Impact of Tumor Microenvironment Composition on Therapeutic Responses and Clinical Outcomes in Cancer

References

• Chen F , ZhuangX, LinLet al. New horizons in tumor microenvironment biology: challenges and opportunities. BMC Med.13, 45 (2015).
   PubMed Web of Science ®Google Scholar
• Junttila MR , de SauvageFJ. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature501(7467), 346–354 (2013).
   PubMed Web of Science ®Google Scholar
• Sounni NE , NoelA. Targeting the tumor microenvironment for cancer therapy. Clin. Chem.59(1), 85–93 (2013).
   PubMed Web of Science ®Google Scholar
• Gkretsi V , StylianouA, PapageorgisP, PolydorouC, StylianopoulosT. Remodeling components of the tumor microenvironment to enhance cancer therapy. Front. Oncol.5, 214 (2015).
   PubMed Web of Science ®Google Scholar
• Ishihara A , YoshidaT, TamakiH, SakakuraT. Tenascin expression in cancer cells and stroma of human breast cancer and its prognostic significance. Clin. Cancer Res.1(9), 1035–1041 (1995).
   PubMed Web of Science ®Google Scholar
• Silacci M , BrackSS, SpathNet al. Human monoclonal antibodies to domain C of tenascin-C selectively target solid tumors in vivo. Protein Eng. Des. Sel.19(10), 471–478 (2006).
   PubMed Web of Science ®Google Scholar
• Rozario T , DeSimoneDW. The extracellular matrix in development and morphogenesis: a dynamic view. Dev. Biol.341(1), 126–140 (2010).
   PubMed Web of Science ®Google Scholar
• Barker HE , CoxTR, ErlerJT. The rationale for targeting the LOX family in cancer. Nat. Rev. Cancer12(8), 540–552 (2012).
   PubMed Web of Science ®Google Scholar
• van Kempen LC , RuiterDJ, van MuijenGN, CoussensLM. The tumor microenvironment: a critical determinant of neoplastic evolution. Eur. J. Cell Biol.82(11), 539–548 (2003).
   PubMed Web of Science ®Google Scholar
• Kalluri R , ZeisbergM. Fibroblasts in cancer. Nat. Rev. Cancer6(5), 392–401 (2006).
   PubMed Web of Science ®Google Scholar
• Olive KP , JacobetzMA, DavidsonCJet al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science324(5933), 1457–1461 (2009).
   PubMed Web of Science ®Google Scholar
• Jacobetz MA , ChanDS, NeesseAet al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut62(1), 112–120 (2013).
   PubMed Web of Science ®Google Scholar
• Venning FA , WullkopfL, ErlerJT. Targeting ECM disrupts cancer progression. Front. Oncol.5, 224 (2015).
   PubMed Web of Science ®Google Scholar
• Reardon DA , AkabaniG, ColemanREet al. Phase II trial of murine (131)I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas. J. Clin. Oncol.20(5), 1389–1397 (2002).
   PubMed Web of Science ®Google Scholar
• Johnson DR , O’NeillBP. Glioblastoma survival in the United States before and during the temozolomide era. J. Neurooncol.107(2), 359–364 (2012).
   PubMed Web of Science ®Google Scholar
• Badruddoja MA , ReardonDA, AkabaniGet al. Phase II trial of iodine 131-labeled murine anti-tenascin monoclonal anti-body 81C6 (M81C6) via surgically created resection cavity in the treatment of patients with recurrent malignant brain tumors. J. Clin. Oncol.22(14 Suppl.), 1569–1569 (2004).
   Web of Science ®Google Scholar
• NCT00615186. Bradmer Pharmaceuticals Inc. https://clinicaltrials.gov/ct2/show/NCT00615186.
   Google Scholar
• Cox TR , BirdD, BakerAMet al. LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Res.73(6), 1721–1732 (2013).
   PubMed Web of Science ®Google Scholar
• Hecht JR , BensonAB3rd, VyushkovD, YangY, BendellJ, VermaU. A Phase II, randomized, double-blind, placebo-controlled study of simtuzumab in combination with FOLFIRI for the second-line treatment of metastatic KRAS mutant colorectal adenocarcinoma. Oncologist22(3), 243–e23 (2017).
