Advances in the discovery and development of selective heme-displacing IDO1 inhibitors

References

• Binnewies M, Roberts EW, Kersten K, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018;24(5):541–550.
   PubMed Web of Science ®Google Scholar
• Wellenstein MD, de Visser KE, De Visser KE. Cancer-cell-intrinsic mechanisms shaping the tumor immune landscape. Immunity. 2018;48(3):399–416.
   PubMed Web of Science ®Google Scholar
• Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 2018;8(9):1069–1086.
   PubMed Web of Science ®Google Scholar
• Zappasodi R, Merghoub T, Wolchok JD. Emerging concepts for immune checkpoint blockade-based combination therapies. Cancer Cell. 2018;33(4):581–598.
   PubMed Web of Science ®Google Scholar
• Mazzarella L, Duso BA, Trapani D, et al. The evolving landscape of ‘next-generation’ immune checkpoint inhibitors: A review. Eur J Cancer. 2019;117:14–31.
   PubMed Web of Science ®Google Scholar
• Wilky BA. Immune checkpoint inhibitors: the linchpins of modern immunotherapy. Immunol Rev. 2019;290(1):6–23.
   PubMed Web of Science ®Google Scholar
• Darvin P, Toor SM, Sasidharan Nair V, et al. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med. 2018;50(12):1–11.
   PubMed Web of Science ®Google Scholar
• Sharma P, Hu-Lieskovan S, Wargo JA, et al. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168(4):707–723.
   PubMed Web of Science ®Google Scholar
• Kumar V, Patel S, Tcyganov E, et al. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 2016;37(3):208–220.
   PubMed Web of Science ®Google Scholar
• Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science. 2015;348(6230):74–80.
   PubMed Web of Science ®Google Scholar
• Vacchelli E, Aranda F, Eggermont A, et al. Trial watch: IDO inhibitors in cancer therapy. Oncoimmunology. 2014;3(10):e957994.
   PubMed Web of Science ®Google Scholar
• Routy JP, Routy B, Graziani GM, et al. The kynurenine pathway is a double-edged sword in immune-privileged sites and in cancer: implications for immunotherapy. IJTR. 2016;9: 67–77.
   Google Scholar
• Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest. 2007;117(5):1147–1154.
   PubMed Web of Science ®Google Scholar
• Curti A, Trabanelli S, Salvestrini V, et al. The role of indoleamine 2,3-dioxygenase in the induction of immune tolerance: focus on hematology. Blood. 2009;113(11):2394–2401.
   PubMed Web of Science ®Google Scholar
• Munn DH, Mellor AL. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol. 2016;37(3):193–207.
   PubMed Web of Science ®Google Scholar
• Uyttenhove C, Pilotte L, Théate I, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 2003;9(10):1269–1274.
   PubMed Web of Science ®Google Scholar
• Taylor MW, Feng GS. Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. Faseb J. 1991;5(11):2516–2522.
   PubMed Web of Science ®Google Scholar
• Muller AJ, DuHadaway JB, Donover PS, et al. Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med. 2005;11(3):312–319.
   PubMed Web of Science ®Google Scholar
• Hwu P, Du MX, Lapointe R, et al. Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. J Immunol. 2000;164(7):3596–3599.
   PubMed Web of Science ®Google Scholar
• Astigiano S, Morandi B, Costa R, et al. Eosinophil granulocytes account for indoleamine 2,3-dioxygenase-mediated immune escape in human non-small cell lung cancer. Neoplasia. 2005;7(4):390–396.
   PubMed Web of Science ®Google Scholar
• Yu J, Du W, Yan F, et al. Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer. J Immunol. 2013;190(7):3783–3797.
   PubMed Web of Science ®Google Scholar
• Godin-Ethier J, Hanafi L-A, Piccirillo CA, et al. 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives. Clin Cancer Res. 2011;17(22):6985–6991.
   PubMed Web of Science ®Google Scholar
• Théate I, van Baren N, Pilotte L, et al. Extensive profiling of the expression of the indoleamine 2,3-dioxygenase 1 protein in normal and tumoral human tissues. Cancer Immunol Res. 2015;3(2):161–172.
