Gut Microbiota and Immune Checkpoint Inhibitors-Based Immunotherapy

Mingming       Tian; Si      Zhang; Yujen      Tseng; Xizhong      Shen; Ling      Dong; Ruyi      Xue
doi:10.2174/1871520621666210706110713
Abstract

Application of immune checkpoint inhibitors (ICIs) is a major breakthrough in the field of cancer therapy, which has displayed tremendous potential in various types of malignancies. However, their response rates range widely in different cancer types and a significant number of patients experience immune-related adverse effects (irAEs) induced by these drugs, limiting the proportion of patients who can truly benefit from ICIs. Gut microbiota has gained increasing attention due to its emerging role in regulating the immune system. In recent years, numerous studies have shown that gut microbiota can modulate antitumor response, as well as decrease the risk of colitis due to ICIs in patients receiving immunotherapy. The present review analyzed recent progress of relevant basic and clinical studies in this area and explored new perspectives to enhance the efficacy of ICIs and alleviate associated irAEs via manipulation of the gut microbiota.
Keywords: Gut microbiota, cancer, immune checkpoint inhibitors, immunotherapy, antitumor response, ICI.
« Previous Next »
Graphical Abstract

[1] 
Wolchok, J.D. PD-1 Blockers. Cell,  2015, 162(5), 937.
[http://dx.doi.org/10.1016/j.cell.2015.07.045] [PMID:  26317459] 
[2] 
Kumar, V.; Chaudhary, N.; Garg, M.; Floudas, C.S.; Soni, P.; Chandra, A.B. Current diagnosis and management of immune related adverse events (irAEs) Induced by immune checkpoint inhibitor therapy. Front. Pharmacol.,  2017, 8, 49.
[http://dx.doi.org/10.3389/fphar.2017.00049] [PMID:  28228726] 
[3] 
Ribatti, D. The concept of immune surveillance against tumors. The first theories. Oncotarget,  2017, 8(4), 7175-7180.
[http://dx.doi.org/10.18632/oncotarget.12739] [PMID:  27764780] 
[4] 
Gonzalez, H.; Hagerling, C.; Werb, Z. Roles of the immune system in cancer: From tumor initiation to metastatic progression. Genes Dev.,  2018, 32(19-20), 1267-1284.
[http://dx.doi.org/10.1101/gad.314617.118] [PMID:  30275043] 
[5] 
Schreiber, R.D.; Old, L.J.; Smyth, M. J. Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion. Science,  2011, 331(6024), 1565-1570.
[http://dx.doi.org/10.1126/science.1203486] [PMID:  21436444] 
[6] 
Arneth, B. Tumor Microenvironment. Medicina (Kaunas),  2019, 56(1), E15.
[http://dx.doi.org/10.3390/medicina56010015] [PMID:  31906017] 
[7] 
Haanen, J.B.; Robert, C. Immune checkpoint inhibitors. Prog. Tumor Res.,  2015, 42, 55-66.
[http://dx.doi.org/10.1159/000437178] [PMID:  26382943] 
[8] 
Wu, Y.X.; Jin, S.H.; Cui, J. Autophagy and immune tolerance. Adv. Exp. Med. Biol.,  2019, 1206, 635-665.
[http://dx.doi.org/10.1007/978-981-15-0602-4_28] [PMID:  31777005] 
[9] 
Zhang, Y.; Zheng, J. Functions of immune checkpoint molecules beyond immune evasion. Adv. Exp. Med. Biol.,  2020, 1248, 201-226.
[http://dx.doi.org/10.1007/978-981-15-3266-5_9] [PMID:  32185712] 
[10] 
Wilky, B.A. Immune checkpoint inhibitors: The linchpins of modern immunotherapy. Immunol. Rev.,  2019, 290(1), 6-23.
[http://dx.doi.org/10.1111/imr.12766] [PMID:  31355494] 
[11] 
Dong, Y.; Sun, Q.; Zhang, X. PD-1 and its ligands are important immune checkpoints in cancer. Oncotarget,  2017, 8(2), 2171-2186.
[http://dx.doi.org/10.18632/oncotarget.13895] [PMID:  27974689] 
[12] 
Jelinek, T.; Mihalyova, J.; Kascak, M.; Duras, J.; Hajek, R. PD-1/PD-L1 inhibitors in haematological malignancies: Update 2017. Immunology,  2017, 152(3), 357-371.
[http://dx.doi.org/10.1111/imm.12788] [PMID:  28685821] 
[13] 
Buchbinder, E.I.; Desai, A. CTLA-4 and PD-1 Pathways: Similarities, differences, and implications of their inhibition. Am. J. Clin. Oncol.,  2016, 39(1), 98-106.
[http://dx.doi.org/10.1097/COC.0000000000000239] [PMID:  26558876] 
[14] 
Rowshanravan, B.; Halliday, N.; Sansom, D.M. CTLA-4: A moving target in immunotherapy. Blood,  2018, 131(1), 58-67.
[http://dx.doi.org/10.1182/blood-2017-06-741033] [PMID:  29118008] 
[15] 
Ascierto, P.A.; Del Vecchio, M.; Robert, C.; Mackiewicz, A.; Chiarion-Sileni, V.; Arance, A.; Lebbé, C.; Bastholt, L.; Hamid, O.; Rutkowski, P.; McNeil, C.; Garbe, C.; Loquai, C.; Dreno, B.; Thomas, L.; Grob, J.J.; Liszkay, G.; Nyakas, M.; Gutzmer, R.; Pikiel, J.; Grange, F.; Hoeller, C.; Ferraresi, V.; Smylie, M.; Schadendorf, D.; Mortier, L.; Svane, I.M.; Hennicken, D.; Qureshi, A.; Maio, M. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: A randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol.,  2017, 18(5), 611-622.
[http://dx.doi.org/10.1016/S1470-2045(17)30231-0] [PMID:  28359784] 
[16] 
Hodi, F.S.; Chiarion-Sileni, V.; Gonzalez, R.; Grob, J.J.; Rutkowski, P.; Cowey, C.L.; Lao, C.D.; Schadendorf, D.; Wagstaff, J.; Dummer, R.; Ferrucci, P.F.; Smylie, M.; Hill, A.; Hogg, D.; Marquez-Rodas, I.; Jiang, J.; Rizzo, J.; Larkin, J.; Wolchok, J.D. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol.,  2018, 19(11), 1480-1492.
[http://dx.doi.org/10.1016/S1470-2045(18)30700-9] [PMID:  30361170] 
[17] 
Ribas, A.; Puzanov, I.; Dummer, R.; Schadendorf, D.; Hamid, O.; Robert, C.; Hodi, F.S.; Schachter, J.; Pavlick, A.C.; Lewis, K.D.; Cranmer, L.D.; Blank, C.U.; O’Day, S.J.; Ascierto, P.A.; Salama, A.K.; Margolin, K.A.; Loquai, C.; Eigentler, T.K.; Gangadhar, T.C.; Carlino, M.S.; Agarwala, S.S.; Moschos, S.J.; Sosman, J.A.; Goldinger, S.M.; Shapira-Frommer, R.; Gonzalez, R.; Kirkwood, J.M.; Wolchok, J.D.; Eggermont, A.; Li, X.N.; Zhou, W.; Zernhelt, A.M.; Lis, J.; Ebbinghaus, S.; Kang, S.P.; Daud, A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): A randomised, controlled, phase 2 trial. Lancet Oncol.,  2015, 16(8), 908-918.
