Research status of PD-1/PD-L1 inhibitors therapy in gastric cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YANG Ze ¹ , PAN Xuehua ² , LI Bo ¹ ,  CHAI Chen ^1,3

1. The First Clinical Medical College of Lanzhou University, Lanzhou 730000, P. R. China;
2. Zhangye City Hospital of Traditional Chinese Medicine, Zhangye, Gansu 734000, P. R. China;
3. Department of General Surgery, the People’s Hospital of Suzhou New District, Suzhou, Jiangsu 215100, P. R. China;

Corresponding author：

CHAI Chen, Email: chaich@lzu.edu.cn

Keywords：

tumor immunotherapy; gastric cancer; PD-1/PD-L1 inhibitor; pembrolizumab; nivolumab

DOI：

10.7507/1007-9424.201907078

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To describe the research status of programmed death receptor protein 1 (PD-1) and its ligand(PD-L1) inhibitors in advanced gastric cancer and to understand the key issues of PD/PD-L1 inhibitors in order to provide atheoretical basis for future research.Method The classical and up to date literatures on the immunotherapy, especially thePD-1/PD-L1 inhibitors in the advanced gastric cancer were reviewed.Results The PD-1/PD-L1 inhibitors were the hot spot in the current research of tumor immunotherapy. The pembrolizumab and nivolumab were the commonly immunosuppressive agents in the current clinical research, which had also achieved the great success in the clinical research of gastriccancer since it was shown the good results in the malignant melanoma and hematological malignancies. In some clinical studies, the PD-1/PD-L1 inhibitors treatment showed the longer overall survival than the conventional chemotherapy, especially in the patient with positive PD-1. However the study still had some issues to be solved, such as no accurate prediction for the beneficiary population, the tumor hyperprogression and so on. It was gratifying that the current research on the basic research of tumor immunity was increasing, then it provided a theoretical support for solving these problems.Conclusions Tumor immunosuppressive therapy such as PD-1/PD-L1 inhibitors brings a new idea in treatment of patients with advanced gastric cancer. Although there are still many problems need to be solved in clinical research, it is believed that PD-1/PD-L1 inhibitors will become one of key players in treatment of patients with advanced gastric cancer in the further study.

Citation： YANG Ze, PAN Xuehua, LI Bo, CHAI Chen. Research status of PD-1/PD-L1 inhibitors therapy in gastric cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2020, 27(3): 379-382. doi: 10.7507/1007-9424.201907078 Copy