   PubMed Web of Science ®Google Scholar
• Benson AB 3rd , WainbergZA, HechtJRet al. A Phase II randomized, double-blind, placebo-controlled study of simtuzumab or placebo in combination with gemcitabine for the first-line treatment of pancreatic adenocarcinoma. Oncologist22(3), 241–e15 (2017).
   PubMed Web of Science ®Google Scholar
• Miller BW , MortonJP, PineseMet al. Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. EMBO Mol. Med.7(8), 1063–1076 (2015).
   PubMed Web of Science ®Google Scholar
• Shiga K , HaraM, NagasakiT, SatoT, TakahashiH, TakeyamaH. Cancer-associated fibroblasts: their characteristics and their roles in tumor growth. Cancers (Basel)7(4), 2443–2458 (2015).
   PubMed Web of Science ®Google Scholar
• Orimo A , GuptaPB, SgroiDCet al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell121(3), 335–348 (2005).
   PubMed Web of Science ®Google Scholar
• Dvorak HF . Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med.315(26), 1650–1659 (1986).
   PubMed Web of Science ®Google Scholar
• Tomasek JJ , GabbianiG, HinzB, ChaponnierC, BrownRA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell Biol.3(5), 349–363 (2002).
   PubMed Web of Science ®Google Scholar
• Polanska UM , OrimoA. Carcinoma-associated fibroblasts: non-neoplastic tumor-promoting mesenchymal cells. J. Cell Physiol.228(8), 1651–1657 (2013).
   PubMed Web of Science ®Google Scholar
• Egeblad M , EwaldAJ, AskautrudHAet al. Visualizing stromal cell dynamics in different tumor microenvironments by spinning disk confocal microscopy. Dis. Model Mech.1(2–3), 155–167; discussion 165 (2008).
   PubMed Web of Science ®Google Scholar
• Bergers G , BenjaminLE. Tumorigenesis and the angiogenic switch. Nat. Rev. Cancer3(6), 401–410 (2003).
   PubMed Web of Science ®Google Scholar
• Hashizume H , BalukP, MorikawaSet al. Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol.156(4), 1363–1380 (2000).
   PubMed Web of Science ®Google Scholar
• Huang Y , GoelS, DudaDG, FukumuraD, JainRK. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res.73(10), 2943–2948 (2013).
   PubMed Web of Science ®Google Scholar
• Wilson WR , HayMP. Targeting hypoxia in cancer therapy. Nat. Rev. Cancer11(6), 393–410 (2011).
   PubMed Web of Science ®Google Scholar
• Vivier E , UgoliniS, BlaiseD, ChabannonC, BrossayL. Targeting natural killer cells and natural killer T-cells in cancer. Nat. Rev. Immunol.12(4), 239–252 (2012).
   PubMed Web of Science ®Google Scholar
• Loeffler DA , JuneauPL, HeppnerGH. Natural killer-cell activity under conditions reflective of tumor micro-environment. Int. J. Cancer48(6), 895–899 (1991).
   PubMed Web of Science ®Google Scholar
• Jain RK . Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell26(5), 605–622 (2014).
   PubMed Web of Science ®Google Scholar
• Jain RK , FinnAV, KolodgieFD, GoldHK, VirmaniR. Antiangiogenic therapy for normalization of atherosclerotic plaque vasculature: a potential strategy for plaque stabilization. Nat. Clin. Pract. Cardiovasc. Med.4(9), 491–502 (2007).
   PubMedGoogle Scholar
• Klosowska-Wardega A , HasumiY, BurmakinMet al. Combined anti-angiogenic therapy targeting PDGF and VEGF receptors lowers the interstitial fluid pressure in a murine experimental carcinoma. PLoS ONE4(12), e8149 (2009).
   PubMed Web of Science ®Google Scholar
• Al-Abd AM , AlamoudiAJ, Abdel-NaimAB, NeamatallahTA, AshourOM. Anti-angiogenic agents for the treatment of solid tumors: potential pathways, therapy and current strategies – a review. J. Adv. Res.8(6), 591–605 (2017).
