胃及胃食管结合部癌免疫治疗的研究进展
|
摘要
免疫系统在调节肿瘤生长过程中起重要作用,它能够识别和清除新出现的"非己"成分,包括肿瘤细胞,发生基因突变的肿瘤细胞能否形成肿瘤取决于肿瘤细胞与免疫系统之间相互作用的结果。肿瘤免疫治疗是一种通过激活人体自身免疫系统来提高组织适应性免疫反应的特异性和长期记忆,以实现持久的肿瘤消退和可能的治愈手段。目前在消化道肿瘤中,大量的临床试验初步成果证实免疫治疗对于胃及胃食管结合部癌有效,本文将其免疫治疗的方法及最新临床进展作一综述。
The immune system which can identify and remove emerging non-self components,including tumor cells,plays an important role in regulating tumor growth. The ability of genetically mutated cells to form tumors depends on the interaction between tumor cells and the immune system. Tumor immunotherapy is a therapy of improving the specificity and long-term memory of tissue-adapted immune response by activating the autoimmune system to achieve lasting tumor regression and possible healing treatments. The preliminary results of clinical trials have confirmed the efficacy of immunotherapy for gastric and gastroesophageal junction cancer at present,and the methods and the latest clinical progress of the immunotherapy are reviewed in this article.
The immune system which can identify and remove emerging non-self components,including tumor cells,plays an important role in regulating tumor growth. The ability of genetically mutated cells to form tumors depends on the interaction between tumor cells and the immune system. Tumor immunotherapy is a therapy of improving the specificity and long-term memory of tissue-adapted immune response by activating the autoimmune system to achieve lasting tumor regression and possible healing treatments. The preliminary results of clinical trials have confirmed the efficacy of immunotherapy for gastric and gastroesophageal junction cancer at present,and the methods and the latest clinical progress of the immunotherapy are reviewed in this article.
引文
[1] Wang C,Zhang J,Cai M,et al. DBGC:a database of human gastric cancer[J]. PLoS One,2015,10(11):e0142591.
[2] Chen W,Zheng R,Baade PD,et al. Cancer statistics in China,2015[J]. CA Cancer J Clin,2016,66(2):115-132.
[3] Melero I,Hervas-Stubbs S,Glennie M,et al. Immunostimulatory monoclonal antibodies for cancer therapy[J]. Nat Rev Cancer,2007,7(2):95-106.
[4] Hodi FS,O'Day SJ,McDermott DF,et al. Improved survival with ipilimumab in patients with metastatic melanoma[J]. N Engl J Med,2010,363(8):711-723.
[5] Bang YJ,Cho JY,Kim YH,et al. Efficacy of sequential ipilimumab monotherapy versus best supportive care for unresectable locally advanced/metastatic gastric or gastroesophageal junction cancer[J]. Clin Cancer Res,2017,23(19):5671-5678.
[6] Zhao Y,Yang W,Huang Y,et al. Evolving roles for targeting CTLA-4 in cancer immunotherapy[J]. Cell Physiol Biochem,2018,47(2):721-734.
[7] Freeman GJ,Long AJ,Iwai Y,et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation[J]. J Exp Med,2000,192(7):1027-1034.
[8] Keir ME,Butte MJ,Freeman GJ,et al. PD-1 and its ligands in tolerance and immunity[J]. Annu Rev Immunol,2008,26:677-704.
[9] 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[J]. Lancet,2017,390(10111):2461-2471.
[10] Kato K,Satoh T,Muro K,et al. A subanalysis of Japanese patients in a randomized,double-blind,placebo-controlled,phase 3 trial of nivolumab for patients with advanced gastric or gastro-esophageal junction cancer refractory to,or intolerant of,at least two previous chemotherapy regimens(ONO-4538-12,ATTRACTION-2)[J]. Gastric Cancer,2019,22(2):344-354.
[11] 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,phaseⅡtrial(ATTRACTION-4)[J]. Ann Oncol,2019,30(2):250-258.