[http://dx.doi.org/10.1016/S1470-2045(15)00083-2] [PMID:  26115796] 
[18] 
Ribas, A.; Wolchok, J.D.; Robert, C.; Kefford, R.; Hamid, O.; Daud, A.; Hwu, W.J.; Weber, J.S.; Joshua, A.M.; Gangadhar, T.C.; Patnaik, A.; Hersey, P.; Dronca, R.; Zarour, H.; Gergich, K.; Lindia, J.A.; Giannotti, M.; Li, X.N.; Ebbinghaus, S.; Kang, S.P.; Hodi, F.S. P0116 Updated clinical efficacy of the anti-PD-1 monoclonal antibody pembrolizumab (MK-3475) in 411 patients with melanoma. Eur. J. Cancer,  2015, 51, e24.
[http://dx.doi.org/10.1016/j.ejca.2015.06.072] 
[19] 
Robert, C.; Schachter, J.; Long, G.V.; Arance, A.; Grob, J.J.; Mortier, L.; Daud, A.; Carlino, M.S.; McNeil, C.; Lotem, M.; Larkin, J.; Lorigan, P.; Neyns, B.; Blank, C.U.; Hamid, O.; Mateus, C.; Shapira-Frommer, R.; Kosh, M.; Zhou, H.; Ibrahim, N.; Ebbinghaus, S.; Ribas, A. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med.,  2015, 372(26), 2521-2532.
[http://dx.doi.org/10.1056/NEJMoa1503093] [PMID:  25891173] 
[20] 
Weber, J.; Mandala, M.; Del Vecchio, M.; Gogas, H.J.; Arance, A.M.; Cowey, C.L.; Dalle, S.; Schenker, M.; Chiarion-Sileni, V.; Marquez-Rodas, I.; Grob, J.J.; Butler, M.O.; Middleton, M.R.; Maio, M.; Atkinson, V.; Queirolo, P.; Gonzalez, R.; Kudchadkar, R.R.; Smylie, M.; Meyer, N.; Mortier, L.; Atkins, M.B.; Long, G.V.; Bhatia, S.; Lebbé, C.; Rutkowski, P.; Yokota, K.; Yamazaki, N.; Kim, T.M.; de Pril, V.; Sabater, J.; Qureshi, A.; Larkin, J.; Ascierto, P.A. Adjuvant nivolumab versus ipilimumab in resected Stage III or IV Melanoma. N. Engl. J. Med.,  2017, 377(19), 1824-1835.
[http://dx.doi.org/10.1056/NEJMoa1709030] [PMID:  28891423] 
[21] 
Weber, J.S.; D’Angelo, S.P.; Minor, D.; Hodi, F.S.; Gutzmer, R.; Neyns, B.; Hoeller, C.; Khushalani, N.I.; Miller, W.H., Jr; Lao, C.D.; Linette, G.P.; Thomas, L.; Lorigan, P.; Grossmann, K.F.; Hassel, J.C.; Maio, M.; Sznol, M.; Ascierto, P.A.; Mohr, P.; Chmielowski, B.; Bryce, A.; Svane, I.M.; Grob, J.J.; Krackhardt, A.M.; Horak, C.; Lambert, A.; Yang, A.S.; Larkin, J. 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. Lancet Oncol.,  2015, 16(4), 375-384.
[http://dx.doi.org/10.1016/S1470-2045(15)70076-8] [PMID:  25795410] 
[22] 
Nomura, M.; Oze, I.; Masuishi, T.; Yokota, T.; Satake, H.; Iwasawa, S.; Kato, K.; Andoh, M. Multicenter prospective phase II trial of nivolumab in patients with unresectable or metastatic mucosal melanoma. Int. J. Clin. Oncol.,  2020, 25(5), 972-977.
[http://dx.doi.org/10.1007/s10147-020-01618-9] [PMID:  31938955] 
[23] 
Eggermont, A.M.M.; Kicinski, M.; Blank, C.U.; Mandala, M.; Long, G.V.; Atkinson, V.; Dalle, S.; Haydon, A.; Khattak, A.; Carlino, M.S.; Sandhu, S.; Larkin, J.; Puig, S.; Ascierto, P.A.; Rutkowski, P.; Schadendorf, D.; Koornstra, R.; Hernandez-Aya, L.; Di Giacomo, A.M.; van den Eertwegh, A.J.M.; Grob, J.J.; Gutzmer, R.; Jamal, R.; Lorigan, P.C.; Krepler, C.; Ibrahim, N.; Marreaud, S.; van Akkooi, A.; Robert, C.; Suciu, S. Association between immune-related adverse events and recurrence-free survival among patients with stage iii melanoma randomized to receive pembrolizumab or placebo: A Secondary analysis of a randomized clinical trial. JAMA Oncol.,  2020, 6(4), 519-527.
[http://dx.doi.org/10.1001/jamaoncol.2019.5570] [PMID:  31895407] 
[24] 
Postow, M.A.; Chesney, J.; Pavlick, A.C.; Robert, C.; Grossmann, K.; McDermott, D.; Linette, G.P.; Meyer, N.; Giguere, J.K.; Agarwala, S.S.; Shaheen, M.; Ernstoff, M.S.; Minor, D.; Salama, A.K.; Taylor, M.; Ott, P.A.; Rollin, L.M.; Horak, C.; Gagnier, P.; Wolchok, J.D.; Hodi, F.S. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med.,  2015, 372(21), 2006-2017.
[http://dx.doi.org/10.1056/NEJMoa1414428] [PMID:  25891304] 
[25] 
Garon, E.B.; Rizvi, N.A.; Hui, R.; Leighl, N.; Balmanoukian, A.S.; Eder, J.P.; Patnaik, A.; Aggarwal, C.; Gubens, M.; Horn, L.; Carcereny, E.; Ahn, M.J.; Felip, E.; Lee, J.S.; Hellmann, M.D.; Hamid, O.; Goldman, J.W.; Soria, J.C.; Dolled-Filhart, M.; Rutledge, R.Z.; Zhang, J.; Lunceford, J.K.; Rangwala, R.; Lubiniecki, G.M.; Roach, C.; Emancipator, K.; Gandhi, L. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med.,  2015, 372(21), 2018-2028.
[http://dx.doi.org/10.1056/NEJMoa1501824] [PMID:  25891174] 
[26] 
Herbst, R.S.; Baas, P.; Kim, D.W.; Felip, E.; Pérez-Gracia, J.L.; Han, J.Y.; Molina, J.; Kim, J.H.; Arvis, C.D.; Ahn, M.J.; Majem, M.; Fidler, M.J.; de Castro, G., Jr; Garrido, M.; Lubiniecki, G.M.; Shentu, Y. Im, E.; Dolled-Filhart, M.; Garon, E.B. 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.
[http://dx.doi.org/10.1016/S0140-6736(15)01281-7] [PMID:  26712084] 
[27] 
Reck, M.; Rodríguez-Abreu, D.; Robinson, A.G.; Hui, R.; Csőszi, T.; Fülöp, A.; Gottfried, M.; Peled, N.; Tafreshi, A.; Cuffe, S.; O’Brien, M.; Rao, S.; Hotta, K.; Leiby, M.A.; Lubiniecki, G.M.; Shentu, Y.; Rangwala, R.; Brahmer, J.R. Pembrolizumab versus chemotherapy for pd-l1-positive non-small-cell lung cancer. N. Engl. J. Med.,  2016, 375(19), 1823-1833.
[http://dx.doi.org/10.1056/NEJMoa1606774] [PMID:  27718847] 
[28] 
Sul, J.; Blumenthal, G.M.; Jiang, X.; He, K.; Keegan, P.; Pazdur, R. FDA approval summary: Pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death-ligand 1. Oncologist,  2016, 21(5), 643-650.