1.	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin, 2019, 69(1): 7-34.
2.	Chen W, Sun K, Zheng R, et al. Cancer incidence and mortality in China, 2014. Chin J Cancer Res, 2018, 30(1): 1-12.
3.	Zhou M, Wang H, Zeng X, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990—2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet, 2019, 394(10204): 1145-1158.
4.	Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2014(ver. 4). Gastric Cancer, 2017, 20(1): 1-19.
5.	Li X, Shao C, Shi Y, et al. Lessons learned from the blockade of immune checkpoints in cancer immunotherapy. J Hematol Oncol, 2018, 11(1): 31.
6.	Riley RS, June CH, Langer R, et al. Delivery technologies for cancer immunotherapy. Nat Rev Drug Discov, 2019, 18(3): 175-196.
7.	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.
8.	Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med, 2018, 378(22): 2093-2104.
9.	Perez-Ruiz E, Minute L, Otano I, et al. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy. Nature, 2019, 569(7756): 428-432.
10.	Sim GC, Radvanyi L. The IL-2 cytokine family in cancer immunotherapy. Cytokine Growth Factor Rev, 2014, 25(4): 377-390.
11.	Bhattacharya P, Budnick I, Singh M, et al. Dual role of GM-CSF as a pro-inflammatory and a regulatory cytokine: implications for immune therapy. J Interferon Cytokine Res, 2015, 35(8): 585-599.
12.	Segal NH, He AR, Doi T, et al. Phase Ⅰ study of single-agent utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer. Clin Cancer Res, 2018, 24(8): 1816-1823.
13.	Sauter CS, Senechal B, Rivière I, et al. CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma. Blood, 2019, 134(7): 626-635.
14.	Caram MEV, Ross R, Lin P, et al. Factors associated with use of sipuleucel-T to treat patients with advanced prostate cancer. JAMA Netw Open, 2019, 2(4): e192589.
15.	Liu K, Tan S, Chai Y, et al. Structural basis of anti-PD-L1 monoclonal antibody avelumab for tumor therapy. Cell Res, 2017, 27(1): 151-153.
16.	Tan S, Chen D, Liu K, et al. Crystal clear: visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies. Protein Cell, 2016, 7(12): 866-877.
17.	Tan S, Zhang CW, Gao GF. Seeing is believing: anti-PD-1/PD-L1 monoclonal antibodies in action for checkpoint blockade tumor immunotherapy. Signal Transduct Target Ther, 2016, 1: 16029.
18.	Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science, 2018, 359(6382): 1350-1355.
19.	Muro K, Chung HC, Shankaran V, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol, 2016, 17(6): 717-726.
20.	Kang YK, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 2017, 390(10111): 2461-2471.
21.	Boku N, Ryu MH, Kato K, et al. Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase Ⅱ trial (ATTRACTION-4). Ann Oncol, 2019, 30(2): 250-258.
22.	Fuchs CS, Doi T, Jang RW, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: Phase 2 clinical KEYNOTE-059 trial. JAMA Oncol, 2018, 4(5): e180013.
23.	Bang YJ, Muro K, Fuchs CS, et al. KEYNOTE-059 cohort 2: Safety and efficacy of pembrolizumab (pembro) plus 5-fluorouracil (5-FU) and cisplatin for first-line (1L) treatment of advanced gastric cancer. J Clin Oncol, 2017, 35(15_suppl): 4012-4012.
24.	Tabernero J, Bang YJ, Fuchs CS, et al. KEYNOTE-062: Phase Ⅲ study of pembrolizumab (MK-3475) alone or in combination with chemotherapy versus chemotherapy alone as first-line therapy for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. J Clin Oncol, 2016, 34(4_suppl): TPS185-TPS185.
25.	Shitara K, Özgüroğlu M, Bang YJ, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet, 2018, 392(10142): 123-133.
26.	Janjigian YY, Bendell JC, Calvo E, et al. CheckMate-032: Phase Ⅰ/Ⅱ, open-label study of safety and activity of nivolumab (nivo) alone or with ipilimumab (ipi) in advanced and metastatic (A/M) gastric cancer (GC). J Clin Oncol, 2016, 34(15_suppl): 4010-4010.
27.	Ganesh K, Stadler ZK, Cercek A, et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol, 2019, 16(6): 361-375.
28.	Acheampong E, Spencer I, Lin W, et al. Is the blood an alternative for programmed cell death ligand 1 assessment in non-small cell lung cancer? Cancers (Basel), 2019, 11(7): pii: E920.
29.	Luchini C, Bibeau F, Ligtenberg MJL, et al. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol, 2019 May 6. pii: mdz116.
30.	Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med, 2017, 9(1): 34.
31.	Chowell D, Morris LGT, Grigg CM, et al. Patient HLA class Ⅰ genotype influences cancer response to checkpoint blockade immunotherapy. Science, 2018, 359(6375): 582-587.
32.	Zang YS, Dai C, Xu X, et al. Comprehensive analysis of potential immunotherapy genomic biomarkers in 1000 Chinese patients with cancer. Cancer Med, 2019, 8(10): 4699-4708.
33.	du Rusquec P, de Calbiac O, Robert M, et al. Clinical utility of pembrolizumab in the management of advanced solid tumors: an evidence-based review on the emerging new data. Cancer Manag Res, 2019, 11: 4297-4312.
34.	Surendran SP, Moon MJ, Park R, et al. Bioactive nanoparticles for cancer immunotherapy. Int J Mol Sci, 2018, 19(12): pii: E3877.
35.	Namiki Y, Fuchigami T, Tada N, et al. Nanomedicine for cancer: lipid-based nanostructures for drug delivery and monitoring. Acc Chem Res, 2011, 44(10): 1080-1093.
36.	Li R, Liu B, Gao J. The application of nanoparticles in diagnosis and theranostics of gastric cancer. Cancer Lett, 2017, 386: 123-130.
37.	Martins F, Sofiya L, Sykiotis GP, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol, 2019, 16(9): 563-580.
38.	Kim CG, Kim KH, Pyo KH, et al. Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer. Ann Oncol, 2019, 30(7): 1104-1113.
39.	Di Pilato M, Kim EY, Cadilha BL, et al. Targeting the CBM complex causes T Nature, 2019, 570(7759): 112-116.