   PubMed Web of Science ®Google Scholar
• Holmgaard RB, Zamarin D, Li Y, et al. Tumor-expressed IDO recruits and activates MDSCs in a treg-dependent manner. Cell Rep. 2015;13(2):412–424.
   PubMed Web of Science ®Google Scholar
• Holmgaard RB, Zamarin D, Munn DH, et al. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med. 2013;210(7):1389–1402.
   PubMed Web of Science ®Google Scholar
• Li A, Barsoumian HB, Schoenhals JE, et al. Indoleamine 2,3-dioxygenase 1 inhibition targets anti-PD1-resistant lung tumors by blocking myeloid-derived suppressor cells. Cancer Lett. 2018;431:54–63.
   PubMed Web of Science ®Google Scholar
• Lee GK, Park HJ, Macleod M, et al. Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Immunology. 2002;107(4):452–460.
   PubMed Web of Science ®Google Scholar
• Fallarino F, Grohmann U, Vacca C, et al. T cell apoptosis by tryptophan catabolism. Cell Death Differ. 2002;9(10):1069–1077.
   PubMed Web of Science ®Google Scholar
• Kolluri SK, Jin U-H, Safe S. Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target. Arch Toxicol. 2017;91(7):2497–2513.
   PubMed Web of Science ®Google Scholar
• Kubli SP, Bassi C, Roux C, et al. AhR controls redox homeostasis and shapes the tumor microenvironment in BRCA1-associated breast cancer. Proc Nat Acad Sci. 2019 116;(9)3604.
   PubMed Web of Science ®Google Scholar
• Mohamed HT, Gadalla R, El-Husseiny N, et al. Inflammatory breast cancer: activation of the aryl hydrocarbon receptor and its target CYP1B1 correlates closely with Wnt5a/b-β-catenin signalling, the stem cell phenotype and disease progression. J Adv Res. 2019;16:75–86.
   PubMed Web of Science ®Google Scholar
• Vacher S, Castagnet P, Chemlali W, et al. High AHR expression in breast tumors correlates with expression of genes from several signaling pathways namely inflammation and endogenous tryptophan metabolism. PLoS One. 2018;13(1):e0190619–e.
   PubMed Web of Science ®Google Scholar
• Cheong JE, Sun L. Targeting the IDO1/TDO2-KYN-AhR pathway for cancer immunotherapy - challenges and opportunities. Trends Pharmacol Sci. 2018;39(3):307–325.
   PubMed Web of Science ®Google Scholar
• Opitz CA, Litzenburger UM, Sahm F, et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature. 2011;478(7368):197–203.
   PubMed Web of Science ®Google Scholar
• Jaronen M, Quintana FJ. Immunological relevance of the coevolution of IDO1 and AHR. Front Immunol. 2014;5:521.
   PubMed Web of Science ®Google Scholar
• DiNatale BC, Murray IA, Schroeder JC, et al. Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling. Toxicol Sci. 2010;115(1):89–97.
   PubMed Web of Science ®Google Scholar
• Nguyen NT, Kimura A, Nakahama T, et al. Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc Natl Acad Sci U S A. 2010;107(46):19961–19966.
   PubMed Web of Science ®Google Scholar
• Xue P, Fu J, Zhou Y. The aryl hydrocarbon receptor and tumor immunity. Front Immunol. 2018;9:286.
   PubMed Web of Science ®Google Scholar
• Liu Y, Liang X, Dong W, et al. Tumor-repopulating cells induce PD-1 expression in CD8(+) T cells by transferring kynurenine and AhR activation. Cancer Cell. 2018;33(3):480–94.e7.
   PubMed Web of Science ®Google Scholar
• Gargaro M, Vacca C, Massari S, et al. Engagement of nuclear coactivator 7 by 3-hydroxyanthranilic acid enhances activation of aryl hydrocarbon receptor in immunoregulatory dendritic cells. Front Immunol. 2019;10:1973.
   PubMed Web of Science ®Google Scholar
• Vilgelm AE, Johnson DB, Richmond A. Combinatorial approach to cancer immunotherapy: strength in numbers. J Leukoc Biol. 2016;100(2):275–290.
   PubMed Web of Science ®Google Scholar
• Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov. 2015;14(8):561–584.
   PubMed Web of Science ®Google Scholar
• Liu X, Shin N, Koblish HK, et al. Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood. 2010;115(17):3520–3530.