[http://dx.doi.org/10.1634/theoncologist.2015-0498] [PMID:  27026676] 
[29] 
Brahmer, J.; Reckamp, K.L.; Baas, P.; Crinò, L.; Eberhardt, W.E.; Poddubskaya, E.; Antonia, S.; Pluzanski, A.; Vokes, E.E.; Holgado, E.; Waterhouse, D.; Ready, N.; Gainor, J.; Arén Frontera, O.; Havel, L.; Steins, M.; Garassino, M.C.; Aerts, J.G.; Domine, M.; Paz-Ares, L.; Reck, M.; Baudelet, C.; Harbison, C.T.; Lestini, B.; Spigel, D.R. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med.,  2015, 373(2), 123-135.
[http://dx.doi.org/10.1056/NEJMoa1504627] [PMID:  26028407] 
[30] 
Fehrenbacher, L.; Spira, A.; Ballinger, M.; Kowanetz, M.; Vansteenkiste, J.; Mazieres, J.; Park, K.; Smith, D.; Artal-Cortes, A.; Lewanski, C.; Braiteh, F.; Waterkamp, D.; He, P.; Zou, W.; Chen, D.S.; Yi, J.; Sandler, A.; Rittmeyer, A. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): A multicentre, open-label, phase 2 randomised controlled trial. Lancet,  2016, 387(10030), 1837-1846.
[http://dx.doi.org/10.1016/S0140-6736(16)00587-0] [PMID:  26970723] 
[31] 
Rittmeyer, A.; Barlesi, F.; Waterkamp, D.; Park, K.; Ciardiello, F.; von Pawel, J.; Gadgeel, S.M.; Hida, T.; Kowalski, D.M.; Dols, M.C.; Cortinovis, D.L.; Leach, J.; Polikoff, J.; Barrios, C.; Kabbinavar, F.; Frontera, O.A.; De Marinis, F.; Turna, H.; Lee, J.S.; Ballinger, M.; Kowanetz, M.; He, P.; Chen, D.S.; Sandler, A.; Gandara, D.R. 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.
[http://dx.doi.org/10.1016/S0140-6736(16)32517-X] [PMID:  27979383] 
[32] 
Antonia, S.J.; Villegas, A.; Daniel, D.; Vicente, D.; Murakami, S.; Hui, R.; Yokoi, T.; Chiappori, A.; Lee, K.H.; de Wit, M.; Cho, B.C.; Bourhaba, M.; Quantin, X.; Tokito, T.; Mekhail, T.; Planchard, D.; Kim, Y.C.; Karapetis, C.S.; Hiret, S.; Ostoros, G.; Kubota, K.; Gray, J.E.; Paz-Ares, L.; de Castro Carpeño, J.; Wadsworth, C.; Melillo, G.; Jiang, H.; Huang, Y.; Dennis, P.A.; Özgüroğlu, M. Durvalumab after chemoradiotherapy in Stage III non-small-cell lung cancer. N. Engl. J. Med.,  2017, 377(20), 1919-1929.
[http://dx.doi.org/10.1056/NEJMoa1709937] [PMID:  28885881] 
[33] 
Gao, S; Li, N; Gao, S; Xue, Q; Ying, J; Wang, S; Tao, X; Zhao, J; Mao, Y; Wang, B; Shao, K; Lei, W; Wang, D; Lv, F; Zhao, L; Zhang, F; Zhao, Z; Su, K; Tan, F; Gao, Y; Sun, N; Wu, D; Yu, Y; Ling, Y; Wang, Z; Duan, C; Tang, W; Zhang, L; He, S; Wu, N; Wang, J; He, J Neoadjuvant PD-1 inhibitor (Sintilimab) in NSCLC. Journal of thoracic oncology : Official publication of the international association for the study of lung cancer.,  2020, 15(5), 816-826.
[34] 
Hellmann, M.D.; Ciuleanu, T.E.; Pluzanski, A.; Lee, J.S.; Otterson, G.A.; Audigier-Valette, C.; Minenza, E.; Linardou, H.; Burgers, S.; Salman, P.; Borghaei, H.; Ramalingam, S.S.; Brahmer, J.; Reck, M.; O’Byrne, K.J.; Geese, W.J.; Green, G.; Chang, H.; Szustakowski, J.; Bhagavatheeswaran, P.; Healey, D.; Fu, Y.; Nathan, F.; Paz-Ares, L. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med.,  2018, 378(22), 2093-2104.
[http://dx.doi.org/10.1056/NEJMoa1801946] [PMID:  29658845] 
[35] 
Motzer, R.J.; Escudier, B.; McDermott, D.F.; George, S.; Hammers, H.J.; Srinivas, S.; Tykodi, S.S.; Sosman, J.A.; Procopio, G.; Plimack, E.R.; Castellano, D.; Choueiri, T.K.; Gurney, H.; Donskov, F.; Bono, P.; Wagstaff, J.; Gauler, T.C.; Ueda, T.; Tomita, Y.; Schutz, F.A.; Kollmannsberger, C.; Larkin, J.; Ravaud, A.; Simon, J.S.; Xu, L.A.; Waxman, I.M.; Sharma, P. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med.,  2015, 373(19), 1803-1813.
[http://dx.doi.org/10.1056/NEJMoa1510665] [PMID:  26406148] 
[36] 
Motzer, R.J.; Tannir, N.M.; McDermott, D.F.; Arén Frontera, O.; Melichar, B.; Choueiri, T.K.; Plimack, E.R.; Barthélémy, P.; Porta, C.; George, S.; Powles, T.; Donskov, F.; Neiman, V.; Kollmannsberger, C.K.; Salman, P.; Gurney, H.; Hawkins, R.; Ravaud, A.; Grimm, M.O.; Bracarda, S.; Barrios, C.H.; Tomita, Y.; Castellano, D.; Rini, B.I.; Chen, A.C.; Mekan, S.; McHenry, M.B.; Wind-Rotolo, M.; Doan, J.; Sharma, P.; Hammers, H.J.; Escudier, B. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med.,  2018, 378(14), 1277-1290.
[http://dx.doi.org/10.1056/NEJMoa1712126] [PMID:  29562145] 
[37] 
Bellmunt, J.; de Wit, R.; Vaughn, D.J.; Fradet, Y.; Lee, J.L.; Fong, L.; Vogelzang, N.J.; Climent, M.A.; Petrylak, D.P.; Choueiri, T.K.; Necchi, A.; Gerritsen, W.; Gurney, H.; Quinn, D.I.; Culine, S.; Sternberg, C.N.; Mai, Y.; Poehlein, C.H.; Perini, R.F.; Bajorin, D.F. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N. Engl. J. Med.,  2017, 376(11), 1015-1026.
[http://dx.doi.org/10.1056/NEJMoa1613683] [PMID:  28212060] 
[38] 
Rosenberg, J.E.; Hoffman-Censits, J.; Powles, T.; van der Heijden, M.S.; Balar, A.V.; Necchi, A.; Dawson, N.; O’Donnell, P.H.; Balmanoukian, A.; Loriot, Y.; Srinivas, S.; Retz, M.M.; Grivas, P.; Joseph, R.W.; Galsky, M.D.; Fleming, M.T.; Petrylak, D.P.; Perez-Gracia, J.L.; Burris, H.A.; Castellano, D.; Canil, C.; Bellmunt, J.; Bajorin, D.; Nickles, D.; Bourgon, R.; Frampton, G.M.; Cui, N.; Mariathasan, S.; Abidoye, O.; Fine, G.D.; Dreicer, R. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial. Lancet,  2016, 387(10031), 1909-1920.