   PubMed Web of Science ®Google Scholar
• Folkman J . Anti-angiogenesis: new concept for therapy of solid tumors. Ann. Surg.175(3), 409–416 (1972).
   PubMed Web of Science ®Google Scholar
• Cao Y . Future options of anti-angiogenic cancer therapy. Chin. J. Cancer35, 21 (2016).
   PubMedGoogle Scholar
• Amin A , ErnstoffMS, InfanteJRet al. A Phase I study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) in combination with sunitinib, pazopanib, or ipilimumab in patients (pts) with metastatic renal cell carcinoma (mRCC). J. Clin. Oncol.31(15 Suppl.), TPS4593–TPS4593 (2013).
   Web of Science ®Google Scholar
• Amin A , PlimackER, InfanteJRet al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma (mRCC). J. Clin. Oncol.32(Suppl. 15), 5010 (2014).
   Google Scholar
• Nakahama K , IsaSI, TamiyaAet al. The association between chemotherapy immediately before nivolumab and outcomes thereafter. Anticancer Res.37(10), 5885–5891 (2017).
   PubMed Web of Science ®Google Scholar
• Wallin JJ , BendellJC, FunkeRet al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat. Commun.7, 12624 (2016).
   PubMed Web of Science ®Google Scholar
• MD Anderson Cancer Center . NCT03074513. https://clinicaltrials.gov/ct2/show/NCT03074513.
   Google Scholar
• Vall d’Hebron Institute of Oncology . NCT02982694. https://clinicaltrials.gov/ct2/show/NCT02982694.
   Google Scholar
• MD Anderson Cancer Center . NCT03175432. https://clinicaltrials.gov/ct2/show/NCT03175432.
   Google Scholar
• Dana-Farber Cancer Institute . NCT02724878. https://clinicaltrials.gov/ct2/show/NCT02724878.
   Google Scholar
• Hoffmann-La Roche . NCT02420821. https://clinicaltrials.gov/ct2/show/NCT02420821.
   Google Scholar
• Rini BI , PowlesT, ChenM, PuhlmannM, AtkinsMB. Phase 3 KEYNOTE-426 trial: pembrolizumab (pembro) plus axitinib versus sunitinib alone in treatment-naive advanced/metastatic renal cell carcinoma (mRCC). J. Clin. Oncol.35(15 Suppl.), TPS4597–TPS4597 (2017).
   Google Scholar
• Vesely MD , KershawMH, SchreiberRD, SmythMJ. Natural innate and adaptive immunity to cancer. Annu. Rev. Immunol.29, 235–271 (2011).
   PubMed Web of Science ®Google Scholar
• Dranoff G . Cytokines in cancer pathogenesis and cancer therapy. Nat. Rev. Cancer4(1), 11–22 (2004).
   PubMed Web of Science ®Google Scholar
• Pandya PH , MurrayME, PollokKE, RenbargerJL. The immune system in cancer pathogenesis: potential therapeutic approaches. J. Immunol. Res. 2016, 4273943 (2016).
   PubMed Web of Science ®Google Scholar
• Zha Z , BucherF, NejatfardAet al. Interferon-gamma is a master checkpoint regulator of cytokine-induced differentiation. Proc. Natl Acad. Sci. USA114(33), E6867–E6874 (2017).
   PubMed Web of Science ®Google Scholar
• Kaplan DH , ShankaranV, DigheASet al. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc. Natl Acad. Sci. USA95(13), 7556–7561 (1998).
   PubMed Web of Science ®Google Scholar
• Eppihimer MJ , GunnJ, FreemanGJet al. Expression and regulation of the PD-L1 immunoinhibitory molecule on microvascular endothelial cells. Microcirculation9(2), 133–145 (2002).
   PubMed Web of Science ®Google Scholar
• Taube JM , AndersRA, YoungGDet al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl. Med.4(127), 127ra137 (2012).
   Web of Science ®Google Scholar
• Herbst RS , SoriaJC, KowanetzMet al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature515(7528), 563–567 (2014).