   PubMed Web of Science ®Google Scholar
• Spranger S, Koblish HK, Horton B, et al. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. J Immunother Cancer. 2014;2:3.
   PubMedGoogle Scholar
• Wainwright DA, Chang AL, Dey M, et al. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin Cancer Res. 2014;20(20):5290–5301.
   PubMed Web of Science ®Google Scholar
• Prendergast GC, Malachowski WP, DuHadaway JB, et al. Discovery of IDO1 inhibitors: from bench to bedside. Cancer Res. 2017;77(24):6795–6811.
   PubMed Web of Science ®Google Scholar
• Nelp MT, Kates PA, Hunt JT, et al. Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form. Proc Natl Acad Sci U S A. 2018;115(13):3249–3254.
   PubMed Web of Science ®Google Scholar
• Lewis-Ballester A, Karkashon S, Batabyal D, et al. Inhibition mechanisms of human indoleamine 2,3 dioxygenase 1. J Am Chem Soc. 2018;140(27):8518–8525.
   PubMed Web of Science ®Google Scholar
• Cheong JE, Ekkati A, Sun L. A patent review of IDO1 inhibitors for cancer. Expert Opin Ther Pat. 2018;28(4):317–330.
   PubMed Web of Science ®Google Scholar
• Pham KN, Yeh S-R. Mapping the binding trajectory of a suicide inhibitor in human indoleamine 2,3-dioxygenase 1. J Am Chem Soc. 2018;140(44):14538–14541.
   PubMed Web of Science ®Google Scholar
• Ortiz-Meoz R, Wang L, Matico R, et al. Characterization of novel inhibition of indoleamine 2,3-dioxygenase by targeting its apo form. bioRxiv. 2018. 324947.
   Google Scholar
• Yue EW, Sparks R, Polam P, et al. INCB24360 (Epacadostat), a highly potent and selective indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor for immuno-oncology. ACS Med Chem Lett. 2017;8(5):486–491.
   PubMed Web of Science ®Google Scholar
• Lewis-Ballester A, Pham KN, Batabyal D, et al. Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase 1. Nat Commun. 2017;8(1):1693.
   PubMedGoogle Scholar
• Wu Y, Xu T, Liu J, et al. Structural insights into the binding mechanism of IDO1 with hydroxylamidine based inhibitor INCB14943. Biochem Biophys Res Commun. 2017;487(2):339–343.
   PubMed Web of Science ®Google Scholar
• Jochems C, Fantini M, Fernando RI, et al. The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumor antigen-specific T cells. Oncotarget. 2016;7(25):37762–37772.
   PubMedGoogle Scholar
• Koblish HK, Hansbury MJ, Bowman KJ, et al. Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDO-expressing tumors. Mol Cancer Ther. 2010;9(2):489–498.
   PubMed Web of Science ®Google Scholar
• Du Q, Feng X, Wang Y, et al. Discovery of phosphonamidate IDO1 inhibitors for the treatment of non-small cell lung cancer. Eur J Med Chem. 2019;182:111629.
   PubMed Web of Science ®Google Scholar
• Reardon DA, Gokhale PC, Klein SR, et al. Abstract 572: inhibition of IDO1 with epacadostat enhances anti-tumor efficacy of PD-1 blockade in a syngeneic glioblastoma (GBM) model. Cancer Res. 2017;77(13 Supplement):572.
   Google Scholar
• Beatty GL, O’Dwyer PJ, Clark J, et al. First-in-human phase I study of the oral inhibitor of indoleamine 2,3-dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies. Clin Cancer Res. 2017;23(13):3269–3276.
   PubMed Web of Science ®Google Scholar
• Long GV, Dummer R, Hamid O, et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 2019;20(8):1083–1097.
   PubMed Web of Science ®Google Scholar
• Chen S, Guo W, Liu X, et al. Design, synthesis and antitumor study of a series of N-cyclic sulfamoylaminoethyl substituted 1,2,5-oxadiazol-3-amines as new indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitors. Eur J Med Chem. 2019;179:38–55.
   PubMed Web of Science ®Google Scholar
• Song X, Sun P, Wang J, et al. Design, synthesis, and biological evaluation of 1,2,5-oxadiazole-3-carboximidamide derivatives as novel indoleamine-2,3-dioxygenase 1 inhibitors. Eur J Med Chem. 2020;189:112059.
