程序性死亡受体-1及其配体抑制剂在结直肠癌中的研究进展
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摘要
目的总结程序性死亡受体-1(PD-1)/程序性死亡配体-1(PD-L1)抑制剂及其联合治疗在结直肠癌中的研究进展并为结直肠癌提供新的治疗方向。方法收集近年来PD-1/PD-L1抑制剂在结直肠癌中应用的研究进展的相关文献并进行综述。结果针对PD-1/PD-L1通路的抗体在结直肠癌患者的临床试验中取得了一定的研究成果,尤其是在高频微卫星不稳定患者中效果更佳,多种抗体联合治疗以及其与化疗、靶向治疗联合应用方案具有更好的生存获益。结论 PD-1/PD-L1抑制剂在高频微卫星不稳定结直肠癌生存获益方面具有一定疗效,尤其是联合方案显示出更好的效果。
Objective To summarize research progress on programmed death 1(PD-1) and programmed deathligand 1(PD-L1) inhibitors and their combination therapies in colorectal cancer and to provide a new treatment direction for colorectal cancer. Method The relevant literatures on the application of the PD-1/PD-L1 inhibitors in the colorectal cancer in recent years were collected and reviewed. Results The clinical trials of anti-PD-1/PD-L1 signaling pathway antibodies had made some achievements in the colorectal cancer, especially in the patients with high frequency microsatellite instability. And the combination therapy of multiple antibodies and the combination with chemotherapy and targeted therapies were more effective. Conclusion PD-1/PD-L1 inhibitors have some certain curative effects on survival of colorectal cancer with high frequency microsatellite instability, especially combination shows a better effect.
Objective To summarize research progress on programmed death 1(PD-1) and programmed deathligand 1(PD-L1) inhibitors and their combination therapies in colorectal cancer and to provide a new treatment direction for colorectal cancer. Method The relevant literatures on the application of the PD-1/PD-L1 inhibitors in the colorectal cancer in recent years were collected and reviewed. Results The clinical trials of anti-PD-1/PD-L1 signaling pathway antibodies had made some achievements in the colorectal cancer, especially in the patients with high frequency microsatellite instability. And the combination therapy of multiple antibodies and the combination with chemotherapy and targeted therapies were more effective. Conclusion PD-1/PD-L1 inhibitors have some certain curative effects on survival of colorectal cancer with high frequency microsatellite instability, especially combination shows a better effect.
引文
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2 Liu Y, Cao X. Immunosuppressive cells in tumor immune escape and metastasis. J Mol Med(Berl), 2016,94(5):509-522.
3 Cioffi M, Trabulo SM, Vallespinos M, et al. The miR-25-93-106b cluster regulates tumor metastasis and immune evasion via modulation of CXCL12 and PD-L1. Oncotarget, 2017, 8(13):21609-21625.
4 Heery CR, O'Sullivan-Coyne G, Madan RA, et al. Avelumab for metastatic or locally advanced previously treated solid tumours(JAVELIN Solid Tumor):a phase la, multicohort, dose-escalation trial. Lancet Oncol, 2017,18(5):587-598.
5 Overman MJ, Kopetz S, McDermott RS, et al.Nivolumab±ipilimumab in treatment(tx)of patients(pts)with metastatic colorectal cancer(mCRC)with and without high microsatellite instability(MSI-H):CheckMate-142 interim results.J Clin Oncol, 2016, 34(15_suppl):3501.
6 Brahmer JR, Drake CG, Wollner I, et al. Phase I study of singleagent anti-programmed death-1(MDX-1106)in refractory solid tumors:safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol, 2010, 28(19):3167-3175.
7 Yamamoto N, Nokihara H, Yamada Y, et al. Phase I study of Nivolumab, an anti-PD-1 antibody, in patients with malignant solid tumors. Invest New Drugs, 2017, 35(2):207-216.
8 Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer(CheckMate 142):an open-label,multicentre, phase 2 study. Lancet Oncol, 2017, 18(9):1182-1191.
9 Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4treatment and RAS mutations in colorectal cancer. N Engl J Med,2013, 369(11):1023-1034.
10 Fumet JD, Isambert N, Hervieu A, et al.PhaseⅠb/Ⅱtrial evaluating the safety, tolerability and immunological activity of durvalumab(MEDI4736)(anti-PD-Ll)plus tremelimumab(antiCTLA-4)combined with FOLFOX in patients with metastatic colorectal cancer. ESMO Open, 2018, 3(4):e000375.
