncol, 2019, 9: 548.
4. Zhao Q, Yu J, Meng X. A good start of immunotherapy in esophageal cancer. Cancer Med, 2019, 8(10): 4519-4526.
5. Leitner J, Grabmeier-Pfistershammer K, Steinberger P. Receptors and ligands implicated in human T cell costimulatory processes. Immunol Lett, 2010, 128(2): 89-97.
6. Sharma P, Allison JP. The future of immune checkpoint therapy. Science, 2015, 348(6230): 56-61.
7. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol, 2008, 26: 677-704.
8. Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther, 2015, 14(4): 847-856.
9. Jiang Y, Chen M, Nie H, et al. PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations. Hum Vaccin Immunother, 2019, 15(5): 1111-1122.
10. Efremova M, Rieder D, Klepsch V, et al. Targeting immune checkpoints potentiates immunoediting and changes the dynamics of tumor evolution. Nat Commun, 2018, 9(1): 32.
11. Sanmamed MF, Chen L. A paradigm shift in cancer immunotherapy: from enhancement to normalization. Cell, 2018, 175(2): 313-326.
12. Doi T, Piha-Paul SA, Jalal SI, et al. Safety and antitumor activity of the anti-programmed death-1 antibody pembrolizumab in patients with advanced esophageal carcinoma. J Clin Oncol, 2018, 36(1): 61-67.
13. Shah MA, Kojima T, Hochhauser D, et al. Efficacy and safety of pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: the phase 2 KEYNOTE-180 study. JAMA Oncol, 2019, 5(4): 546-550.
14. Kojima T, Muro K, Francois E, et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase Ⅲ KEYNOTE-181 study. J Clin Oncol, 2019, 37: 2.
15. Kudo T, Hamamoto Y, Kato K, et al. Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. Lancet Oncol, 2017, 18(5): 631-639.
16. Huang J, Xu B, Mo H, et al. Safety, activity, and biomarkers of SHR-1210, an anti-PD-1 antibody, for patients with advanced esophageal carcinoma. Clin Cancer Res, 2018, 24(6): 1296-1304.
17. Zitvogel L, Galluzzi L, Smyth MJ, et al. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity, 2013, 39(1): 74-88.
18. Ramakrishnan R, Huang C, Cho HI, et al. Autophagy induced by conventional chemotherapy mediates tumor cell sensitivity to immunotherapy. Cancer Res, 2012, 72(21): 5483-5493.
19. Pol J, Vacchelli E, Aranda F, et al. Trial watch: immunogenic cell death inducers for anticancer chemotherapy. Oncoimmunology, 2015, 4(4): e1008866.
20. Pasquier E, Kavallaris M, André N. Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol, 2010, 7(8): 455-465.
21. Bang YJ, Kang YK, Catenacci DV, et al. Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase Ⅱ nonrandomized KEYNOTE-059 study. Gastric Cancer, 2019, 22(4): 828-837.
22. Xu N, Shen L, Jiang H, et al. Efficacy and safety of sintilimab in combination with XELOX in first-line gastric or gastroesophageal junction carcinoma (GC/GEJC). J Clin Oncol, 2019, 37(15 suppl): 4042-4042.
23. Kato K, Shah MA, Enzinger P, et al. KEYNOTE-590: phase Ⅲ studyof first-line chemotherapy with or without pembrolizumab for advanced esophageal cancer. Future Oncol, 2019, 15(10): 1057-1066.
24. Terme M, Pernot S, Marcheteau E, et al. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res, 2013, 73(2): 539-549.
25. Zhang B, Qi L, Wang X, et al. Phase 2 study of camrelizumab (anti-PD-1 antibody) combined with apatinib and chemotherapy for the first-line treatment of advanced esophageal squamous cell carcinoma. J Clin Oncol, 2019, 37(15 suppl): 4033.
26. Shen L, Peng Z, Zhang Y, et al. Camrelizumab combined with capecitabine and oxaliplatin followed by camrelizumab and apatinib as first-line therapy for advanced or metastatic gastric or gastroesophageal junction cancer: updated results from a multicenter, open label phase Ⅱ trial. J Clin Oncol, 2019, 37 (15 suppl): 4031.