   PubMed Web of Science ®Google Scholar
• Zhang H, Liu K, Pu Q, et al. Discovery of amino-cyclobutarene-derived indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors for cancer immunotherapy. ACS Med Chem Lett. 2019;10(11):1530–1536.
   PubMed Web of Science ®Google Scholar
• Sugimoto H, Oda S, Otsuki T, et al. Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase. Proc Natl Acad Sci U S A. 2006;103(8):2611–2616.
   PubMed Web of Science ®Google Scholar
• Kumar S, Waldo JP, Jaipuri FA, et al. Discovery of clinical candidate (1R,4r)-4-((R)-2-((S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexan-1-ol (navoximod), a potent and selective inhibitor of indoleamine 2,3-dioxygenase 1. J Med Chem. 2019;62(14):6705–6733.
   PubMed Web of Science ®Google Scholar
• Wang Y-J, Fletcher R, Yu J, et al. Immunogenic effects of chemotherapy-induced tumor cell death. Genes Dis. 2018;5(3):194–203.
   PubMed Web of Science ®Google Scholar
• Jung KH, LoRusso P, Burris H, et al. Phase I study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) administered with PD-L1 inhibitor (atezolizumab) in advanced solid tumors. Clin Cancer Res. 2019;25(11):3220–3228.
   PubMed Web of Science ®Google Scholar
• Nayak-Kapoor A, Hao Z, Sadek R, et al. Phase Ia study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors. J Immunother Cancer. 2018;6(1):61.
   PubMedGoogle Scholar
• Tu W, Yang F, Xu G, et al. Discovery of imidazoisoindole derivatives as highly potent and orally active indoleamine-2,3-dioxygenase inhibitors. ACS Med Chem Lett. 2019;10(6):949–953.
   PubMed Web of Science ®Google Scholar
• Crosignani S, Bingham P, Bottemanne P, et al. Discovery of a novel and selective indoleamine 2,3-dioxygenase (IDO-1) inhibitor 3-(5-fluoro-1h-indol-3-yl)pyrrolidine-2,5-dione (EOS200271/PF-06840003) and its characterization as a potential clinical candidate. J Med Chem. 2017;60(23):9617–9629.
   PubMed Web of Science ®Google Scholar
• Gomes B, Driessens G, Bartlett D, et al. Characterization of the selective indoleamine 2,3-dioxygenase-1 (IDO1) catalytic inhibitor EOS200271/PF-06840003 supports IDO1 as a critical resistance mechanism to PD-(L)1 blockade therapy. Mol Cancer Ther. 2018;17(12):2530–2542.
   PubMed Web of Science ®Google Scholar
• Zhu F, Aisa HA, Zhang J, et al. Development of a robust process for the preparation of high-quality 4-methylenepiperidine hydrochloride. Org Process Res Dev. 2018;22(1):91–96.
   Web of Science ®Google Scholar
• Yap TA, Sahebjam S, Hong DS, et al. First-in-human study of KHK2455, a long-acting, potent and selective indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor, in combination with mogamulizumab (Moga), an anti-CCR4 monoclonal antibody, in patients (pts) with advanced solid tumors. J clin oncol. 2018;36(15_suppl):3040.
   PubMed Web of Science ®Google Scholar
• Hunt JT, Balog A, Huang C, et al. 4964: structure, in vitro biology and in vivo pharmacodynamic characterization of a novel clinical IDO1 inhibitor. Cancer Res. 2017;77(13 Supplement):4964.
   Google Scholar
• Siu LL, KG QC, Pachynski R, et al. BMS-986205, an optimized indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, is well tolerated with potent pharmacodynamic (PD) activity, alone and in combination with nivolumab (nivo) in advanced cancers in a phase 1/2a trial [abstract]. Cancer Res. 2017;77(13 Suppl):Abstractnr CT116.
   Google Scholar
• Sonpavde G, Necchi A, Gupta S, et al. ENERGIZE: a Phase III study of neoadjuvant chemotherapy alone or with nivolumab with/without linrodostat mesylate for muscle-invasive bladder cancer. Future Oncol. 2020;16(2):4359–4368.