11 Das S, Ciombor KK, Haraldsdottir S, et al. Promising new agents for colorectal cancer. Curr Treat Options Oncol, 2018, 19(6):29.
12 Xu R, Xu C, Liu C, et al. Efficacy and safety of bevacizumab-based combination therapy for treatment of patients with metastatic colorectal cancer. Onco Targets Ther, 2018, 11:8605-8621.
13 Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.N Engl J Med, 2009, 360(14):1408-1417.
14 Peeters M, Karthaus M, Rivera F, et al. Panitumumab in metastatic colorectal cancer:the importance of tumour RAS status. Drugs,2015, 75(7):731-748.
15 Nazemalhosseini-Mojarad E, Mohammadpour S, Torshizi Esafahani A, et al. Intratumoral infiltrating lymphocytes correlate with improved survival in colorectal cancer patients:Independent of oncogenetic features. J Cell Physiol, 2019, 234(4):4768-4777.
16 Mlecnik B, Van den Eynde M, Bindea G, et al. Comprehensive intrametastatic immune quantification and major impact of immunoscore on survival. J Natl Cancer Inst, 2018,110(1).
17 Toh JWT, de Souza P, Lim SH, et al. The potential value of immunotherapy in colorectal cancers:review of the evidence for programmed death-1 inhibitor therapy. Clin Colorectal Cancer,2016,15(4):285-291.
18 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology:Colon Cancer, version 2.2017.[2017-06-20].https://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
19 Bilgin B, Sendur MA, Biilent Akinci M, et al. Targeting the PD-1pathway:a new hope for gastrointestinal cancers. Curr Med Res Opin, 2017, 33(4):749-759.
20 Le DT, Uram JN, Wang H. Programmed death-1 blockade in mismatch repair deficient colorectal cancer. Chicago:ASCOAnnual Meeting, 2016.
21 Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med, 2015, 372(26):2509-2520.
22 Marginean EC, Melosky B. Is there a role for programmed death ligand-1 testing and immunotherapy in colorectal cancer with micro satellite instability? partⅡ—the challenge of programmed death ligand-1 testing and its role in microsatellite instabilityhigh colorectal Cancer. Arch Pathol Lab Med, 2018,142(1):26-34.
23 Nebot-Bral L, Coutzac C, Kannouche PL, et al. Why is immunotherapy effective(or not)in patients with MSI/MMRD tumors? Bull Cancer, 2019,106(2):105-113.
24 Llosa NJ, Cruise M, Tam A, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov, 2015, 5(1):43-51.
25 Gatalica Z, Snyder C, Maney T, et al. Programmed cell death 1(PD-1)and its ligand(PD-L1)in common cancers and their correlation with molecular cancer type. Cancer Epidemiol Biomarkers Prev, 2014,23(12):2965-2970.
26 Lee LH, Cavalcanti MS, Segal NH, et al. Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal carcinoma.Mod Pathol, 2016, 29(11):1433-1442.
27 Droeser RA, Hirt C, Viehl CT, et al. Clinical impact of programmed cell death ligand 1 expression in colorectal cancer.Eur J Cancer, 2013, 49(9):2233-2242.
28 Valentini AM, Di Pinto F, Cariola F, et al. PD-L1 expression in colorectal cancer defines three subsets of tumor immune microenvironments. Oncotarget, 2018, 9(9):8584-8596.
29 Smith KM, Desai J. Nivolumab for the treatment of colorectal cancer. Expert Rev Anticancer Ther, 2018,18(7):611-618.
30 Ott PA, Hodi FS, Kaufman HL, et al. Combination immunotherapy:a road map. J Immunother Cancer, 2017, 5:16.
31 Wei SC, Levine JH, Cogdill AP, et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell,2017,170(6):1120-1133.
32 Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol, 2018, 36(8):773-779.
33 Jindal V. Immune checkpoint inhibitors in gastrointestinal malignancies. J Gastrointest Oncol, 2018, 9(2):390-403.
34 Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma.N Engl J Med, 2017, 377(14):1345-1356.
35 Tapia Rico G, Price TJ. Atezolizumab for the treatment of colorectal cancer:the latest evidence and clinical potential. Expert Opin Biol Ther, 2018,18(4):449-457.