[http://dx.doi.org/10.1016/S0140-6736(16)00561-4] [PMID:  26952546] 
[39] 
Sharma, P.; Retz, M.; Siefker-Radtke, A.; Baron, A.; Necchi, A.; Bedke, J.; Plimack, E.R.; Vaena, D.; Grimm, M.O.; Bracarda, S.; Arranz, J.Á.; Pal, S.; Ohyama, C.; Saci, A.; Qu, X.; Lambert, A.; Krishnan, S.; Azrilevich, A.; Galsky, M.D. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre, single-arm, phase 2 trial. Lancet Oncol.,  2017, 18(3), 312-322.
[http://dx.doi.org/10.1016/S1470-2045(17)30065-7] [PMID:  28131785] 
[40] 
Powles, T.; O’Donnell, P.H.; Massard, C.; Arkenau, H.T.; Friedlander, T.W.; Hoimes, C.J.; Lee, J.L.; Ong, M.; Sridhar, S.S.; Vogelzang, N.J.; Fishman, M.N.; Zhang, J.; Srinivas, S.; Parikh, J.; Antal, J.; Jin, X.; Gupta, A.K.; Ben, Y.; Hahn, N.M. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: Updated results from a phase 1/2 Open-label Study. JAMA Oncol.,  2017, 3(9), e17.2411
[http://dx.doi.org/10.1001/jamaoncol.2017.2411] [PMID:  28817753] 
[41] 
Apolo, A.B.; Infante, J.R.; Balmanoukian, A.; Patel, M.R.; Wang, D.; Kelly, K.; Mega, A.E.; Britten, C.D.; Ravaud, A.; Mita, A.C.; Safran, H.; Stinchcombe, T.E.; Srdanov, M.; Gelb, A.B.; Schlichting, M.; Chin, K.; Gulley, J.L. Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: Results from a multicenter, phase ib study. J. Clin. Oncol.,  2017, 35(19), 2117-2124.
[http://dx.doi.org/10.1200/JCO.2016.71.6795] [PMID:  28375787] 
[42] 
Kwon, E.D.; Drake, C.G.; Scher, H.I.; Fizazi, K.; Bossi, A.; van den Eertwegh, A.J.; Krainer, M.; Houede, N.; Santos, R.; Mahammedi, H.; Ng, S.; Maio, M.; Franke, F.A.; Sundar, S.; Agarwal, N.; Bergman, A.M.; Ciuleanu, T.E.; Korbenfeld, E.; Sengeløv, L.; Hansen, S.; Logothetis, C.; Beer, T.M.; McHenry, M.B.; Gagnier, P.; Liu, D.; Gerritsen, W.R. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (ca184-043): A multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol.,  2014, 15(7), 700-712.
[http://dx.doi.org/10.1016/S1470-2045(14)70189-5] [PMID:  24831977] 
[43] 
Le, D.T.; Uram, J.N.; Wang, H.; Bartlett, B.R.; Kemberling, H.; Eyring, A.D.; Skora, A.D.; Luber, B.S.; Azad, N.S.; Laheru, D.; Biedrzycki, B.; Donehower, R.C.; Zaheer, A.; Fisher, G.A.; Crocenzi, T.S.; Lee, J.J.; Duffy, S.M.; Goldberg, R.M.; de la Chapelle, A.; Koshiji, M.; Bhaijee, F.; Huebner, T.; Hruban, R.H.; Wood, L.D.; Cuka, N.; Pardoll, D.M.; Papadopoulos, N.; Kinzler, K.W.; Zhou, S.; Cornish, T.C.; Taube, J.M.; Anders, R.A.; Eshleman, J.R.; Vogelstein, B.; Diaz, L.A., Jr PD-1 Blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med.,  2015, 372(26), 2509-2520.
[http://dx.doi.org/10.1056/NEJMoa1500596] [PMID:  26028255] 
[44] 
Overman, M.J.; Lonardi, S.; Wong, K.Y.M.; Lenz, H.J.; Gelsomino, F.; Aglietta, M.; Morse, M.A.; Van Cutsem, E.; McDermott, R.; Hill, A.; Sawyer, M.B.; Hendlisz, A.; Neyns, B.; Svrcek, M.; Moss, R.A.; Ledeine, J.M.; Cao, Z.A.; Kamble, S.; Kopetz, S.; André, T. 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.
[http://dx.doi.org/10.1200/JCO.2017.76.9901] [PMID:  29355075] 
[45] 
Overman, M.J.; McDermott, R.; Leach, J.L.; Lonardi, S.; Lenz, H.J.; Morse, M.A.; Desai, J.; Hill, A.; Axelson, M.; Moss, R.A.; Goldberg, M.V.; Cao, Z.A.; Ledeine, J.M.; Maglinte, G.A.; Kopetz, S.; André, T. 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.
[http://dx.doi.org/10.1016/S1470-2045(17)30422-9] [PMID:  28734759] 
[46] 
André, T.; Shiu, K.K.; Kim, T.W.; Jensen, B.V.; Jensen, L.H.; Punt, C.; Smith, D.; Garcia-Carbonero, R.; Benavides, M.; Gibbs, P.; de la Fouchardiere, C.; Rivera, F.; Elez, E.; Bendell, J.; Le, D.T.; Yoshino, T.; Van Cutsem, E.; Yang, P.; Farooqui, M.Z.H.; Marinello, P.; Diaz, L.A., Jr Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N. Engl. J. Med.,  2020, 383(23), 2207-2218.
[http://dx.doi.org/10.1056/NEJMoa2017699] [PMID:  33264544] 
[47] 
Toor, S.M.; Murshed, K.; Al-Dhaheri, M.; Khawar, M.; Abu Nada, M.; Elkord, E. Immune checkpoints in circulating and tumor-infiltrating CD4+ T cell subsets in colorectal cancer patients. Front. Immunol.,  2019, 10, 2936.
[http://dx.doi.org/10.3389/fimmu.2019.02936] [PMID:  31921188] 
[48] 
Ferris, R.L.; Blumenschein, G., Jr; Fayette, J.; Guigay, J.; Colevas, A.D.; Licitra, L.; Harrington, K.; Kasper, S.; Vokes, E.E.; Even, C.; Worden, F.; Saba, N.F.; Iglesias Docampo, L.C.; Haddad, R.; Rordorf, T.; Kiyota, N.; Tahara, M.; Monga, M.; Lynch, M.; Geese, W.J.; Kopit, J.; Shaw, J.W.; Gillison, M.L. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N. Engl. J. Med.,  2016, 375(19), 1856-1867.
[http://dx.doi.org/10.1056/NEJMoa1602252] [PMID:  27718784] 
[49] 
Mehra, R.; Seiwert, T.Y.; Gupta, S.; Weiss, J.; Gluck, I.; Eder, J.P.; Burtness, B.; Tahara, M.; Keam, B.; Kang, H.; Muro, K.; Geva, R.; Chung, H.C.; Lin, C.C.; Aurora-Garg, D.; Ray, A.; Pathiraja, K.; Cheng, J.; Chow, L.Q.M.; Haddad, R. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: Pooled analyses after long-term follow-up in KEYNOTE-012. Br. J. Cancer,  2018, 119(2), 153-159.
[http://dx.doi.org/10.1038/s41416-018-0131-9] [PMID:  29955135] 
[50] 
El-Khoueiry, A.B.; Sangro, B.; Yau, T.; Crocenzi, T.S.; Kudo, M.; Hsu, C.; Kim, T.Y.; Choo, S.P.; Trojan, J.; Welling, T.H.R.; Meyer, T.; Kang, Y.K.; Yeo, W.; Chopra, A.; Anderson, J.; Dela Cruz, C.; Lang, L.; Neely, J.; Tang, H.; Dastani, H.B.; Melero, I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet,  2017, 389(10088), 2492-2502.
