基于抗PD-1/PD-L1单抗免疫阻断治疗以及疗效相关标志物的研究进展
摘要
肿瘤的免疫疗法是肿瘤治疗的重大突破,基于抗PD-1/PD-L1单抗的肿瘤免疫阻断治疗在临床上取得了越来越广泛的应用。在多种类型肿瘤治疗中,抗PD-1/PD-L1单抗药物在部分患者中获得了持续而明显的效果,多种药物相继上市。文章就抗PD-1/PD-L1单抗免疫阻断治疗以及疗效标志物的研究进展进行综述。
引文
[1] 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.
[2] Boussiotis VA.Molecular and biochemical aspects of the PD-1 checkpoint pathway[J].N Engl J Med,2016,375(18):1767-1778.
[3] 徐圣杰,王亚男,王士玉,等.阻断PD-1/PD-L1通路的免疫疗法在恶性肿瘤治疗中的研究进展[J].现代免疫学,2018,38(6):493-497.
[4] Zou W,Wolchok JD,Chen L.PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy:Mechanisms,response biomarkers,and combinations[J].Sci Transl Med,2016,8(328):328rv4.
[5] Weber JS,D'angelo SP,Minor D,et al.Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037):A randomised,controlled,open-label,phase 3 trial[J].Lancet Oncol,2015,16(4):375-384.
[6] Borghaei H,Paz-Ares L,Horn L,et al.Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer[J].N Engl J Med,2015,373(17):1627-1639.
[7] Horn L,Mansfield AS,Szczesna A,et al.First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer[J].N Engl J Med,2018,379(23):2220-2229.
[8] Balar AV,Galsky MD,Rosenberg JE,et al.Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma:A single-arm,multicentre,phase 2 trial[J].Lancet,2017,389(10064):67-76.
[9] Motzer RJ,Escudier B,Mcdermott DF,et al.Nivolumab versus everolimus in advanced renal-cell carcinoma[J].N Engl J Med,2015,373(19):1803-1813.
[10] Larkins E,Blumenthal GM,Yuan W,et al.FDA approval summary:Pembrolizumab for the treatment of recurrent or metastatic head and neck squamous cell carcinoma with disease progression on or after platinum-containing chemotherapy[J].Oncologist,2017,22(7):873-878.
[11] Migden MR,Rischin D,Schmults CD,et al.PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma[J].N Engl J Med,2018,379(4):341-351.
[12] Ribas A,Wolchok JD.Cancer immunotherapy using checkpoint blockade[J].Science,2018,359(6382):1350-1355.
[13] Hellmann MD,Ciuleanu TE,Pluzanski A,et al.Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden[J].N Engl J Med,2018,378(22):2093-2104.
[14] Schumacher TN,Schreiber RD.Neoantigens in cancer immunotherapy[J].Science,2015,348(6230):69-74.
[15] Chan TA,Yarchoan M,Jaffee E,et al.Development of tumor mutation burden as an immunotherapy biomarker:Utility for the oncology clinic[J].Ann Oncol,2019,30(1):44-56.
[16] Turajlic S,Litchfield K,Xu H,et al.Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype:A pan-cancer analysis[J].Lancet Oncol,2017,18(8):1009-1021.
[17] Chalmers ZR,Connelly CF,Fabrizio D,et al.Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden[J].Genome Med,2017,9(1):34.
[18] Le DT,Durham JN,Smith KN,et al.Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade[J].Science,2017,357(6349):409-413.
[19] Dudley JC,Lin MT,Le DT,et al.Microsatellite instability as a biomarker for PD-1 blockade[J].Clin Cancer Res,2016,22(4):813-820.
[20] Balar AV,Castellano D,O'donnell PH,et al.First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052):A multicentre,single-arm,phase 2 study[J].Lancet Oncol,2017,18(11):1483-1492.
[21] Sharma P,Callahan MK,Bono P,et al.Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032):A multicentre,open-label,two-stage,multi-arm,phase 1/2 trial[J].Lancet Oncol,2016,17(11):1590-1598.
[22] Cottrell TR,Taube JM.PD-L1 and emerging biomarkers in immune checkpoint blockade therapy[J].Cancer J,2018,24(1):41-46.
[23] Gibney GT,Weiner LM,Atkins MB.Predictive biomarkers for checkpoint inhibitor-based immunotherapy[J].Lancet Oncol,2016,17(12):e542-e551.
[24] Scheper W,Kelderman S,Fanchi LF,et al.Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers[J].Nat Med,2019,25(1):89-94.
[25] Amsen D,Hombrink P,van Lier RAW.Tumor immunity requires border patrol to fight the enemy within[J].Nat Immunol,2017,18(8):870-872.
[26] Galon J,Bruni D.Approaches to treat immune hot,altered and cold tumours with combination immunotherapies[J].Nat Rev Drug Discov,2019,18(3):197-218.