36 Wang CY, Thudium KB, Han MH, et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res, 2014,2(9):846-856.
37 Dovedi SJ, Illidge TM. The antitumor immune response generated by fractionated radiation therapy may be limited by tumor cell adaptive resistance and can be circumvented by PD-L1 blockade.Oncoimmunology, 2015, 4(7):e1016709.
38 Pfirschke C,Engblom C, Rickelt S, et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy.Immunity, 2016, 44(2):343-354.
39 Vincent J, Mignot G, Chalmin F, et al. 5-fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res, 2010,70(8):3052-3061.
40 Bruchard M, Mignot G, Derangere V, et al. Chemotherapytriggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth.Nat Med, 2013, 19(1):57-64.
41 Dosset M, Vargas TR, Lagrange A, et al. PD-1/PD-L1 pathway:an adaptive immune resistance mechanism to immunogenic chemotherapy in colorectal cancer. Oncoimmunology, 2018, 7(6):e1433981.
42 Safi Shahda AM. A phase II study of pembrolizumab in combination with mFOLFOX6 for patients with advanced colorectal cancer. J Clin Oncol,2017, 35(15_suppl):3541.
2 Liu Y, Cao X. Immunosuppressive cells in tumor immune escape and metastasis. J Mol Med(Berl), 2016,94(5):509-522.
3 Cioffi M, Trabulo SM, Vallespinos M, et al. The miR-25-93-106b cluster regulates tumor metastasis and immune evasion via modulation of CXCL12 and PD-L1. Oncotarget, 2017, 8(13):21609-21625.
4 Heery CR, O'Sullivan-Coyne G, Madan RA, et al. Avelumab for metastatic or locally advanced previously treated solid tumours(JAVELIN Solid Tumor):a phase la, multicohort, dose-escalation trial. Lancet Oncol, 2017,18(5):587-598.
5 Overman MJ, Kopetz S, McDermott RS, et al.Nivolumab±ipilimumab in treatment(tx)of patients(pts)with metastatic colorectal cancer(mCRC)with and without high microsatellite instability(MSI-H):CheckMate-142 interim results.J Clin Oncol, 2016, 34(15_suppl):3501.
6 Brahmer JR, Drake CG, Wollner I, et al. Phase I study of singleagent anti-programmed death-1(MDX-1106)in refractory solid tumors:safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol, 2010, 28(19):3167-3175.
7 Yamamoto N, Nokihara H, Yamada Y, et al. Phase I study of Nivolumab, an anti-PD-1 antibody, in patients with malignant solid tumors. Invest New Drugs, 2017, 35(2):207-216.
8 Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer(CheckMate 142):an open-label,multicentre, phase 2 study. Lancet Oncol, 2017, 18(9):1182-1191.
9 Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4treatment and RAS mutations in colorectal cancer. N Engl J Med,2013, 369(11):1023-1034.
10 Fumet JD, Isambert N, Hervieu A, et al.PhaseⅠb/Ⅱtrial evaluating the safety, tolerability and immunological activity of durvalumab(MEDI4736)(anti-PD-Ll)plus tremelimumab(antiCTLA-4)combined with FOLFOX in patients with metastatic colorectal cancer. ESMO Open, 2018, 3(4):e000375.
11 Das S, Ciombor KK, Haraldsdottir S, et al. Promising new agents for colorectal cancer. Curr Treat Options Oncol, 2018, 19(6):29.
12 Xu R, Xu C, Liu C, et al. Efficacy and safety of bevacizumab-based combination therapy for treatment of patients with metastatic colorectal cancer. Onco Targets Ther, 2018, 11:8605-8621.
13 Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.N Engl J Med, 2009, 360(14):1408-1417.
14 Peeters M, Karthaus M, Rivera F, et al. Panitumumab in metastatic colorectal cancer:the importance of tumour RAS status. Drugs,2015, 75(7):731-748.
15 Nazemalhosseini-Mojarad E, Mohammadpour S, Torshizi Esafahani A, et al. Intratumoral infiltrating lymphocytes correlate with improved survival in colorectal cancer patients:Independent of oncogenetic features. J Cell Physiol, 2019, 234(4):4768-4777.
16 Mlecnik B, Van den Eynde M, Bindea G, et al. Comprehensive intrametastatic immune quantification and major impact of immunoscore on survival. J Natl Cancer Inst, 2018,110(1).