   PubMed Web of Science ®Google Scholar
• Ribas A , RobertC, HodiFSet al. Association of response to programmed death receptor 1 (PD-1) blockade with pembrolizumab (MK-3475) with an interferon-inflammatory immune gene signature. J. Clin. Oncol.33(15 Suppl.), 3001–3001 (2015).
   Web of Science ®Google Scholar
• Ferrantini M , CaponeI, BelardelliF. Interferon-alpha and cancer: mechanisms of action and new perspectives of clinical use. Biochimie89(6–7), 884–893 (2007).
   PubMed Web of Science ®Google Scholar
• Popovic LS , Matovina-BrkoG, PopovicM. Checkpoint inhibitors in the treatment of urological malignancies. ESMO Open2(2), e000165 (2017).
   PubMed Web of Science ®Google Scholar
• Motzer RJ , HutsonTE, TomczakPet al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N. Engl. J. Med.356(2), 115–124 (2007).
   PubMed Web of Science ®Google Scholar
• Parker BS , RautelaJ, HertzogPJ. Antitumour actions of interferons: implications for cancer therapy. Nat. Rev. Cancer16(3), 131–144 (2016).
   PubMed Web of Science ®Google Scholar
• Minasian LM , MotzerRJ, GluckL, MazumdarM, VlamisV, KrownSE. Interferon alfa-2a in advanced renal cell carcinoma: treatment results and survival in 159 patients with long-term follow-up. J. Clin. Oncol.11(7), 1368–1375 (1993).
   PubMed Web of Science ®Google Scholar
• Negrier S , EscudierB, LassetCet al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d’Immunotherapie. N. Engl. J. Med.338(18), 1272–1278 (1998).
   PubMed Web of Science ®Google Scholar
• Taniguchi T , MatsuiH, FujitaTet al. Structure and expression of a cloned cDNA for human interleukin-2. Nature302(5906), 305–310 (1983).
   PubMed Web of Science ®Google Scholar
• Boyman O , SprentJ. The role of interleukin-2 during homeostasis and activation of the immune system. Nat. Rev. Immunol.12(3), 180–190 (2012).
   PubMed Web of Science ®Google Scholar
• Kryczek I , WeiS, ZouLet al. Cutting edge: Th17 and regulatory T-cell dynamics and the regulation by IL-2 in the tumor microenvironment. J. Immunol.178(11), 6730–6733 (2007).
   PubMed Web of Science ®Google Scholar
• Rosenberg SA , YangJC, TopalianSLet al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA271(12), 907–913 (1994).
   PubMed Web of Science ®Google Scholar
• SEER, National Cancer Institute . Cancer stat facts: kidney and renal pelvis cancer. http://seer.cancer.gov/statfacts/html/kidrp.html.
   Google Scholar
• Fyfe G , FisherRI, RosenbergSA, SznolM, ParkinsonDR, LouieAC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J. Clin. Oncol.13(3), 688–696 (1995).
   PubMed Web of Science ®Google Scholar
• Belldegrun AS , KlatteT, ShuchBet al. Cancer-specific survival outcomes among patients treated during the cytokine era of kidney cancer (1989–2005): a benchmark for emerging targeted cancer therapies. Cancer113(9), 2457–2463 (2008).
   PubMed Web of Science ®Google Scholar
• Atkins MB , LotzeMT, DutcherJPet al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J. Clin. Oncol.17(7), 2105–2116 (1999).
   PubMed Web of Science ®Google Scholar
• Curotto de Lafaille MA , LafailleJJ. Natural and adaptive foxp3+ regulatory T-cells: more of the same or a division of labor?Immunity30(5), 626–635 (2009).
   PubMed Web of Science ®Google Scholar
• Zou W . Regulatory T-cells, tumour immunity and immunotherapy. Nat. Rev. Immunol.6(4), 295–307 (2006).
   PubMed Web of Science ®Google Scholar
• Oleinika K , NibbsRJ, GrahamGJ, FraserAR. Suppression, subversion and escape: the role of regulatory T-cells in cancer progression. Clin. Exp. Immunol.171(1), 36–45 (2013).