[12] 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[J]. JAMA Oncol,2018,4(5):e180013.
[13] 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 phaseⅡnonrandomized KEYNOTE-059 study[J]. Gastric Cancer,2019.[Epub ahead of print]
[14] Chung HC,Arkenau HT,Lee J,et al. Avelumab(anti-PDL1)as first-line switch-maintenance or second-line therapy in patients with advanced gastric or gastroesophageal junction cancer:phase 1b results from the JAVELIN Solid Tumor trial[J]. J Immunother Cancer,2019,7(1):30.
[15] Alsina M,Moehler M,Hierro C,et al. Immunotherapy for gastric cancer:a focus on immune checkpoints[J]. Target Oncol,2016,11(4):469-477.
[16] Bang YJ,Ruiz EY,Van Cutsem E,et al. PhaseⅢ,randomized trial of avelumab versus physician’s choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer:primary analysis of JAVELIN Gastric 300[J]. Ann Oncol,2018,29(10):2052-2060.
[17] Asaoka Y,Ijichi H,Koike K. PD-1 blockade in tumors with mismatch-repair deficiency[J]. N Engl J Med,2015,373(20):1979.
[18] Grogg KL,Lohse CM,Pankratz VS,et al. Lymphocyte-rich gastric cancer:associations with Epstein-Barr virus,microsatellite instability,histology,and survival[J]. Mod Pathol,2003,16(7):641-651.
[19] Kim KJ,Lee KS,Cho HJ,et al. Prognostic implications of tumor-infiltrating FoxP3+regulatory T cells and CD8+cytotoxic T cells in microsatellite-unstable gastric cancers[J].Hum Pathol,2014,45(2):285-293.
[20] Bockorny B,Pectasides E. The emerging role of immunotherapy in gastric and esophageal adenocarcinoma[J].Future Oncol,2016,12(15):1833-1846.
[21] Masuzawa T,Fujiwara Y,Okada K,et al. PhaseⅠ/Ⅱstudy of S-1 plus cisplatin combined with peptide vaccines for human vascular endothelial growth factor receptor 1 and 2 in patients with advanced gastric cancer[J]. Int J Oncol,2012,41(4):1297-1304.
[22] Sundar R,Rha SY,Yamaue H,et al. A phaseⅠ/Ⅰb study of OTSGC-A24 combined peptide vaccine in advanced gastric cancer[J]. BMC Cancer,2018,18(1):332.
[23] Bang YJ,Van Cutsem E,Feyereislova A,et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer(ToGA):a phase 3,open-label,randomised controlled trial[J]. Lancet,2010,376(9742):687-697.
[24] Ilhan-Mutlu A,Taghizadeh H,Beer A,et al. Correlation of trastuzumab-based treatment with clinical characteristics and prognosis in HER2-positive gastric and gastroesophageal junction cancer:a retrospective single center analysis[J]. Cancer Biol Ther,2018,19(3):169-174.
[25] Fuchs CS,Tomasek J,Yong CJ,et al. Ramucirumab monotherapy for previously treated advanced gas tric or gastro-oesophageal junction adenocarcinoma(REGARD):an international,randomised,multicentre,placebo-controlled,phase 3 trial[J]. Lancet,2014,383(9911):31-39.
[26] Tehfe M,Tabchi S,Laterza MM,et al. Ramucirumab in HER-2-positive gastroesophageal adenocarcinoma:an argument for overcoming trastuzumab resistance[J]. Future Oncol,2018,14(3):223-228.
[27] Al-Batran SE,Schuler MH,et al. Antibody improves survival in gastric cancer[J]. Cancer Discov,2016,6(8):OF8.
[28] Goff SL,Dudley ME,Citrin DE,et al. Randomized,prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma[J]. J Clin Oncol,2016,34(20):2389-2397.
[29] Besser MJ,Shapira-Frommer R,Schachter J. Tumor-infiltrating lymphocytes:clinical experience[J]. Cancer J,2015,21(6):465-469.