   PubMed Web of Science ®Google Scholar
• Fraunhoffer KJ, DelMonte AJ, Beutner GL, et al. Rapid development of a commercial process for linrodostat, an indoleamine 2,3-dioxygenase (IDO) inhibitor. Org Process Res Dev. 2019;23(11):2482–2498.
   Web of Science ®Google Scholar
• Dorsey FC, Benhadji KA, Sams LL, et al. Abstract 5245: identification and characterization of the IDO1 inhibitor LY3381916. Cancer Res. 2018;78(13 Supplement):5245.
   Web of Science ®Google Scholar
• Kotecki N, O’Neil B, Jalal S, et al. 113P - A phase I study of an anti-ido1 inhibitor (LY3381916) as monotherapy and in combination with an anti-PD-L1 antibody (LY3300054) in patients with advanced cancer. Ann Oncol. 2019;30:xi41–xi2.
   Web of Science ®Google Scholar
• Pham KN, Lewis-Ballester A, Yeh S-R. Structural basis of inhibitor selectivity in human indoleamine 2,3-dioxygenase 1 and tryptophan dioxygenase. J Am Chem Soc. 2019;141(47):18771–18779.
   PubMed Web of Science ®Google Scholar
• Markwalder JA, Seitz SP, Blat Y, et al. Identification and optimization of a novel series of indoleamine 2,3-dioxygenase inhibitors. Bioorg Med Chem Lett. 2017;27(3):582–585.
   PubMed Web of Science ®Google Scholar
• Williams DK, Markwalder JA, Balog AJAJ, et al. Development of a series of novel o-phenylenediamine-based indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. Bioorg Med Chem Lett. 2018;28(4):732–736.
   PubMed Web of Science ®Google Scholar
• Yang X, Cai S, Liu X, et al. Design, synthesis and biological evaluation of 2,5-dimethylfuran-3-carboxylic acid derivatives as potential IDO1 inhibitors. Bioorg Med Chem. 2019;27(8):1605–1618.
   PubMed Web of Science ®Google Scholar
• BJVd E, Baren N, Baurain J-F. Is there a clinical future for IDO1 inhibitors after the failure of epacadostat in melanoma? Ann Rev Cancer Biol. 2020;4(1): 241–256.
   Google Scholar
• Grohmann U, Mondanelli G, Belladonna ML, et al. Amino-acid sensing and degrading pathways in immune regulation. Cytokine Growth Factor Rev. 2017;35:37–45.
   PubMed Web of Science ®Google Scholar
• Pallotta MT, Orabona C, Volpi C, et al. Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nat Immunol. 2011;12(9):870–878.
   PubMed Web of Science ®Google Scholar
• Pilotte L, Larrieu P, Stroobant V, et al. Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc Natl Acad Sci U S A. 2012;109(7):2497–2502.
   PubMed Web of Science ®Google Scholar
• Schramme F, Crosignani S, Frederix K, et al. Inhibition of tryptophan-dioxygenase activity increases the antitumor efficacy of immune checkpoint inhibitors. Cancer Immunol Res. 2020;8(1):32–45.
   PubMed Web of Science ®Google Scholar
• Hoffmann D, Dvorakova T, Stroobant V, et al. Tryptophan 2,3-dioxygenase expression identified in human hepatocellular carcinoma cells and in intratumoral pericytes of most cancers. Cancer Immunol Res. 2020;8(1):19–31.
   PubMed Web of Science ®Google Scholar
• Nevler A, Muller AJ, Sutanto-Ward E, et al. Host IDO2 gene status influences tumor progression and radiotherapy response in KRAS-driven sporadic pancreatic cancers. Clin Cancer Res. 2019;25(2):724–734.
   PubMed Web of Science ®Google Scholar
• Löb S, Königsrainer A, Zieker D, et al. IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism. Cancer Immunol Immunother. 2009;58(1):153–157.
   PubMed Web of Science ®Google Scholar
• Yu CP, Song YL, Zhu ZM, et al. Targeting TDO in cancer immunotherapy. Med Oncol. 2017;34(5):73.
   PubMed Web of Science ®Google Scholar
• Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359(6382):1350–1355.
   PubMed Web of Science ®Google Scholar