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin, 2019, 69(1): 7-34.
2. Chen W, Sun K, Zheng R, et al. Cancer incidence and mortality in China, 2014. Chin J Cancer Res, 2018, 30(1): 1-12.
3. Zhou M, Wang H, Zeng X, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990—2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet, 2019, 394(10204): 1145-1158.
4. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2014(ver. 4). Gastric Cancer, 2017, 20(1): 1-19.
5. Li X, Shao C, Shi Y, et al. Lessons learned from the blockade of immune checkpoints in cancer immunotherapy. J Hematol Oncol, 2018, 11(1): 31.
6. Riley RS, June CH, Langer R, et al. Delivery technologies for cancer immunotherapy. Nat Rev Drug Discov, 2019, 18(3): 175-196.
7. 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.
8. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med, 2018, 378(22): 2093-2104.
9. Perez-Ruiz E, Minute L, Otano I, et al. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy. Nature, 2019, 569(7756): 428-432.
10. Sim GC, Radvanyi L. The IL-2 cytokine family in cancer immunotherapy. Cytokine Growth Factor Rev, 2014, 25(4): 377-390.
11. Bhattacharya P, Budnick I, Singh M, et al. Dual role of GM-CSF as a pro-inflammatory and a regulatory cytokine: implications for immune therapy. J Interferon Cytokine Res, 2015, 35(8): 585-599.
12. Segal NH, He AR, Doi T, et al. Phase Ⅰ study of single-agent utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer. Clin Cancer Res, 2018, 24(8): 1816-1823.
13. Sauter CS, Senechal B, Rivière I, et al. CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma. Blood, 2019, 134(7): 626-635.
14. Caram MEV, Ross R, Lin P, et al. Factors associated with use of sipuleucel-T to treat patients with advanced prostate cancer. JAMA Netw Open, 2019, 2(4): e192589.
15. Liu K, Tan S, Chai Y, et al. Structural basis of anti-PD-L1 monoclonal antibody avelumab for tumor therapy. Cell Res, 2017, 27(1): 151-153.
16. Tan S, Chen D, Liu K, et al. Crystal clear: visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies. Protein Cell, 2016, 7(12): 866-877.
17. Tan S, Zhang CW, Gao GF. Seeing is believing: anti-PD-1/PD-L1 monoclonal antibodies in action for checkpoint blockade tumor immunotherapy. Signal Transduct Target Ther, 2016, 1: 16029.
18. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science, 2018, 359(6382): 1350-1355.
19. Muro K, Chung HC, Shankaran V, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol, 2016, 17(6): 717-726.
20. Kang YK, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 2017, 390(10111): 2461-2471.
21. Boku N, Ryu MH, Kato K, et al. Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase Ⅱ trial (ATTRACTION-4). Ann Oncol, 2019, 30(2): 250-258.
22. Fuchs CS, Doi T, Jang RW, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: Phase 2 clinical KEYNOTE-059 trial. JAMA Oncol, 2018, 4(5): e180013.
23. Bang YJ, Muro K, Fuchs CS, et al. KEYNOTE-059 cohort 2: Safety and efficacy of pembrolizumab (pembro) plus 5-fluorouracil (5-FU) and cisplatin for first-line (1L) treatment of advanced gastric cancer. J Clin Oncol, 2017, 35(15_suppl): 4012-4012.
24. Tabernero J, Bang YJ, Fuchs CS, et al. KEYNOTE-062: Phase Ⅲ study of pembrolizumab (MK-3475) alone or in combination with chemotherapy versus chemotherapy alone as first-line therapy for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. J Clin Oncol, 2016, 34(4_suppl): TPS185-TPS185.
25. Shitara K, Özgüroğlu M, Bang YJ, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet, 2018, 392(10142): 123-133.
26. Janjigian YY, Bendell JC, Calvo E, et al. CheckMate-032: Phase Ⅰ/Ⅱ, open-label study of safety and activity of nivolumab (nivo) alone or with ipilimumab (ipi) in advanced and metastatic (A/M) gastric cancer (GC). J Clin Oncol, 2016, 34(15_suppl): 4010-4010.
27. Ganesh K, Stadler ZK, Cercek A, et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol, 2019, 16(6): 361-375.
28. Acheampong E, Spencer I, Lin W, et al. Is the blood an alternative for programmed cell death ligand 1 assessment in non-small cell lung cancer? Cancers (Basel), 2019, 11(7): pii: E920.
29. Luchini C, Bibeau F, Ligtenberg MJL, et al. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol, 2019 May 6. pii: mdz116.
30. Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med, 2017, 9(1): 34.
31. Chowell D, Morris LGT, Grigg CM, et al. Patient HLA class Ⅰ genotype influences cancer response to checkpoint blockade immunotherapy. Science, 2018, 359(6375): 582-587.
32. Zang YS, Dai C, Xu X, et al. Comprehensive analysis of potential immunotherapy genomic biomarkers in 1000 Chinese patients with cancer. Cancer Med, 2019, 8(10): 4699-4708.
33. du Rusquec P, de Calbiac O, Robert M, et al. Clinical utility of pembrolizumab in the management of advanced solid tumors: an evidence-based review on the emerging new data. Cancer Manag Res, 2019, 11: 4297-4312.
34. Surendran SP, Moon MJ, Park R, et al. Bioactive nanoparticles for cancer immunotherapy. Int J Mol Sci, 2018, 19(12): pii: E3877.
35. Namiki Y, Fuchigami T, Tada N, et al. Nanomedicine for cancer: lipid-based nanostructures for drug delivery and monitoring. Acc Chem Res, 2011, 44(10): 1080-1093.
36. Li R, Liu B, Gao J. The application of nanoparticles in diagnosis and theranostics of gastric cancer. Cancer Lett, 2017, 386: 123-130.
37. Martins F, Sofiya L, Sykiotis GP, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol, 2019, 16(9): 563-580.
38. Kim CG, Kim KH, Pyo KH, et al. Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer. Ann Oncol, 2019, 30(7): 1104-1113.
39. Di Pilato M, Kim EY, Cadilha BL, et al. Targeting the CBM complex causes T Nature, 2019, 570(7759): 112-116.

Previous Article
Research progress on the relationship between estrogen metabolism and breast cancer
Next Article
Clinical advances in prognostic factors and predictive methods of liver transplantation

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research status of PD-1/PD-L1 inhibitors therapy in gastric cancer

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content