[30] Abrahao-Machado LF,Scapulatempo-Neto C. HER2 testing in gastric cancer:an update[J]. World J Gastroenterol,2016,22(19):4619-4625.
[31] Kobold S,Steffen J,Chaloupka M,et al. Selective bispecific T cell recruiting antibody and antitumor activity of adoptive T cell transfer[J]. J Natl Cancer Inst,2015,107(1):364.
[32] Kim M,Pyo S,Kang CH,et al. Folate receptor 1(FOLR1)targeted chimeric antigen receptor(CAR)T cells for the treatment of gastric cancer[J]. PLoS One, 2018, 13(6):e0198347.
[33] Galluzzi L,Zitvogel L,Kroemer G. Immunological mechanisms underneath the efficacy of cancer therapy[J]. Cancer Immunol Res,2016,4(11):895-902.
[34] Demaria S,Coleman CN,Formenti SC. Radiotherapy:changing the game in immunotherapy[J]. Trends Cancer,2016,2(6):286-294.
[2] Chen W,Zheng R,Baade PD,et al. Cancer statistics in China,2015[J]. CA Cancer J Clin,2016,66(2):115-132.
[3] Melero I,Hervas-Stubbs S,Glennie M,et al. Immunostimulatory monoclonal antibodies for cancer therapy[J]. Nat Rev Cancer,2007,7(2):95-106.
[4] Hodi FS,O'Day SJ,McDermott DF,et al. Improved survival with ipilimumab in patients with metastatic melanoma[J]. N Engl J Med,2010,363(8):711-723.
[5] Bang YJ,Cho JY,Kim YH,et al. Efficacy of sequential ipilimumab monotherapy versus best supportive care for unresectable locally advanced/metastatic gastric or gastroesophageal junction cancer[J]. Clin Cancer Res,2017,23(19):5671-5678.
[6] Zhao Y,Yang W,Huang Y,et al. Evolving roles for targeting CTLA-4 in cancer immunotherapy[J]. Cell Physiol Biochem,2018,47(2):721-734.
[7] Freeman GJ,Long AJ,Iwai Y,et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation[J]. J Exp Med,2000,192(7):1027-1034.
[8] Keir ME,Butte MJ,Freeman GJ,et al. PD-1 and its ligands in tolerance and immunity[J]. Annu Rev Immunol,2008,26:677-704.
[9] 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[J]. Lancet,2017,390(10111):2461-2471.
[10] Kato K,Satoh T,Muro K,et al. A subanalysis of Japanese patients in a randomized,double-blind,placebo-controlled,phase 3 trial of nivolumab for patients with advanced gastric or gastro-esophageal junction cancer refractory to,or intolerant of,at least two previous chemotherapy regimens(ONO-4538-12,ATTRACTION-2)[J]. Gastric Cancer,2019,22(2):344-354.
[11] 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,phaseⅡtrial(ATTRACTION-4)[J]. Ann Oncol,2019,30(2):250-258.
[12] 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[J]. JAMA Oncol,2018,4(5):e180013.
[13] 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 phaseⅡnonrandomized KEYNOTE-059 study[J]. Gastric Cancer,2019.[Epub ahead of print]
[14] Chung HC,Arkenau HT,Lee J,et al. Avelumab(anti-PDL1)as first-line switch-maintenance or second-line therapy in patients with advanced gastric or gastroesophageal junction cancer:phase 1b results from the JAVELIN Solid Tumor trial[J]. J Immunother Cancer,2019,7(1):30.
[15] Alsina M,Moehler M,Hierro C,et al. Immunotherapy for gastric cancer:a focus on immune checkpoints[J]. Target Oncol,2016,11(4):469-477.
[16] Bang YJ,Ruiz EY,Van Cutsem E,et al. PhaseⅢ,randomized trial of avelumab versus physician’s choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer:primary analysis of JAVELIN Gastric 300[J]. Ann Oncol,2018,29(10):2052-2060.