[http://dx.doi.org/10.1016/S0140-6736(17)31046-2] [PMID:  28434648] 
[51] 
Fuchs, C.S.; Doi, T.; Jang, R.W.; Muro, K.; Satoh, T.; Machado, M.; Sun, W.; Jalal, S.I.; Shah, M.A.; Metges, J-P.; Garrido, M.; Golan, T.; Mandala, M.; Wainberg, Z.A.; Catenacci, D.V.; Ohtsu, A.; Shitara, K.; Geva, R.; Bleeker, J.; Ko, A.H.; Ku, G.; Philip, P.; Enzinger, P.C.; Bang, Y-J.; Levitan, D.; Wang, J.; Rosales, M.; Dalal, R.P.; Yoon, H.H. 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-e180013.
[http://dx.doi.org/10.1001/jamaoncol.2018.0013] [PMID:  29543932] 
[52] 
Janjigian, Y.Y.; Bendell, J.; Calvo, E.; Kim, J.W.; Ascierto, P.A.; Sharma, P.; Ott, P.A.; Peltola, K.; Jaeger, D.; Evans, J.; de Braud, F.; Chau, I.; Harbison, C.T.; Dorange, C.; Tschaika, M.; Le, D.T. CheckMate-032 Study: efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer. J. Clin. Oncol.,  2018, 36(28), 2836-2844.
[http://dx.doi.org/10.1200/JCO.2017.76.6212] [PMID:  30110194] 
[53] 
Fuchs, C.S.; Niedzwiecki, D.; Mamon, H.J.; Tepper, J.E.; Ye, X.; Swanson, R.S.; Enzinger, P.C.; Haller, D.G.; Dragovich, T.; Alberts, S.R.; Bjarnason, G.A.; Willett, C.G.; Gunderson, L.L.; Goldberg, R.M.; Venook, A.P.; Ilson, D.; O’Reilly, E.; Ciombor, K.; Berg, D.J.; Meyerhardt, J.; Mayer, R.J. Adjuvant chemoradiotherapy with epirubicin, cisplatin, and fluorouracil compared with adjuvant chemoradiotherapy with fluorouracil and leucovorin after curative resection of gastric cancer: Results from calgb 80101 (alliance). J. Clin. Oncol.,  2017, 35(32), 3671-3677.
[http://dx.doi.org/10.1200/JCO.2017.74.2130] [PMID:  28976791] 
[54] 
Maubec, E.; Boubaya, M.; Petrow, P.; Beylot-Barry, M.; Basset-Seguin, N.; Deschamps, L.; Grob, J.J.; Dréno, B.; Scheer-Senyarich, I.; Bloch-Queyrat, C.; Leccia, M.T.; Stefan, A.; Saiag, P.; Grange, F.; Meyer, N.; de Quatrebarbes, J.; Dinulescu, M.; Legoupil, D.; Machet, L.; Dereure, O.; Zehou, O.; Montaudié, H.; Wierzbicka-Hainaut, E.; Le Corre, Y.; Mansard, S.; Guégan, S.; Arnault, J.P.; Dalac, S.; Aubin, F.; Alloux, C.; Lopez, I.; Cherbal, S.; Tibi, A.; Lévy, V.; Phase, I.I. Study of pembrolizumab as first-line, single-drug therapy for patients with unresectable cutaneous squamous cell carcinomas. J. Clin. Oncol.,  2020, 38(26), 3051-3061.
[http://dx.doi.org/10.1200/JCO.19.03357] [PMID:  32730186] 
[55] 
Schoenfeld, J.D.; Hanna, G.J.; Jo, V.Y.; Rawal, B.; Chen, Y.H.; Catalano, P.S.; Lako, A.; Ciantra, Z.; Weirather, J.L.; Criscitiello, S.; Luoma, A.; Chau, N.; Lorch, J.; Kass, J.I.; Annino, D.; Goguen, L.; Desai, A.; Ross, B.; Shah, H.J.; Jacene, H.A.; Margalit, D.N.; Tishler, R.B.; Wucherpfennig, K.W.; Rodig, S.J.; Uppaluri, R.; Haddad, R.I. Neoadjuvant nivolumab or nivolumab plus ipilimumab in untreated oral cavity squamous cell carcinoma: A Phase 2 open-label randomized clinical trial. JAMA Oncol.,  2020, 6(10), 1563-1570.
[http://dx.doi.org/10.1001/jamaoncol.2020.2955] [PMID:  32852531] 
[56] 
Xiong, Y.; Neskey, D.M.; Horton, J.D.; Paulos, C.M.; Knochelmann, H.M.; Armeson, K.E.; Young, M.R.I. Immunological effects of nivolumab immunotherapy in patients with oral cavity squamous cell carcinoma. BMC Cancer,  2020, 20(1), 229.
[http://dx.doi.org/10.1186/s12885-020-06726-3] [PMID: 32183719] 
[57] 
Capdevila, J.; Wirth, L.J.; Ernst, T.; Ponce Aix, S.; Lin, C.C.; Ramlau, R.; Butler, M.O.; Delord, J.P.; Gelderblom, H.; Ascierto, P.A.; Fasolo, A.; Führer, D.; Hütter-Krönke, M.L.; Forde, P.M.; Wrona, A.; Santoro, A.; Sadow, P.M.; Szpakowski, S.; Wu, H.; Bostel, G.; Faris, J.; Cameron, S.; Varga, A.; Taylor, M. PD-1 blockade in anaplastic thyroid carcinoma. J. Clin. Oncol.,  2020, 38(23), 2620-2627.
[http://dx.doi.org/10.1200/JCO.19.02727] [PMID:  32364844] 
[58] 
Kaufman, H.L.; Russell, J.; Hamid, O.; Bhatia, S.; Terheyden, P.; D’Angelo, S.P.; Shih, K.C.; Lebbé, C.; Linette, G.P.; Milella, M.; Brownell, I.; Lewis, K.D.; Lorch, J.H.; Chin, K.; Mahnke, L.; von Heydebreck, A.; Cuillerot, J.M.; Nghiem, P. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: A multicentre, single-group, open-label, phase 2 trial. Lancet Oncol.,  2016, 17(10), 1374-1385.
[http://dx.doi.org/10.1016/S1470-2045(16)30364-3] [PMID:  27592805] 
[59] 
Ansell, S.M.; Lesokhin, A.M.; Borrello, I.; Halwani, A.; Scott, E.C.; Gutierrez, M.; Schuster, S.J.; Millenson, M.M.; Cattry, D.; Freeman, G.J.; Rodig, S.J.; Chapuy, B.; Ligon, A.H.; Zhu, L.; Grosso, J.F.; Kim, S.Y.; Timmerman, J.M.; Shipp, M.A.; Armand, P. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N. Engl. J. Med.,  2015, 372(4), 311-319.
[http://dx.doi.org/10.1056/NEJMoa1411087] [PMID:  25482239] 
[60] 
Younes, A.; Santoro, A.; Shipp, M.; Zinzani, P.L.; Timmerman, J.M.; Ansell, S.; Armand, P.; Fanale, M.; Ratanatharathorn, V.; Kuruvilla, J.; Cohen, J.B.; Collins, G.; Savage, K.J.; Trneny, M.; Kato, K.; Farsaci, B.; Parker, S.M.; Rodig, S.; Roemer, M.G.; Ligon, A.H.; Engert, A. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: A multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol.,  2016, 17(9), 1283-1294.