17 Toh JWT, de Souza P, Lim SH, et al. The potential value of immunotherapy in colorectal cancers:review of the evidence for programmed death-1 inhibitor therapy. Clin Colorectal Cancer,2016,15(4):285-291.
18 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology:Colon Cancer, version 2.2017.[2017-06-20].https://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
19 Bilgin B, Sendur MA, Biilent Akinci M, et al. Targeting the PD-1pathway:a new hope for gastrointestinal cancers. Curr Med Res Opin, 2017, 33(4):749-759.
20 Le DT, Uram JN, Wang H. Programmed death-1 blockade in mismatch repair deficient colorectal cancer. Chicago:ASCOAnnual Meeting, 2016.
21 Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med, 2015, 372(26):2509-2520.
22 Marginean EC, Melosky B. Is there a role for programmed death ligand-1 testing and immunotherapy in colorectal cancer with micro satellite instability? partⅡ—the challenge of programmed death ligand-1 testing and its role in microsatellite instabilityhigh colorectal Cancer. Arch Pathol Lab Med, 2018,142(1):26-34.
23 Nebot-Bral L, Coutzac C, Kannouche PL, et al. Why is immunotherapy effective(or not)in patients with MSI/MMRD tumors? Bull Cancer, 2019,106(2):105-113.
24 Llosa NJ, Cruise M, Tam A, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov, 2015, 5(1):43-51.
25 Gatalica Z, Snyder C, Maney T, et al. Programmed cell death 1(PD-1)and its ligand(PD-L1)in common cancers and their correlation with molecular cancer type. Cancer Epidemiol Biomarkers Prev, 2014,23(12):2965-2970.
26 Lee LH, Cavalcanti MS, Segal NH, et al. Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal carcinoma.Mod Pathol, 2016, 29(11):1433-1442.
27 Droeser RA, Hirt C, Viehl CT, et al. Clinical impact of programmed cell death ligand 1 expression in colorectal cancer.Eur J Cancer, 2013, 49(9):2233-2242.
28 Valentini AM, Di Pinto F, Cariola F, et al. PD-L1 expression in colorectal cancer defines three subsets of tumor immune microenvironments. Oncotarget, 2018, 9(9):8584-8596.
29 Smith KM, Desai J. Nivolumab for the treatment of colorectal cancer. Expert Rev Anticancer Ther, 2018,18(7):611-618.
30 Ott PA, Hodi FS, Kaufman HL, et al. Combination immunotherapy:a road map. J Immunother Cancer, 2017, 5:16.
31 Wei SC, Levine JH, Cogdill AP, et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell,2017,170(6):1120-1133.
32 Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol, 2018, 36(8):773-779.
33 Jindal V. Immune checkpoint inhibitors in gastrointestinal malignancies. J Gastrointest Oncol, 2018, 9(2):390-403.
34 Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma.N Engl J Med, 2017, 377(14):1345-1356.
35 Tapia Rico G, Price TJ. Atezolizumab for the treatment of colorectal cancer:the latest evidence and clinical potential. Expert Opin Biol Ther, 2018,18(4):449-457.
36 Wang CY, Thudium KB, Han MH, et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res, 2014,2(9):846-856.
37 Dovedi SJ, Illidge TM. The antitumor immune response generated by fractionated radiation therapy may be limited by tumor cell adaptive resistance and can be circumvented by PD-L1 blockade.Oncoimmunology, 2015, 4(7):e1016709.
38 Pfirschke C,Engblom C, Rickelt S, et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy.Immunity, 2016, 44(2):343-354.
39 Vincent J, Mignot G, Chalmin F, et al. 5-fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res, 2010,70(8):3052-3061.
40 Bruchard M, Mignot G, Derangere V, et al. Chemotherapytriggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth.Nat Med, 2013, 19(1):57-64.
41 Dosset M, Vargas TR, Lagrange A, et al. PD-1/PD-L1 pathway:an adaptive immune resistance mechanism to immunogenic chemotherapy in colorectal cancer. Oncoimmunology, 2018, 7(6):e1433981.
42 Safi Shahda AM. A phase II study of pembrolizumab in combination with mFOLFOX6 for patients with advanced colorectal cancer. J Clin Oncol,2017, 35(15_suppl):3541.