[17] Asaoka Y,Ijichi H,Koike K. PD-1 blockade in tumors with mismatch-repair deficiency[J]. N Engl J Med,2015,373(20):1979.
[18] Grogg KL,Lohse CM,Pankratz VS,et al. Lymphocyte-rich gastric cancer:associations with Epstein-Barr virus,microsatellite instability,histology,and survival[J]. Mod Pathol,2003,16(7):641-651.
[19] Kim KJ,Lee KS,Cho HJ,et al. Prognostic implications of tumor-infiltrating FoxP3+regulatory T cells and CD8+cytotoxic T cells in microsatellite-unstable gastric cancers[J].Hum Pathol,2014,45(2):285-293.
[20] Bockorny B,Pectasides E. The emerging role of immunotherapy in gastric and esophageal adenocarcinoma[J].Future Oncol,2016,12(15):1833-1846.
[21] Masuzawa T,Fujiwara Y,Okada K,et al. PhaseⅠ/Ⅱstudy of S-1 plus cisplatin combined with peptide vaccines for human vascular endothelial growth factor receptor 1 and 2 in patients with advanced gastric cancer[J]. Int J Oncol,2012,41(4):1297-1304.
[22] Sundar R,Rha SY,Yamaue H,et al. A phaseⅠ/Ⅰb study of OTSGC-A24 combined peptide vaccine in advanced gastric cancer[J]. BMC Cancer,2018,18(1):332.
[23] Bang YJ,Van Cutsem E,Feyereislova A,et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer(ToGA):a phase 3,open-label,randomised controlled trial[J]. Lancet,2010,376(9742):687-697.
[24] Ilhan-Mutlu A,Taghizadeh H,Beer A,et al. Correlation of trastuzumab-based treatment with clinical characteristics and prognosis in HER2-positive gastric and gastroesophageal junction cancer:a retrospective single center analysis[J]. Cancer Biol Ther,2018,19(3):169-174.
[25] Fuchs CS,Tomasek J,Yong CJ,et al. Ramucirumab monotherapy for previously treated advanced gas tric or gastro-oesophageal junction adenocarcinoma(REGARD):an international,randomised,multicentre,placebo-controlled,phase 3 trial[J]. Lancet,2014,383(9911):31-39.
[26] Tehfe M,Tabchi S,Laterza MM,et al. Ramucirumab in HER-2-positive gastroesophageal adenocarcinoma:an argument for overcoming trastuzumab resistance[J]. Future Oncol,2018,14(3):223-228.
[27] Al-Batran SE,Schuler MH,et al. Antibody improves survival in gastric cancer[J]. Cancer Discov,2016,6(8):OF8.
[28] Goff SL,Dudley ME,Citrin DE,et al. Randomized,prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma[J]. J Clin Oncol,2016,34(20):2389-2397.
[29] Besser MJ,Shapira-Frommer R,Schachter J. Tumor-infiltrating lymphocytes:clinical experience[J]. Cancer J,2015,21(6):465-469.
[30] Abrahao-Machado LF,Scapulatempo-Neto C. HER2 testing in gastric cancer:an update[J]. World J Gastroenterol,2016,22(19):4619-4625.
[31] Kobold S,Steffen J,Chaloupka M,et al. Selective bispecific T cell recruiting antibody and antitumor activity of adoptive T cell transfer[J]. J Natl Cancer Inst,2015,107(1):364.
[32] Kim M,Pyo S,Kang CH,et al. Folate receptor 1(FOLR1)targeted chimeric antigen receptor(CAR)T cells for the treatment of gastric cancer[J]. PLoS One, 2018, 13(6):e0198347.
[33] Galluzzi L,Zitvogel L,Kroemer G. Immunological mechanisms underneath the efficacy of cancer therapy[J]. Cancer Immunol Res,2016,4(11):895-902.
[34] Demaria S,Coleman CN,Formenti SC. Radiotherapy:changing the game in immunotherapy[J]. Trends Cancer,2016,2(6):286-294.