   PubMed Web of Science ®Google Scholar
• Galon J , CostesA, Sanchez-CaboFet al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science313(5795), 1960–1964 (2006).
   PubMed Web of Science ®Google Scholar
• Pages F , BergerA, CamusMet al. Effector memory T-cells, early metastasis, and survival in colorectal cancer. N. Engl. J. Med.353(25), 2654–2666 (2005).
   PubMed Web of Science ®Google Scholar
• Vignali DA , CollisonLW, WorkmanCJ. How regulatory T-cells work. Nat. Rev. Immunol.8(7), 523–532 (2008).
   PubMed Web of Science ®Google Scholar
• Facciabene A , MotzGT, CoukosG. T-regulatory cells: key players in tumor immune escape and angiogenesis. Cancer Res.72(9), 2162–2171 (2012).
   PubMed Web of Science ®Google Scholar
• Fallarino F , GrohmannU, HwangKWet al. Modulation of tryptophan catabolism by regulatory T-cells. Nat. Immunol.4(12), 1206–1212 (2003).
   PubMed Web of Science ®Google Scholar
• de Coana YP , WolodarskiM, PoschkeIet al. Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T-cells in long-term survivors with advanced melanoma. Oncotarget8(13), 21539–21553 (2017).
   PubMedGoogle Scholar
• Nocentini G , RonchettiS, CuzzocreaS, RiccardiC. GITR/GITRL: more than an effector T-cell co-stimulatory system. Eur. J. Immunol.37(5), 1165–1169 (2007).
   PubMed Web of Science ®Google Scholar
• Igarashi H , CaoY, IwaiHet al. GITR ligand-costimulation activates effector and regulatory functions of CD4+ T-cells. Biochem. Biophys. Res. Commun.369(4), 1134–1138 (2008).
   PubMed Web of Science ®Google Scholar
• Coe D , BegomS, AddeyC, WhiteM, DysonJ, ChaiJG. Depletion of regulatory T-cells by anti-GITR mAb as a novel mechanism for cancer immunotherapy. Cancer Immunol. Immunother.59(9), 1367–1377 (2010).
   PubMed Web of Science ®Google Scholar
• Aida K , MiyakawaR, SuzukiKet al. Suppression of Tregs by anti-glucocorticoid induced TNF receptor antibody enhances the antitumor immunity of interferon-alpha gene therapy for pancreatic cancer. Cancer Sci.105(2), 159–167 (2014).
   PubMed Web of Science ®Google Scholar
• Lu L , XuX, ZhangB, ZhangR, JiH, WangX. Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs. J. Transl. Med.12, 36 (2014).
   PubMed Web of Science ®Google Scholar
• Leap Therapeutics, Inc. NCT01239134. https://clinicaltrials.gov/ct2/show/NCT01239134.
   Google Scholar
• MedImmune LLC . NCT02583165. https://clinicaltrials.gov/ct2/show/NCT02583165.
   Google Scholar
• Incyte Corporation . NCT02697591. https://clinicaltrials.gov/ct2/show/NCT02697591.
   Google Scholar
• Munn DH , ZhouM, AttwoodJTet al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science281(5380), 1191–1193 (1998).
   PubMed Web of Science ®Google Scholar
• Moon YW , HajjarJ, HwuP, NaingA. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J. Immunother. Cancer3(1), 51 (2015).
   PubMedGoogle Scholar
• Platten M , WickW, Van den EyndeBJ. Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res.72(21), 5435–5440 (2012).
   PubMed Web of Science ®Google Scholar
• Uyttenhove C , PilotteL, StroobantV, ColauD, ParmentierN, BoonT. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat. Med.9(10), 1269 (2003).
   PubMed Web of Science ®Google Scholar
• Chuang S-C , FanidiA, UelandPMet al. Circulating biomarkers of tryptophan and the kynurenine pathway and lung cancer risk. Cancer Epidemiol. Prevent. Biomarkers23(3), 461–468 (2014).
   PubMed Web of Science ®Google Scholar
• Brandacher G , PerathonerA, LadurnerRet al. Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T-cells. Clin. Cancer Res.12(4), 1144–1151 (2006).
