简介：Therehavebeenexponentialgainsinimmuno-oncologyinrecenttimesthroughthedevelopmentofimmunecheckpointinhibitors.AlreadyapprovedbytheU.S.FoodandDrugAdministrationforadvancedmelanomaandnon-smallcelllungcancer,immunecheckpointinhibitorsalsoappearstohavesignificantantitumoractivityinmultipleothertumortypes.Anexcitingcomponentofimmunotherapyisthedurabilityofantitumorresponsesobserved,withsomepatientsachievingdiseasecontrolformanyyears.Nevertheless,notallpatientsbenefit,andeffortsshouldthusnowfocusonimprovingtheefficacyofimmunotherapythroughtheuseofcombinationapproachesandpredictivebiomarkersofresponseandresistance.Therearemultiplepotentialrationalcombinationsusinganimmunotherapybackbone,includingexistingtreatmentssuchasradiotherapy,chemotherapyormolecularlytargetedagents,aswellasotherimmunotherapeutics.Theaimofsuchantitumorstrategieswillbetoraisethetailonthesurvivalcurvebyincreasingthenumberoflongtermsurvivors,whilemanaginganyadditiveorsynergistictoxicitiesthatmayarisewithimmunotherapycombinations.Rationaltrialdesignsbasedonaclearunderstandingoftumorbiologyanddrugpharmacologyremainparamount.Thisarticlereviewsthebiologyunderpinningimmuno-oncology,discussesexistingandnovelimmunotherapeuticcombinationscurrentlyindevelopment,thechallengesofpredictivebiomarkersofresponseandresistanceandtheimpactofimmuno-oncologyonearlyphaseclinicaltrialdesign.

简介：Acutemyeloidleukemia(AML)ischaracterizedbytheaccumulationofcirculatingimmatureblaststhatexhibituncontrolledgrowth,lacktheabilitytoundergonormaldifferentiation,andhavedecreasedsensitivitytoapoptosis.Accumulatingevidenceshowsthebonemarrow(BM)nicheiscriticaltothemaintenanceandretentionofhematopoieticstemcells(HSC),includingleukemiastemcells(LSC),andanincreasingnumberofstudieshavedemonstratedthatcrosstalkbetweenLSCandthestromalcellsassociatedwiththisnichegreatlyinfluencesleukemiainitiation,progression,andresponsetotherapy.Undeniably,stromalcellsintheBMnicheprovideasanctuaryinwhichLSCcanacquireadrug-resistantphenotypeandtherebyevadechemotherapyinduceddeath.YinandYang,theancientChinesephilosophicalconcept,vividlyportraystheintricateanddynamicinteractionsbetweenLSCandtheBMniche.Infact,LSC-inducedmicroenvironmentalreprogrammingcontributessignificantlytoleukemogenesis.Thus,identifyingthecriticalsignalingpathwaysinvolvedintheseinteractionswillcontributetotargetoptimizationandcombinatorialdrugtreatmentstrategiestoovercomeacquireddrugresistanceandpreventrelapsefollowingtherapy.Inthisreview,wedescribesomeofthecriticalsignalingpathwaysmediatingBMniche-LSCinteraction,includingSDF1/CXCL12,Wnt/β-catenin,VCAM/VLA-4/NF-κB,CD44,andhypoxiaasanewly-recognizedphysicaldeterminantofresistance,andoutlinetherapeuticstrategiesforovercomingtheseresistancefactors.