[http://dx.doi.org/10.1016/S1470-2045(16)30167-X] [PMID:  27451390] 
[61] 
Chen, R.; Zinzani, P.L.; Fanale, M.A.; Armand, P.; Johnson, N.A.; Brice, P.; Radford, J.; Ribrag, V.; Molin, D.; Vassilakopoulos, T.P.; Tomita, A.; von Tresckow, B.; Shipp, M.A.; Zhang, Y.; Ricart, A.D.; Balakumaran, A.; Moskowitz, C.H. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic hodgkin lymphoma. J. Clin. Oncol.,  2017, 35(19), 2125-2132.
[http://dx.doi.org/10.1200/JCO.2016.72.1316] [PMID:  28441111] 
[62] 
Gao, J.; Navai, N.; Alhalabi, O.; Siefker-Radtke, A.; Campbell, M.T.; Tidwell, R.S.; Guo, C.C.; Kamat, A.M.; Matin, S.F.; Araujo, J.C.; Shah, A.Y.; Msaouel, P.; Corn, P.; Wang, J.; Papadopoulos, J.N.; Yadav, S.S.; Blando, J.M.; Duan, F.; Basu, S.; Liu, W.; Shen, Y.; Zhang, Y.; Macaluso, M.D.; Wang, Y.; Chen, J.; Zhang, J.; Futreal, A.; Dinney, C.; Allison, J.P.; Goswami, S.; Sharma, P. Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma. Nat. Med.,  2020, 26(12), 1845-1851.
[http://dx.doi.org/10.1038/s41591-020-1086-y] [PMID:  33046869] 
[63] 
Khoja, L.; Day, D.; Wei-Wu, Chen T.; Siu, L.L.; Hansen, A.R. Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: A systematic review. Ann. Oncol.,  2017, 28(10), 2377-2385.
[http://dx.doi.org/10.1093/annonc/mdx286] [PMID:  28945858] 
[64] 
Postow, M.A.; Sidlow, R.; Hellmann, M.D. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med.,  2018, 378(2), 158-168.
[http://dx.doi.org/10.1056/NEJMra1703481] [PMID:  29320654] 
[65] 
Costello, E.K.; Stagaman, K.; Dethlefsen, L.; Bohannan, B.J.; Relman, D.A. The application of ecological theory toward an understanding of the human microbiome. Science,  2012, 336(6086), 1255-1262.
[http://dx.doi.org/10.1126/science.1224203] [PMID:  22674335] 
[66] 
Dzutsev, A.; Goldszmid, R.S.; Viaud, S.; Zitvogel, L.; Trinchieri, G. The role of the microbiota in inflammation, carcinogenesis, and cancer therapy. Eur. J. Immunol.,  2015, 45(1), 17-31.
[http://dx.doi.org/10.1002/eji.201444972] [PMID:  25328099] 
[67] 
Roy, S.; Trinchieri, G. Microbiota: A key orchestrator of cancer therapy. Nat. Rev. Cancer,  2017, 17(5), 271-285.
[http://dx.doi.org/10.1038/nrc.2017.13] [PMID:  28303904] 
[68] 
Vétizou, M.; Daillère, R.; Zitvogel, L. [Gut microbiota and efficacy of cancer therapies]. Biol. Aujourdhui,  2017, 211(1), 51-67. [Gut microbiota and efficacy of cancer therapies].
[PMID: 28682227] 
[69] 
Koh, A.Y. Potential for monitoring gut microbiota for diagnosing infections and graft-versus-host disease in cancer and stem cell transplant patients. Clin. Chem.,  2017, 63(11), 1685-1694.
[http://dx.doi.org/10.1373/clinchem.2016.259499] [PMID:  28720679] 
[70] 
Kåhrström, C.T.; Pariente, N.; Weiss, U. Intestinal microbiota in health and disease. Nature,  2016, 535(7610), 47.
[http://dx.doi.org/10.1038/535047a] [PMID:  27383978] 
[71] 
Viaud, S.; Saccheri, F.; Mignot, G.; Yamazaki, T.; Daillère, R.; Hannani, D.; Enot, D.P.; Pfirschke, C.; Engblom, C.; Pittet, M.J.; Schlitzer, A.; Ginhoux, F.; Apetoh, L.; Chachaty, E.; Woerther, P.L.; Eberl, G.; Bérard, M.; Ecobichon, C.; Clermont, D.; Bizet, C.; Gaboriau-Routhiau, V.; Cerf-Bensussan, N.; Opolon, P.; Yessaad, N.; Vivier, E.; Ryffel, B.; Elson, C.O.; Doré, J.; Kroemer, G.; Lepage, P.; Boneca, I.G.; Ghiringhelli, F.; Zitvogel, L. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science,  2013, 342(6161), 971-976.
[http://dx.doi.org/10.1126/science.1240537] [PMID:  24264990] 
[72] 
Iida, N.; Dzutsev, A.; Stewart, C.A.; Smith, L.; Bouladoux, N.; Weingarten, R.A.; Molina, D.A.; Salcedo, R.; Back, T.; Cramer, S.; Dai, R.M.; Kiu, H.; Cardone, M.; Naik, S.; Patri, A.K.; Wang, E.; Marincola, F.M.; Frank, K.M.; Belkaid, Y.; Trinchieri, G.; Goldszmid, R.S. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science,  2013, 342(6161), 967-970.
[http://dx.doi.org/10.1126/science.1240527] [PMID:  24264989] 
[73] 
Masahata, K.; Umemoto, E.; Kayama, H.; Kotani, M.; Nakamura, S.; Kurakawa, T.; Kikuta, J.; Gotoh, K.; Motooka, D.; Sato, S.; Higuchi, T.; Baba, Y.; Kurosaki, T.; Kinoshita, M.; Shimada, Y.; Kimura, T.; Okumura, R.; Takeda, A.; Tajima, M.; Yoshie, O.; Fukuzawa, M.; Kiyono, H.; Fagarasan, S.; Iida, T.; Ishii, M.; Takeda, K. Generation of colonic IgA-secreting cells in the caecal patch. Nat. Commun.,  2014, 5, 3704.
[http://dx.doi.org/10.1038/ncomms4704] [PMID:  24718324] 
[74] 
Atarashi, K.; Tanoue, T.; Shima, T.; Imaoka, A.; Kuwahara, T.; Momose, Y.; Cheng, G.; Yamasaki, S.; Saito, T.; Ohba, Y.; Taniguchi, T.; Takeda, K.; Hori, S.; Ivanov, I.I.; Umesaki, Y.; Itoh, K.; Honda, K. Induction of colonic regulatory t cells by indigenous clostridium species. Science,  2011, 331(6015), 337-341.
[http://dx.doi.org/10.1126/science.1198469] [PMID:  21205640] 
[75] 
Atarashi, K.; Tanoue, T.; Oshima, K.; Suda, W.; Nagano, Y.; Nishikawa, H.; Fukuda, S.; Saito, T.; Narushima, S.; Hase, K.; Kim, S.; Fritz, J.V.; Wilmes, P.; Ueha, S.; Matsushima, K.; Ohno, H.; Olle, B.; Sakaguchi, S.; Taniguchi, T.; Morita, H.; Hattori, M.; Honda, K. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature,  2013, 500(7461), 232-236.
[http://dx.doi.org/10.1038/nature12331] [PMID:  23842501] 
[76] 
Obata, Y.; Furusawa, Y.; Endo, T.A.; Sharif, J.; Takahashi, D.; Atarashi, K.; Nakayama, M.; Onawa, S.; Fujimura, Y.; Takahashi, M.; Ikawa, T.; Otsubo, T.; Kawamura, Y.I.; Dohi, T.; Tajima, S.; Masumoto, H.; Ohara, O.; Honda, K.; Hori, S.; Ohno, H.; Koseki, H.; Hase, K. The epigenetic regulator Uhrf1 facilitates the proliferation and maturation of colonic regulatory T cells. Nat. Immunol.,  2014, 15(6), 571-579.