[27] Teng MW,Ngiow SF,Ribas A,et al.Classifying cancers based on T-cell infiltration and PD-L1[J].Cancer Res,2015,75(11):2139-2145.
[28] Galon J,Bruni D.Approaches to treat immune hot,altered and cold tumours with combination immunotherapies[J].Nat Rev Drug Discov,2019,18(3):197-218.
[29] Maleki Vareki S.High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors[J].J Immunother Cancer,2018,6(1):157.
[30] Skoulidis F,Goldberg ME,Greenawalt DM,et al.STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma[J].Cancer Discov,2018,8(7):822-835.
[31] Peng W,Chen JQ,Liu C,et al.Loss of PTEN promotes resistance to T cell-mediated immunotherapy[J].Cancer Discov,2016,6(2):202-216.
[32] Nam SJ,Lee C,Park JH,et al.Decreased PBRM1 expre-ssion predicts unfavorable prognosis in patients with clear cell renal cell carcinoma[J].Urol Oncol,2015,33(8):340.e9-344.e16.
[33] Fujisawa Y,Yoshino K,Otsuka A,et al.Baseline neutrophil to lymphocyte ratio combined with serum lactate dehydrogenase level associated with outcome of nivolumab immunotherapy in a Japanese advanced melanoma population[J].Br J Dermatol,2018,179(1):213-215.
[34] Zhou J,Mahoney KM,Giobbie-Hurder A,et al.Soluble PD-L1 as a biomarker in malignant melanoma treated with checkpoint blockade[J].Cancer Immunol Res,2017,5(6):480-492.
[35] Krieg C,Nowicka M,Guglietta S,et al.High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy[J].Nat Med,2018,24(2):144-153.
[36] Kamphorst AO,Pillai RN,Yang S,et al.Proliferation of PD-1+CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients[J].Proc Natl Acad Sci U S A,2017,114(19):4993-4998.
[37] Matson V,Fessler J,Bao R,et al.The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients[J].Science,2018,359(6371):104-108.
[38] Gopalakrishnan V,Spencer CN,Nezi L,et al.Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients[J].Science,2018,359(6371):97-103.
[39] Routy B,Le Chatelier E,Derosa L,et al.Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors[J].Science,2018,359(6371):91-97.
[40] Chowell D,Morris LGT,Grigg CM,et al.Patient HLA class Ⅰ genotype influences cancer response to checkpoint blockade immunotherapy[J].Science,2018,359(6375):582-587.
[41] Moreira A,Gross S,Kirchberger MC,et al.Senescence markers:Predictive for response to checkpoint inhibitors[J].Int J Cancer,2019,144(5):1147-1150.
[2] Boussiotis VA.Molecular and biochemical aspects of the PD-1 checkpoint pathway[J].N Engl J Med,2016,375(18):1767-1778.
[3] 徐圣杰,王亚男,王士玉,等.阻断PD-1/PD-L1通路的免疫疗法在恶性肿瘤治疗中的研究进展[J].现代免疫学,2018,38(6):493-497.
[4] Zou W,Wolchok JD,Chen L.PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy:Mechanisms,response biomarkers,and combinations[J].Sci Transl Med,2016,8(328):328rv4.
[5] Weber JS,D'angelo SP,Minor D,et al.Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037):A randomised,controlled,open-label,phase 3 trial[J].Lancet Oncol,2015,16(4):375-384.
[6] Borghaei H,Paz-Ares L,Horn L,et al.Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer[J].N Engl J Med,2015,373(17):1627-1639.
[7] Horn L,Mansfield AS,Szczesna A,et al.First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer[J].N Engl J Med,2018,379(23):2220-2229.
[8] Balar AV,Galsky MD,Rosenberg JE,et al.Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma:A single-arm,multicentre,phase 2 trial[J].Lancet,2017,389(10064):67-76.
[9] Motzer RJ,Escudier B,Mcdermott DF,et al.Nivolumab versus everolimus in advanced renal-cell carcinoma[J].N Engl J Med,2015,373(19):1803-1813.
[10] Larkins E,Blumenthal GM,Yuan W,et al.FDA approval summary:Pembrolizumab for the treatment of recurrent or metastatic head and neck squamous cell carcinoma with disease progression on or after platinum-containing chemotherapy[J].Oncologist,2017,22(7):873-878.
[11] Migden MR,Rischin D,Schmults CD,et al.PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma[J].N Engl J Med,2018,379(4):341-351.
[12] Ribas A,Wolchok JD.Cancer immunotherapy using checkpoint blockade[J].Science,2018,359(6382):1350-1355.
[13] Hellmann MD,Ciuleanu TE,Pluzanski A,et al.Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden[J].N Engl J Med,2018,378(22):2093-2104.