27. Herbst RS, Arkenau HT, Santana-Davila R, et al. Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial. Lancet Oncol, 2019, 20(8): 1109-1123.
28. Janjigian YY, Maron SB, Chatila WK, et al. First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial. Lancet Oncol, 2020, 21(6): 821-831.
29. Gameiro SR, Jammeh ML, Wattenberg MM, et al. Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. Oncotarget, 2014, 5(2): 403-416.
30. de la Cruz-Merino L, Illescas-Vacas A, Grueso-López A, et al. Radiation for awakening the dormant immune system, a promising challenge to be explored. Front Immunol, 2014, 5: 102.
31. Walle T, Martinez Monge R, Cerwenka A, et al. Radiation effects on antitumor immune responses: current perspectives and challenges. Ther Adv Med Oncol, 2018, 10: 1758834017742575.
32. Shapiro J, van Lanschot JJB, Hulshof MCCM, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results ofa randomised controlled trial. Lancet Oncol, 2015, 16(9): 1090-1098.
33. de Clercq NC, van den Ende T, van Berge Henegouwen MI, et al. A phase Ⅱ feasibility trial of neoadjuvant chemoradiotherapy combined with atezolizumab for resectable esophageal adenocarcinoma: the PERFECT trial. J Clin Oncol, 2019, 37 (15 suppl): 4045.
34. Hong MH, Kim H, Park SY, et al. A phase Ⅱ trial of preoperative chemoradiotherapy and pembrolizumab for locally advanced esophageal squamous cell carcinoma (ESCC). J Clin Oncol, 2019, 37(15 suppl): 4027.
35. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet, 2016, 387(10027): 1540-1550.
36. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet, 2017, 389(10066): 255-265.
37. Ma J, Li J, Qian M, et al. PD-L1 expression and the prognostic significance in gastric cancer: a retrospective comparison of three PD-L1 antibody clones (SP142, 28-8 and E1L3N). Diagn Pathol, 2018, 13(1): 91.
38. Dong J, Zhu D, Tang X, et al. Circulating tumor cells in pulmonary vein and peripheral arterial provide a metric for PD-L1 diagnosis and prognosis of patients with non-small cell lung cancer. PLoS One, 2019, 14(7): e0220306.
39. Yue C, Jiang Y, Li P, et al. Dynamic change of PD-L1 expression on circulating tumor cells in advanced solid tumor patients undergoing PD-1 blockade therapy. Oncoimmunology, 2018, 7(7): e1438111.
40. Strati A, Koutsodontis G, Papaxoinis G, et al. Prognostic significance of PD-L1 expression on circulating tumor cells in patients with head and neck squamous cell carcinoma. Ann Oncol, 2017, 28(8): 1923-1933.
41. Guo W, Wang P, Li N, et al. Prognostic value of PD-L1 in esophageal squamous cell carcinoma: a meta-analysis. Oncotarget, 2017, 9(17): 13920-13933.
42. Ajani JA, D’Amico TA, Bentrem DJ, et al. Esophageal and Esophagogastric junction cancers, version 2. 2019, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw, 2019, 17(7): 855-883.
43. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N EnglJ Med, 2015, 373(2): 123-135.
44. O’Donnell JS, Long GV, Scolyer RA, et al. Resistance to PD-1/PD-L1 checkpoint inhibition. Cancer Treat Rev, 2017, 52: 71-81.
45. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science, 2017, 357(6349): 409-413.
46. Kong P, Wang J, Song Z, et al. Circulating lymphocytes, PD-L1 expression on tumor-infiltrating lymphocytes, and survival of colorectal cancer patients with different mismatch repair gene status. J Cancer, 2019, 10(7): 1745-1754.
47. Dudley JC, Lin MT, Le DT, et al. Microsatellite instability asa biomarker for PD-1 blockade. Clin Cancer Res, 2016, 22(4): 813-820.
48. Mills AM, Dill EA, Moskaluk CA, et al. The relationship between mismatch repair deficiency and PD-L1 expression in breast carcinoma. Am J Surg Pathol, 2018, 42(2): 183-191.
49. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med, 2017, 377(25): 2500-2501.

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