[http://dx.doi.org/10.1038/ni.2886] [PMID:  24777532] 
[77] 
Smith, P.M.; Howitt, M.R.; Panikov, N.; Michaud, M.; Gallini, C.A.; Bohlooly-Y, M.; Glickman, J.N.; Garrett, W. The microbial metabolites, short-chain fatty acids, regulate colonic Treg Cell Homeostasis. Sci.,  2013, 341(6145), 569-573.
[78] 
Furusawa, Y.; Obata, Y.; Fukuda, S.; Endo, T.A.; Nakato, G.; Takahashi, D.; Nakanishi, Y.; Uetake, C.; Kato, K.; Kato, T.; Takahashi, M.; Fukuda, N.N.; Murakami, S.; Miyauchi, E.; Hino, S.; Atarashi, K.; Onawa, S.; Fujimura, Y.; Lockett, T.; Clarke, J.M.; Topping, D.L.; Tomita, M.; Hori, S.; Ohara, O.; Morita, T.; Koseki, H.; Kikuchi, J.; Honda, K.; Hase, K.; Ohno, H. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature,  2013, 504(7480), 446-450.
[http://dx.doi.org/10.1038/nature12721] [PMID:  24226770] 
[79] 
Chaput, N.; Lepage, P.; Coutzac, C.; Soularue, E.; Le Roux, K.; Monot, C.; Boselli, L.; Routier, E.; Cassard, L.; Collins, M.; Vaysse, T.; Marthey, L.; Eggermont, A.; Asvatourian, V.; Lanoy, E.; Mateus, C.; Robert, C.; Carbonnel, F. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann. Oncol.,  2017, 28(6), 1368-1379.
[http://dx.doi.org/10.1093/annonc/mdx108] [PMID:  28368458] 
[80] 
Gopalakrishnan, V.; Spencer, C.N.; Nezi, L.; Reuben, A.; Andrews, M.C.; Karpinets, T.V.; Prieto, P.A.; Vicente, D.; Hoffman, K.; Wei, S.C.; Cogdill, A.P.; Zhao, L.; Hudgens, C.W.; Hutchinson, D.S.; Manzo, T.; Petaccia de Macedo, M.; Cotechini, T.; Kumar, T.; Chen, W.S.; Reddy, S.M.; Szczepaniak Sloane, R.; Galloway-Pena, J.; Jiang, H.; Chen, P.L.; Shpall, E.J.; Rezvani, K.; Alousi, A.M.; Chemaly, R.F.; Shelburne, S.; Vence, L.M.; Okhuysen, P.C.; Jensen, V.B.; Swennes, A.G.; McAllister, F.; Marcelo Riquelme Sanchez, E.; Zhang, Y.; Le Chatelier, E.; Zitvogel, L.; Pons, N.; Austin-Breneman, J.L.; Haydu, L.E.; Burton, E.M.; Gardner, J.M.; Sirmans, E.; Hu, J.; Lazar, A.J.; Tsujikawa, T.; Diab, A.; Tawbi, H.; Glitza, I.C.; Hwu, W.J.; Patel, S.P.; Woodman, S.E.; Amaria, R.N.; Davies, M.A.; Gershenwald, J.E.; Hwu, P.; Lee, J.E.; Zhang, J.; Coussens, L.M.; Cooper, Z.A.; Futreal, P.A.; Daniel, C.R.; Ajami, N.J.; Petrosino, J.F.; Tetzlaff, M.T.; Sharma, P.; Allison, J.P.; Jenq, R.R.; Wargo, J.A. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science,  2018, 359(6371), 97-103.
[http://dx.doi.org/10.1126/science.aan4236] [PMID:  29097493] 
[81] 
Routy, B.; Le Chatelier, E.; Derosa, L.; Duong, C.P.M.; Alou, M.T.; Daillère, R.; Fluckiger, A.; Messaoudene, M.; Rauber, C.; Roberti, M.P.; Fidelle, M.; Flament, C.; Poirier-Colame, V.; Opolon, P.; Klein, C.; Iribarren, K.; Mondragón, L.; Jacquelot, N.; Qu, B.; Ferrere, G.; Clémenson, C.; Mezquita, L.; Masip, J.R.; Naltet, C.; Brosseau, S.; Kaderbhai, C.; Richard, C.; Rizvi, H.; Levenez, F.; Galleron, N.; Quinquis, B.; Pons, N.; Ryffel, B.; Minard-Colin, V.; Gonin, P.; Soria, J.C.; Deutsch, E.; Loriot, Y.; Ghiringhelli, F.; Zalcman, G.; Goldwasser, F.; Escudier, B.; Hellmann, M.D.; Eggermont, A.; Raoult, D.; Albiges, L.; Kroemer, G.; Zitvogel, L. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Sci.,  2018, 359(6371), 91-97.
[http://dx.doi.org/10.1126/science.aan3706] [PMID:  29097494] 
[82] 
Viaud, S.; Daillère, R.; Yamazaki, T.; Lepage, P.; Boneca, I.; Goldszmid, R.; Trinchieri, G.; Zitvogel, L. Why should we need the gut microbiota to respond to cancer therapies? OncoImmunology,  2014, 3(1), e27.574
[http://dx.doi.org/10.4161/onci.27574] [PMID:  24800167] 
[83] 
Zitvogel, L.; Galluzzi, L.; Viaud, S.; Vétizou, M.; Daillère, R.; Merad, M.; Kroemer, G. Cancer and the gut microbiota: An unexpected link. Sci. Transl. Med.,  2015, 7(271), 271.ps1
[http://dx.doi.org/10.1126/scitranslmed.3010473] [PMID:  25609166] 
[84] 
Derosa, L.; Routy, B.; Fidelle, M.; Iebba, V.; Alla, L.; Pasolli, E.; Segata, N.; Desnoyer, A.; Pietrantonio, F.; Ferrere, G.; Fahrner, J.E.; Le Chatellier, E.; Pons, N.; Galleron, N.; Roume, H.; Duong, C.P.M.; Mondragón, L.; Iribarren, K.; Bonvalet, M.; Terrisse, S.; Rauber, C.; Goubet, A.G.; Daillère, R.; Lemaitre, F.; Reni, A.; Casu, B.; Alou, M.T.; Alves Costa Silva, C.; Raoult, D.; Fizazi, K.; Escudier, B.; Kroemer, G.; Albiges, L.; Zitvogel, L. Gut bacteria composition drives primary resistance to cancer immunotherapy in renal cell carcinoma patients. Eur. Urol.,  2020, 78(2), 195-206.
[http://dx.doi.org/10.1016/j.eururo.2020.04.044] [PMID: 32376136] 
[85] 
Mager, L.F.; Burkhard, R.; Pett, N.; Cooke, N.C.A.; Brown, K.; Ramay, H.; Paik, S.; Stagg, J.; Groves, R.A.; Gallo, M.; Lewis, I.A.; Geuking, M.B.; McCoy, K.D. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science,  2020, 369(6510), 1481-1489.
[http://dx.doi.org/10.1126/science.abc3421] [PMID: 32792462 ] 
[86] 
Matson, V.; Fessler, J.; Bao, R.; Chongsuwat, T.; Zha, Y.; Alegre, M.L.; Luke, J.J.; Gajewski, T.F. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science,  2018, 359(6371), 104-108.