   PubMed Web of Science ®Google Scholar
• Ino K , YoshidaN, KajiyamaHet al. Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer. Br. J. Cancer95(11), 1555 (2006).
   PubMed Web of Science ®Google Scholar
• Okamoto A , NikaidoT, OchiaiKet al. Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clin. Cancer Res.11(16), 6030–6039 (2005).
   PubMed Web of Science ®Google Scholar
• Pan K , WangH, ChenM-set al. Expression and prognosis role of indoleamine 2,3-dioxygenase in hepatocellular carcinoma. J. Cancer Res. Clin. Oncol.134(11), 1247–1253 (2008).
   PubMed Web of Science ®Google Scholar
• Laimer K , TroesterB, KlossFet al. Expression and prognostic impact of indoleamine 2,3-dioxygenase in oral squamous cell carcinomas. Oral Oncol.47(5), 352–357 (2011).
   PubMed Web of Science ®Google Scholar
• Ino K , YamamotoE, ShibataKet al. Inverse correlation between tumoral indoleamine 2,3-dioxygenase expression and tumor-infiltrating lymphocytes in endometrial cancer: its association with disease progression and survival. Clin. Cancer Res.14(8), 2310–2317 (2008).
   PubMed Web of Science ®Google Scholar
• Witkiewicz AK , CostantinoCL, MetzRet al. Genotyping and expression analysis of IDO2 in human pancreatic cancer: a novel, active target. J. Am. Coll. Surg.208(5), 781–787 (2009).
   PubMed Web of Science ®Google Scholar
• Hamid O , SchmidtH, NissanAet al. A prospective Phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J. Translat. Med.9(1), 204 (2011).
   PubMedGoogle Scholar
• Beatty GL , O’DwyerPJ, ClarkJet 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).
   Web of Science ®Google Scholar
• Gangadhar TC , SchneiderBJ, BauerTMet al. Efficacy and safety of epacadostat plus pembrolizumab treatment of NSCLC: preliminary Phase I/II results of ECHO-202/KEYNOTE-037. J. Clin. Oncol.35(Suppl. 15), 9014 (2017).
   Google Scholar
• Hamid O , BauerTM, SpiraAIet al. Epacadostat plus pembrolizumab in patients with SCCHN: preliminary Phase I/II results from ECHO-202/KEYNOTE-037. J. Clin. Oncol.35(Suppl. 15), 6010 (2017).
   Google Scholar
• Lara P , BauerTM, HamidOet al. Epacadostat plus pembrolizumab in patients with advanced RCC: preliminary Phase I/II results from ECHO-202/KEYNOTE-037. J. Clin. Oncol.35(Suppl. 15), 4515 (2017).
   Google Scholar
• Smith DC , GajewskiT, HamidOet al. Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: preliminary Phase I/II results of ECHO-202/KEYNOTE-037. J. Clin. Oncol.35(Suppl. 15), 4503 (2017).
   Google Scholar
• Gangadhar T , HamidO, SmithDet al. Epacadostat plus pembrolizumab in patients with advanced melanoma and select solid tumors: Updated Phase 1 results from ECHO-202/KEYNOTE-037. Ann. Oncol.27(Suppl. 6), (2016).
   Google Scholar
• Perez RP , RieseMJ, LewisKDet al. Epacadostat plus nivolumab in patients with advanced solid tumors: preliminary Phase I/II results Of ECHO-204. J. Clin. Oncol.35(Suppl. 15), 3003 (2017).
   Google Scholar
• Spira AI , HamidO, BauerTMet al. Efficacy/safety of epacadostat plus pembrolizumab in triple-negative breast cancer and ovarian cancer: Phase I/II ECHO-202 study. J. Clin. Oncol.35(Suppl. 15), 1103 (2017).
   PubMedGoogle Scholar
• NCT02178722. Incyte Corporation . https://clinicaltrials.gov/ct2/show/NCT02178722.
   Google Scholar
• The ASCO Post . Epacadostat combined with pembrolizumab in patients with unresectable or metastatic melanoma. www.ascopost.com/News/58726.
   Google Scholar