[14] Schumacher TN,Schreiber RD.Neoantigens in cancer immunotherapy[J].Science,2015,348(6230):69-74.
[15] Chan TA,Yarchoan M,Jaffee E,et al.Development of tumor mutation burden as an immunotherapy biomarker:Utility for the oncology clinic[J].Ann Oncol,2019,30(1):44-56.
[16] Turajlic S,Litchfield K,Xu H,et al.Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype:A pan-cancer analysis[J].Lancet Oncol,2017,18(8):1009-1021.
[17] Chalmers ZR,Connelly CF,Fabrizio D,et al.Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden[J].Genome Med,2017,9(1):34.
[18] Le DT,Durham JN,Smith KN,et al.Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade[J].Science,2017,357(6349):409-413.
[19] Dudley JC,Lin MT,Le DT,et al.Microsatellite instability as a biomarker for PD-1 blockade[J].Clin Cancer Res,2016,22(4):813-820.
[20] Balar AV,Castellano D,O'donnell PH,et al.First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052):A multicentre,single-arm,phase 2 study[J].Lancet Oncol,2017,18(11):1483-1492.
[21] Sharma P,Callahan MK,Bono P,et al.Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032):A multicentre,open-label,two-stage,multi-arm,phase 1/2 trial[J].Lancet Oncol,2016,17(11):1590-1598.
[22] Cottrell TR,Taube JM.PD-L1 and emerging biomarkers in immune checkpoint blockade therapy[J].Cancer J,2018,24(1):41-46.
[23] Gibney GT,Weiner LM,Atkins MB.Predictive biomarkers for checkpoint inhibitor-based immunotherapy[J].Lancet Oncol,2016,17(12):e542-e551.
[24] Scheper W,Kelderman S,Fanchi LF,et al.Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers[J].Nat Med,2019,25(1):89-94.
[25] Amsen D,Hombrink P,van Lier RAW.Tumor immunity requires border patrol to fight the enemy within[J].Nat Immunol,2017,18(8):870-872.
[26] Galon J,Bruni D.Approaches to treat immune hot,altered and cold tumours with combination immunotherapies[J].Nat Rev Drug Discov,2019,18(3):197-218.
[27] Teng MW,Ngiow SF,Ribas A,et al.Classifying cancers based on T-cell infiltration and PD-L1[J].Cancer Res,2015,75(11):2139-2145.
[28] Galon J,Bruni D.Approaches to treat immune hot,altered and cold tumours with combination immunotherapies[J].Nat Rev Drug Discov,2019,18(3):197-218.
[29] Maleki Vareki S.High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors[J].J Immunother Cancer,2018,6(1):157.
[30] Skoulidis F,Goldberg ME,Greenawalt DM,et al.STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma[J].Cancer Discov,2018,8(7):822-835.
[31] Peng W,Chen JQ,Liu C,et al.Loss of PTEN promotes resistance to T cell-mediated immunotherapy[J].Cancer Discov,2016,6(2):202-216.
[32] Nam SJ,Lee C,Park JH,et al.Decreased PBRM1 expre-ssion predicts unfavorable prognosis in patients with clear cell renal cell carcinoma[J].Urol Oncol,2015,33(8):340.e9-344.e16.
[33] Fujisawa Y,Yoshino K,Otsuka A,et al.Baseline neutrophil to lymphocyte ratio combined with serum lactate dehydrogenase level associated with outcome of nivolumab immunotherapy in a Japanese advanced melanoma population[J].Br J Dermatol,2018,179(1):213-215.
[34] Zhou J,Mahoney KM,Giobbie-Hurder A,et al.Soluble PD-L1 as a biomarker in malignant melanoma treated with checkpoint blockade[J].Cancer Immunol Res,2017,5(6):480-492.
[35] Krieg C,Nowicka M,Guglietta S,et al.High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy[J].Nat Med,2018,24(2):144-153.
[36] Kamphorst AO,Pillai RN,Yang S,et al.Proliferation of PD-1+CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients[J].Proc Natl Acad Sci U S A,2017,114(19):4993-4998.
[37] Matson V,Fessler J,Bao R,et al.The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients[J].Science,2018,359(6371):104-108.
[38] Gopalakrishnan V,Spencer CN,Nezi L,et al.Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients[J].Science,2018,359(6371):97-103.
[39] Routy B,Le Chatelier E,Derosa L,et al.Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors[J].Science,2018,359(6371):91-97.
[40] Chowell D,Morris LGT,Grigg CM,et al.Patient HLA class Ⅰ genotype influences cancer response to checkpoint blockade immunotherapy[J].Science,2018,359(6375):582-587.
[41] Moreira A,Gross S,Kirchberger MC,et al.Senescence markers:Predictive for response to checkpoint inhibitors[J].Int J Cancer,2019,144(5):1147-1150.