[http://dx.doi.org/10.1126/science.aao3290] [PMID:  29302014] 
[87] 
Alsaab, H.O.; Sau, S.; Alzhrani, R.; Tatiparti, K.; Bhise, K.; Kashaw, S.K.; Iyer, A.K. PD-1 and PD-L1 Checkpoint signaling inhibition for cancer immunotherapy: Mechanism, combinations, and clinical outcome. Front. Pharmacol.,  2017, 8, 561.
[http://dx.doi.org/10.3389/fphar.2017.00561] [PMID:  28878676] 
[88] 
Sivan, A.; Corrales, L.; Hubert, N.; Williams, J.B.; Aquino-Michaels, K.; Earley, Z.M.; Benyamin, F.W.; Lei, Y.M.; Jabri, B.; Alegre, M.L.; Chang, E.B.; Gajewski, T.F. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science,  2015, 350(6264), 1084-1089.
[http://dx.doi.org/10.1126/science.aac4255] [PMID:  26541606] 
[89] 
Matson, V.; Fessler, J.; Bao, R.; Chongsuwat, T.; Zha, Y.; Alegre, M-L.; Luke, J.J.; Gajewski, T.F. The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients. Sci.,  2018, 359(6371), 104-105.
[http://dx.doi.org/10.1126/science.aao3290] 
[90] 
Bertrand, A.; Kostine, M.; Barnetche, T.; Truchetet, M.E.; Schaeverbeke, T. Immune related adverse events associated with anti-CTLA-4 antibodies: Systematic review and meta-analysis. BMC Med.,  2015, 13, 211.
[http://dx.doi.org/10.1186/s12916-015-0455-8] [PMID:  26337719] 
[91] 
Vétizou, M.; Pitt, J.M.; Daillère, R.; Lepage, P.; Waldschmitt, N.; Flament, C.; Rusakiewicz, S.; Routy, B.; Roberti, M.P.; Duong, C.P.; Poirier-Colame, V.; Roux, A.; Becharef, S.; Formenti, S.; Golden, E.; Cording, S.; Eberl, G.; Schlitzer, A.; Ginhoux, F.; Mani, S.; Yamazaki, T.; Jacquelot, N.; Enot, D.P.; Bérard, M.; Nigou, J.; Opolon, P.; Eggermont, A.; Woerther, P.L.; Chachaty, E.; Chaput, N.; Robert, C.; Mateus, C.; Kroemer, G.; Raoult, D.; Boneca, I.G.; Carbonnel, F.; Chamaillard, M.; Zitvogel, L. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science,  2015, 350(6264), 1079-1084.
[http://dx.doi.org/10.1126/science.aad1329] [PMID:  26541610] 
[92] 
Dubin, K.; Callahan, M.K.; Ren, B.; Khanin, R.; Viale, A.; Ling, L.; No, D.; Gobourne, A.; Littmann, E.; Huttenhower, C.; Pamer, E.G.; Wolchok, J.D. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat. Commun.,  2016, 7, 10391.
[http://dx.doi.org/10.1038/ncomms10391] [PMID:  26837003] 
[93] 
Ahmed, J.; Kumar, A.; Parikh, K.; Anwar, A.; Knoll, B.M.; Puccio, C.; Chun, H.; Fanucchi, M.; Lim, S.H. Use of broad-spectrum antibiotics impacts outcome in patients treated with immune checkpoint inhibitors. OncoImmunol.,  2018, 7(11), e15.07670
[http://dx.doi.org/10.1080/2162402X.2018.1507670] [PMID:  30377571] 
[94] 
Zhao, S.; Gao, G.; Li, W.; Li, X.; Zhao, C.; Jiang, T.; Jia, Y.; He, Y.; Li, A.; Su, C.; Ren, S.; Chen, X.; Zhou, C. Antibiotics are associated with attenuated efficacy of anti-PD-1/PD-L1 therapies in Chinese patients with advanced non-small cell lung cancer. Lung Cancer,  2019, 130, 10-17.
[http://dx.doi.org/10.1016/j.lungcan.2019.01.017] [PMID:  30885328] 
[95] 
Pinato, D.J.; Howlett, S.; Ottaviani, D.; Urus, H.; Patel, A.; Mineo, T.; Brock, C.; Power, D.; Hatcher, O.; Falconer, A.; Ingle, M.; Brown, A.; Gujral, D.; Partridge, S.; Sarwar, N.; Gonzalez, M.; Bendle, M.; Lewanski, C.; Newsom-Davis, T.; Allara, E.; Bower, M. Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. JAMA Oncol.,  2019, 5(12), 1774-1778.
[http://dx.doi.org/10.1001/jamaoncol.2019.2785] [PMID:  31513236] 
[96] 
Wang, F.; Yin, Q.; Chen, L.; Davis, M.M. Bifidobacterium can mitigate intestinal immunopathology in the context of CTLA-4 blockade. Proc. Natl. Acad. Sci. USA,  2018, 115(1), 157-161.
[http://dx.doi.org/10.1073/pnas.1712901115] [PMID:  29255057] 
[97] 
Frankel, A.E.; Coughlin, L.A.; Kim, J.; Froehlich, T.W.; Xie, Y.; Frenkel, E.P.; Koh, A.Y. Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia,  2017, 19(10), 848-855.
[http://dx.doi.org/10.1016/j.neo.2017.08.004] [PMID: 28923537] 
[98] 
Wei, S.C.; Levine, J.H.; Cogdill, A.P.; Zhao, Y.; Anang, N.A.S.; Andrews, M.C.; Sharma, P.; Wang, J.; Wargo, J.A.; Pe’er, D.; Allison, J.P. Distinct cellular mechanisms underlie anti-CTLA-4 and Anti-PD-1 checkpoint blockade. Cell,  2017, 170(6), 1120-1133.e17.
[http://dx.doi.org/10.1016/j.cell.2017.07.024] [PMID:  28803728] 
[99] 
Carthon, B.C.; Wolchok, J.D.; Yuan, J.; Kamat, A.; Ng Tang, D.S.; Sun, J.; Ku, G.; Troncoso, P.; Logothetis, C.J.; Allison, J.P.; Sharma, P. Preoperative CTLA-4 blockade: Tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin. Cancer Res.,  2010, 16(10), 2861-2871.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-0569] [PMID:  20460488] 
[100] 
Bhutiani, N.; Schucht, J.E.; Miller, K.R.; McClave, S.A. Technical aspects of fecal microbial transplantation (FMT). Curr. Gastroenterol. Rep.,  2018, 20(7), 30.
[http://dx.doi.org/10.1007/s11894-018-0636-7] [PMID: 29886561] 
[101] 
Wang, Y.; Wiesnoski, D.H.; Helmink, B.A.; Gopalakrishnan, V.; Choi, K.; DuPont, H.L.; Jiang, Z-D.; Abu-Sbeih, H.; Sanchez, C.A.; Chang, C-C.; Parra, E.R.; Francisco-Cruz, A.; Raju, G.S.; Stroehlein, J.R.; Campbell, M.T.; Gao, J.; Subudhi, S.K.; Maru, D.M.; Blando, J.M.; Lazar, A.J.; Allison, J.P.; Sharma, P.; Tetzlaff, M.T.; Wargo, J.A.; Jenq, R.R. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat. Med.,  2018, 24(12), 1804-1808.
[http://dx.doi.org/10.1038/s41591-018-0238-9] [PMID:  30420754] 
Rights & Permissions Print Cite
Article Metrics
30
1
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1871520621666210706110713	Print ISSN 1871-5206
Publisher Name Bentham Science Publisher	Online ISSN 1875-5992
Anti-Cancer Agents in Medicinal Chemistry

Gut Microbiota and Immune Checkpoint Inhibitors-Based Immunotherapy

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract
