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TEN YEARS OF ACCELERATING CURES: Highlights from the Melanoma Research Alliance 10th Annual Scientific Retreat
2018
CONTENTS
1
LetterfromChiefScienceOfficerand ScientificProgramDirector 02
FutureChallengesInMelanoma 03
OptimizingtheUseofImmunotherapy 07
MRAResearchersExploringaDiverstity ofTreatmentStrategies 09
TacklingBrainMetastases 11
ApplyingArtificialIntelligencetoMelanomaDetection 13
MaintainingthePaceofMelanomaInnovationinthe EraofanEvolvingStandardofCare 14
Agenda 15
ParticipantList 19
RetreatSponsors 30
For the Melanoma Research Alliance (MRA), promoting collaboration and conversation among key stakeholders in the melanoma community is central to our mission. One way MRA achieves this is through our Annual Scientific Retreat, which this year was held February 28-March 2, 2018, in Washington, D.C, and marked the tenth anniversary of this important gathering. This invitation-only, think-tank style conference brings together nearly 300 academic investigators, pharmaceutical and biotech representatives, government officials, donors, and patient advocates.
At MRA’s Tenth Annual Scientific Retreat, participants heard about the latest discoveries in melanoma prevention, diagnosis, and treatment, many of which are being made by MRA-funded investigators. They also learned firsthand from individuals personally affected by melanoma and discussed ways in which the different sectors of the melanoma community can work together to ensure the momentum of the past decade of discoveries and treatment approvals continues.
Presentations and panel discussions touched on a variety of topics, spanning early discovery research to the latest changes in clinical practice. Researchers provided new insights into how melanoma metastasizes, including identifying new therapeutic targets. They also discussed factors that may influence whether patients will respond to immunotherapy, which include such things as the composition of a patient’s gut microbiome. Other highlights included recent practice changing results that emerged in the past year that impact patients with later stage, surgically removable melanoma. Together, the presentations highlighted the incredible progress of the past decade and illuminated the path forward so that all melanoma patients may have an effective therapy.
The Scientific Retreat also featured several satellite sessions, including the Young Investigators’ Breakfast and the Industry Roundtable, which engaged participants in conversations around effective collaboration and maintaining the rapid pace of progress in preventing, diagnosing, and treating melanoma, repectively. A group of melanoma patient advocates also gathered to learn from one another and to hear updates on the latest science from leading melanoma researchers.
We at MRA are delighted to host such important and productive conversations. We know they will spur the next wave of progress and lead to a day when suffering and death from melanoma will be a thing of the past.
Sincerely,
LETTER FROM CHIEF SCIENCE OFFICER AND SCIENTIFIC PROGRAM DIRECTOR
Louise M. Perkins, Ph.D. Chief Science Officer
Louise M. Perkins, Ph.D. Chief Science Officer
Kristen L. Mueller, Ph.D.Scientific Program Director
Kristen L. Mueller, Ph.D.Scientific Program Director
2
3
FUTURE CHALLENGES IN MELANOMA
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4
TenyearsagowhenSamanthaStinchcomb’sfatherwasdiagnosedwithadvancedmelanoma,hisdoctortoldhisfamilytherewaslittlethattheycoulddotosavehislife.Hediedafewyearslater.“Fewerpatientsandtheirfamiliesarebeingtoldthatanymore,”Samanthatoldtheaudienceatthe10thAnnualMelanomaResearchAllianceScientificRetreatheldinWashington,DC,February28-March2,2018.
Thisthemeofprogressagainstthebackdropoffuturechallengesechoedthroughoutthe10thAnnualRetreat.FromtheopeninglecturebyDr.SuzanneTopalianon“ADecadeofProgressinMelanoma”totheIndustryRoundtablethatfocusedon“MaintainingthePaceofMelanomaInnovationintheEraofanEvolvingStandardofCare”–successesandremainingchallengeswereputinfocus.
Intheopeninglecture,Topalian,ofJohnsHopkinsUniversity,summeduptheadvancementssaying“thisishead-spinningprogress.”Tenyearsago,advancedmelanomapatientsonlyhadthreetreatmentoptions,andnoneofthemwerethateffective.Now,incontrast,thereare11FDA-approvedtherapiesforthissamegroupofpatientsandabouthalfofthesepeopleexperiencesubstantialbenefit.
ButTopalianandseveralotherclinicianswerequicktopointout,thatwhiletheglassishalffull,itisalsohalfempty.Inshort–toomanypatientswithmetastaticmelanomastilldiefromthiscancer.Overhalfofpatientswithcutaneousmelanomaeitherfailtorespondorrelapseearly,despitereceivingthelatesttreatments.Moreoveritisstillparticularlydangerousforpatientswithocular,acral,orotherrareformsofmelanoma,forwhomcurrenttreatmentsarenotusuallyaseffectiveastheyareforthemorecommoncutaneousmelanomasthatariseonsun-exposedpartsoftheskin.“Therearestillpocketsofneedthathavetobeaddressed,”notedDr.JeddWolchokofMemorialSloanKetteringCancerCenter.
Putting MRA Out of BusinessAtthisgatheringof300ofthebestandbrightestmelanomaclinicians,researchers,advocatesandotherkeysstakeholders,muchofthediscussionfocusedonwhatneedstobedonenexttocuremelanomaand“putMRAoutofbusinessassoonaspossible,”asMRAco-founderDebraBlacksuccinctlyputsit.Ideaswereplentiful;includingfurtheringourunderstandingofthebiologyofrare,hard-to-treatmelanomasubtypesandthetumormicroenvironment,whichcontainsavarietyofcelltypesthatcanimpactonwhetheratherapywillwork,aswellasdevelopingbetterwaystopredictwhichpatientsarelikelytorespondtowhichtreatments.Improvingtheunderstandingandtreatmentofdrugresistancealsocontinuestobeamajorfocusofresearch,alongwithdeterminingwhichdrugstocombinetobesttreatmelanomapatients.
Stopping Melanoma From Coming BackParticipantsalsostressedtheimportanceofpursuingearlier-stagetreatmentavenuesthatarecurrentlygainingmomentumintheclinic.Oneistreatingpatientswithhighrisk,butsurgicallyremovablemelanomas,withvarioustherapiestoreducetheriskofmelanomacomingback(adjuvanttherapy).Sometherapies,suchasinterferon,ipilimumab,nivolumabandcombinationDabrafenibandTrametinib,arealreadyapprovedintheadjuvantsetting,andothertreatmentshaveshownpromisingresultsinrecentclinicaltrials.Asecond,relatedstrategy,calledneoadjuvanttherapy,involvestreatingmelanomapatientstoreducethepresenceofcancerpriortoremovingtheirtumorssurgically.
Samantha Stinchcomb
Suzanne Topalian
5
FUTURE CHALLENGES IN MELANOMA (CONT.)
Earlyclinicalresultsforneoadjuvanttherapyshowrealpromise;however,noneoadjuvanttherapiesarecurrentlyFDA-approved.Giventhegame-changingnatureoftheseapproaches,expertsstressedtheimportanceofdesigningclinicaltrialsandstudiesinawaythatrevealhowthedrugsareworkinginmelanomaandthesurroundingcellularenvironments.Thiscouldbecriticalinformationtoimprovethewaywetreatmelanomaforallpatients.
When Should Patients Stop Treatment?Anotherconceptthatgeneratedbuzzamongparticipantswaswhenandhowtostopdrugtherapyformelanomapatients.Forexample,theimmunotherapydrugsnivolumabandpembrolizumabaregiventopatientsuntildiseaseprogressionorunacceptablesideeffectsdevelop.Withinfusionsrequiredevery2-4weeksdependingonthedoseanddrug,thisisasubstantialburden,especiallyforthosepatientswhorespondlong-term.Putbluntly,researchersjustdon’tknowhowlongthesedrugsneedtobetakentobemosteffective.Dr.PatrickHwuoftheMDAndersonCancerCenterstressedthatstoppingsuchtreatmentsshouldbeaccompaniedbysurveillanceforearlyrecurrenceofmelanoma,butalsonotedthatweneedbetter,noninvasivemethodstodetectrecurrence.OnepromisingwaytodothismightbetouseatestformelanomatumorDNAcirculatingintheblood,knownasliquidbiopsies.Anearlyclinicaltestofthisincoloncancerenableddoctorstodetectarecurrenceupto6monthspriortothecancerbeingseeninascan.Inaddition,Topalian,Wolchok,andDr.GeorginaLongoftheUniversityofSydneystressedtheneedto
researchwhetherperiodic‘booster’treatmentswouldimprovethelong-termeffectivenessofmelanomadrugs,particularlywithinthecontextofimmunotherapies.
Aligning Basic and Clinical ResearchDr.RichardMaraisofCancerResearchUKManchesterInstitutepointedoutthatthefastpaceofmelanomaresearchrequiresfrequentinteractionbetweenbasicandclinicalresearchers.HenotedthatthelaboratoryworkdelineatingthemolecularpathwaysthatdrivemelanomaledustotargetedtherapiesknownasBRAFandMEKinhibitorsandimmunotherapies,andsuggestwaystoovercometreatmentresistance.Maraisstressedthecontinuedneedtounderstandthebasicbiologyofmelanomaanditstreatments,andforbasicbiologyresearcherstoexploreanswerstoquestionsthatarerelevanttoclinicians.“AnamazingMRAachievementhasbeentocreateacommunitywherebasicandclinicalresearcherscanmeet.Thediscussionswe’vehadherewillcontinueatothermeetings,”Maraissaid.AsMRAPresidentandCEOMichaelKaplanstressedinhisclosingstatementattheretreat,“Wetakeseriouslytheword‘Alliance’inMRA’sname.”
Collaborating for SuccessTheneedforevermorecollaborationamongmultiplesectorswasstressedbyalltypesofstakeholders,includingrepresentativesfromindustryandthefederalgovernment,aswellasbyacademicresearchersandpatients.Drs.RichardPazdurandMarcTheoretoftheFDAnotedthecollaborationstheiragencyfosteredsothatseveralcancerbiomarkersordrugsfrommultiplecompaniescanbetestedconcurrentlyinthesameclinicalstudy.TheFDAhasalsobeguninteractingwithdrugcompaniesearlierinthedrugdevelopmentprocesstoensuredrugsponsorscollecttheinformationneededforregulatorydecisions.
Severalindustryparticipantsnotedthenumerousstudiesalreadyunderwayinwhichdrugcompaniesarecollaboratingwitheachothertoclinicallytestcombinationtherapies,andDr.EladSharonfromtheNationalCancerInstitute(NCI)notedthathisagencyworkscloselywiththeFDAandpharmaceuticalcompaniestomakesuregovernment-sponsoredtrialsareinnovativeandnotduplicatingwhatindustrycandoonitsown.“Thereisanunprecedentedlevelofcollaborationnow,”Pazdurnoted,butadded“everyonehastheirownfavoritedrugthattheywanttotest.”HesuggestedNCIcouldhelpensurethatthemostpromisingcombinationsareenteringclinicaltrials.
“Weneedtobreakdownthecommercialbarrierssowecangetthemoleculestogetherthatwillgiveusthebestoutcome,”saidLong,andshealongwithDr.CarolineRobertofInstitutGustaveRoussyaddedtheimportanceofsharingdatainordertostreamlinethedevelopmentofdrugsandbiomarkerteststhatwouldhelpphysiciansgivetherighttreatmenttotherightpatient.Georgina Long
6
Designing Clinical Trials of the FutureTheFDAalongwithacademicandindustryscientistsareworkinghand-in-handtoensurethatclinicaltrialsareproducingthehighestqualitydatapossiblewhilebalancingtheneedtogetlifesavingtreatmentstothepeoplewhoneedthemthemostasquicklyaspossible.TheFDAhasdemonstrateditswillingnesstobeflexibleinthetypesofdataandstudiesitwillacceptforitsapprovalofnewcancerdrugssoastospeedtheentryofneweffectivetreatmentsintotheclinic.AccordingtoPazdur:“Itusedtobethatyouhadtopresentdatafromarandomized,controlledtrialorgohome,butthat’snolongerthecase.”
Inclinicaltrials,anendpointistheprimaryoutcomethatisbeingmeasured.Inoncology,thisisoftenacomparisonofthedurationofpatientsurvivalorlengthoftimebeforeprogressionusingtheexperimentaltherapycomparedtothoseusingthestandardofcare.Severalresearchersadvocatedfortheneedtodevelopadditionalendpointsinclinicaltrialstodetermineifatreatmentiseffective.Thesecouldbepatient-reportedoutcomes,circulatingtumormarkersorameasureoftumorcellsintissuesamplesremovedduringsurgeryorbiopsy.Suchexpandeddefinitions ofsuccesswillfurtheracceleratethedevelopmentofnewmelanomatreatments.
Mostclinicaltrialssetstricteligibilitycriteriainordertominimizetheeffectofotherfactorsthatcouldobscuretheeffectoftheexperimentaldrug.However,strictcriteriarestrictpatientenrollment,limitaccesstotheexperimentaltherapy,andmaymaketrialresultslessgeneralizabletoreal-worldpatientpopulations.Forexample,abouthalfoflate-stagemelanomapatientshavebrainmetastaseshoweverpeoplewithbrainmetastaseshavebeenhistoricallyexcludedfrommoststudies.Severalresearchersadvocatedforadoptingmodernizedclinical
trialeligibilitycriteriatoincludethesegroupsandotherstobothspeeddrugdevelopmentandprovidebetterinsightintoefficacyandside-effectsearlier.
Bringing Research HomeWhenSamanthaStinchcomb’sfatherdiedin2010,shethoughtthechapterofherlifethatintersectedwithmelanomawasover.Sadly,thathasnotbeenthecase.Fartoooften,saidStinchcomb,sheleavesherdermatologist’sofficeintearsbecauseofthenumerousprecancerousmolesdetectedonherskinthatwilllaterneedtoberemoved.Sheiscomfortedbytheincredibleprogressbeingmadeinthetreatmentoflate-stagedisease,butknowsthatmoreworkisneededtoensuretheendofsufferinganddeathduetomelanomaonceandforall.“Researchtoendmelanomasoundsgoodtome.Yourworkmeansmoretomorrows,”saidStinchcomb.
Richard Pazdur
“ Research to end melanoma sounds good to me. Your work means more tomorrows”
Debra Black
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Perhapsthedecade’sgreatestachievementinmelanomatreatmenthasbeentheFDAapprovalofcancerimmunotherapytreatmentscalledcheckpointinhibitors.Thisclassofdrugsincludeipilimumab,nivolumabandpembrolizumab.Thesetherapiesharnessthepoweroftheimmunesystemtofendoffdisease–includingmelanoma.Manypatientstreatedwiththesedrugsexperiencedurableresponses,andinafractionofpatientsexpertssuspectthedrugsarecurative.
Predicting Response and RecurrenceWhileimmunotherapyhasbeenanincredibleadvance,thereisstillroomforimprovement.Forexample,onlyabouthalfofpatientswithadvancedmelanomarespondtothesetreatments,andinsomecases,patientsmaynotseetheirtumorsstarttoshrinkuntilseveralmonthsafterstartingtherapy.Thisisproblematicbecausesomepatientswithadvanceddiseasehavewidespreadandbulkytumors.Inaddition,immunotherapycansometimestriggerserious,andattimesirreversible,autoimmuneconditionssuchasthyroiddysfunctionordiabetes.Researchersdonotyetunderstandwhysomepeopledevelopthesesideeffectsandothersdonot.Thisisespeciallyimportantasphysiciansincreasinglyturntoadjuvantimmunotherapyforearly-stagemelanomapatients,whereasubstantialfractionofpatientsmayneverexperiencearecurrenceaftertheirprimarymelanomaisremoved.
“We’vemadetremendousprogressinthetreatmentofcancerwithimmunotherapy,butresponsesaren’tuniversalandnotalwaysdurable,soweneed[betterpredictive]markersofresponse,”stressedDr.JenniferWargoofMDAndersonCancerCenter.
Tohelpunderstandwhichpatientswithadvancedmelanomawillbenefitfromimmunotherapy,researchersaretryingtoidentifymolecularfeatures–calledbiomarkers–intumorsorinthepatient’simmunecellsthatcanpredictaneffectiveresponsetotreatment.Forpatientswithearly-stagemelanoma,researchersaresearchingforbiomarkersthatindicatehighrecurrencerisk.SeveralMRA-fundedresearchersreportedontheirgroundbreakingeffortstofindthesebiomarkersatthelatest MRAscientificretreat.
TotrytoidentifybiomarkersthatcanpredictriskofrecurrenceinStage2or3surgicallyremovablemelanoma,Dr.YvonneSaengerofColumbiaUniversityinNewYorkCityexaminedpatients’tumorsamples.Shediscoveredthataparticularpatternofgeneexpression,aswellasthepresenceofonetypeofimmunecell,calleda‘killer’Tcell,andtheabsenceofanother,calledamacrophage,werecorrelatedwithagreaterlikelihoodoflong-termsurvival.“Wehopethiswillhelppatientsdecidewhether theyshouldget[adjuvant]immunotherapyaftersurgery,” Saengersaid.
Melanoma at Single Cell ResolutionDr.IdoAmitoftheWeizmannInstituteofScienceinIsraelpresentedhisworkusingpowerfulnewsinglecellsequencingandimagingtechnologieshedevelopedtodetermineinfinedetailthedifferentimmunecellsubtypeswithinandsurroundingtumors.“Whenwewantedtoidentifybiomarkersofrespondersversusnon-responderstotreatment,wesawacomplexzooofmanydifferenttypesofimmunecellsandfunctionsintumorsamplesthatcurrentmarkerscouldn’tdescribe,”hesaidwhenexplainingwhyhedevelopedthesetechniques.“Thetumormicroenviormentisextremelycomplex,yetunderstandingthesecellsandhow
OPTIMIZING THE USE OF IMMUNOTHERAPY
Ido Amit
Yvonne Saenger
8
theychangeinpatientsiscriticaltoidentifynewmarkersforrapidandeffectivetumorcharacterization,andidentificationofnovelimmunemodulatorypathways.”
OneofAmit’stechnologiescalled‘singlecellRNAsequencing’essentiallyprovidesasnapshotofallthegenesexpressedbyanindividualcellpluckedfromatumor.Theadvantageofthistechnologyisthatitgivesresearchersamuchmorecompletepictureofthecomplexnetworkofcellsthatmakeupatumoranditssurroundingtissue.Sofar,Amithasusedhistechniqueontumorsamplesfrom26patientswithmelanomaandhasuncovered“verydramaticdifferencesbetweenpatientsinthetypesofTcellsseenintheirtumors,”hesaid.Hisresearchidentifiedspecificpopulationsofimmunecells,someofwhichkilltumorsandothersthatblocktheanti-tumorimmuneresponse.“Oursingle-celltechnologiesprovideunprecedentedopportunitiestodrawamoreaccuratepictureofthevariouscelltypesandunderlyingtumor-immuneinteractionsandresponse totherapies,”.
Can the Microbiome Predict the Effectiveness of Immunotherapy?Otherpromisingtreatmentresponsebiomarkersarenotfoundonpatients’tumororimmunecells,butratherinthemorethan100trillionmicrobesthatinhabittheirbodies,especiallythosethatresideinthegut.Thisecosystemofmicrobes,collectivelyknownasthehumanmicrobiome,hasbecomeamajorfocusofcancerresearch,asmountingevidencerevealsitmayalterourriskofdevelopingvariouscancersandhowapatientmayrespondtoimmunotherapieslikepembrolizumab,nivolumab,andipilimumab.
Dr.ThomasGajewskioftheUniversityofChicagofoundthatcertainbacterialivinginthegutofmelanomapatientswerelinkedtopatients’abilitytorespondtoimmunotherapytargetingthePD-1molecule.Couldgutbacteriabeabiomarkerforresponsetoimmunotherapyinmelanomapatients?“It’scertainlyonparwith
otherbiomarkersenrichingforresponders,”Gajewskisaid,butaddedthat,“Themicrobiomeisn’teverything.Tumormutationfactorsmatter,andgermlinepolymorphismsarealsolikelyimportant.Butitcouldbeabetterbiomarkerthanmutationalloadandshouldbeexploredfurtherandintegratedwithothers.”
Inmousemodels,Gajewskifoundtransferringtheimmuneresponse-promotingbacteriatomicewithmelanomaviastooltransplantsimprovedtheirresponsetoimmunotherapy.Thissuggeststhatthemicrobiomemaynotonlyserveasaresponsebiomarker,butthatonedayprobioticsdesignedtocontain‘good’bacteriamayimprovethetreatmentofpatientswholackinflamedtumors.
Inanindependentsetofrelatedstudies,WargofoundthatthemicrobiomeofpatientswithmelanomawhorespondedtoPD-1-targetingimmunotherapydifferedfromthosewhodidnot.LikeGajewski,shealsofoundthatanabundanceofcertainbacteriainthegutcorrelatedwitha“hot”immuneresponsetotumors,whileahighabundanceofotherspecieslinkedtoa“cold”response.AbundantBifidobacteriumspeciesdidnotsurfaceasamajorindicatorofresponseinWargo’sstudies,asitdidinGajewski’sresearch.ButthemicrobialsignatureWargofoundthatindicatedaneffectiveresponsetoimmunotherapyhasalsobeenreportedbyresearchersstudyingpatientswithlungandkidneycancertreatedwithcheckpointinhibitors,Wargonoted.Sheandothersarecurrentlytestinganumberofstrategiestoseeiftheycanimproveresponsestoimmunotherapiesinmelanomaandothercancerpatients.“Canwemodulatethegutmicrobiometoenhanceresponsestoimmunotherapy?Yes!Butthatneedstobetestedwithinaclinicaltrial,”Wargostressed.
Thomas Gajewski
Jennifer Wargo
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Overthepast10years,wehavemadetremendousstridesinthetreatmentofmelanoma,with11newtreatmentsearningFDAapproval.Butlessthanhalfofpatientsrespondtothesetreatments,meaningthatthebattleagainstmelanomaisfarfromoverandmoretreatmentsaredesperatelyneeded.MRA-fundedresearchersarepursuingpromisingnewstrategies-likeblockingmelanomametastasis;findingnewdrugtargets;orputtinganolddiabetesdrugtoworkagainstmelanoma–tobettertreatandultimatelycuremelanoma.
Preventing Melanoma SpreadDr.MarisolSoengasoftheSpanishNationalCancerResearchCenterisworkingonbetterunderstandingwhysomepatientswithmelanomaseetheircancerspreadrapidlyfollowingsurgery,whileothersdon’t.Usinggeneticallyengineeredmouseandzebrafishmodels,whichenableliveimagingoftheearlymetastaticprocessasitunfolds,Soengas’teamdiscoveredaproteincalledMidkine,whichmelanomacellsproducebeforetheyspreadthroughoutthebody.Midkinehelpstorolloutthewelcomematformetastatictumorcellsbymakingthesesites‘permissive’locationswheretheycantakeupresidence,essentiallypavingthewayformetastasis.ThemoreMidkineproduced,theworsetheprognosisforthepatients.
Dr.AshaniWeeraratnaoftheWistarInstitute,amemberofSoengas’L’OrealParis–MRAteam,exploredtheeffectsofagingonmetastasis.Todothis,shecomparedatypeofskincellcalledfibroblastsfrompeople25to35yearsoldwiththosefromolderindividuals.Shefoundthatfibroblaststakenfromolderpeopleproducedanalteredarrayofproteinsthatpromotedmetastasis.Proteinsproducedbythese‘aged’fibroblastsinstructedtumorcellstomigratetoandcolonizelymphnodes,andpromotedthegrowthofbloodvesselsneededtosupportthegrowthoftumorcellsatmetastaticsites.SoengasandWeeraratnaplantotestexperimentaldrugsthattargettheseandothermetastasis-supportingmoleculesinclinicaltrials.
Blocking Tumor Escape
Dr.KaiWucherpfennigofDana-FarberCancerInstitutereportedonhislatestfindingsonMICA,amoleculefoundonthesurfaceofstressedordamagedcellsthatsignalstotheimmunesystemthatthesecellsshouldbekilled.TumorcellsaresmartandshedMICAfromtheirsurfacetoevadedeath.Infact,patientswhoshedhighamountsofMICArespondedpoorlytotheimmunecheckpointinhibitoripilimumab,suggestingthatsheddingMICAhelpsmelanomaevadetheanti-tumorimmuneresponse.Toovercomethis,WucherpfennigdevelopedanantibodythatinhibitsMICAsheddingbytumorcells.WhenWucherpfennigtestedtheantibodyinmicewithmelanoma,hefounditreducedthenumberoflungandlivermetastases.Wucherpfennigplanstostarttestingtheantibodyinpatientswithcancerwithinthenextyear,withthehopesitwillenhancetumorkillingbytheimmunesystem.
Adding Radiation Therapy to Enhance Checkpoint BlockadeDr.RobertVonderheideoftheUniversityofPennsylvania’sAbramsonCancerCenterexploredapotentialsynergisticcombinationtreatmentformelanoma—radiationtherapyfollowedbytreatmentwithimmunotherapy.Vonderheidewaspromptedtoexploreifradiationcouldjumpstartanimmuneresponseafterapatientwithadvancedmelanomawhodidnotrespondtotwodifferentimmunotherapyagentswasgivenradiationtherapytorelievepainhewasexperiencingfromatumorinhischest.Strikingly,thepatiententeredanearlycompleteremission,whichisstillongoingmorethan7yearslater.Moreover,asmallsubsetofpatientsexperiencedtumorregressioninanearlystageclinicaltrialtestingthecombinationofradiotherapyandtheFDA-approvedimmunotherapyipilimumab,suggestingthepromiseofthiscombinedapproach.
Vonderheideandhiscolleaguesnextturnedtomousemodelstobetterunderstandhowradiationtherapyandimmunotherapysynergize,andrevealpotentialcausesofwhythisapproachdoesn’tworkinallpatients.Forinstance,whentheresearcherscomparedtumorsthatrespondedtothecombinationofradiotherapyandtheCTLA-4inhibitoripilimumabtothosethatdidnot,theyfoundhighlevelsofamoleculecalledPD-L1onthesurfaceofnon-respondingtumorcells.AddingaPD-1inhibitor,similartonivolumaborpembrolizumabtoipilimumabandradiotherapyimprovedresponsesinmice.Thissuggeststhatathree-partcombinationmayleadtoimprovedresponsesinpatients.“Thebottomlineisthatthreetreatments—ananti-CTLA-4drug,ananti-PD-L1drug,andradiationallhavedifferentmechanismsofactionsoshouldbesynergisticwhencombined,”Vonderheidesaid.Heandhiscolleaguesarecurrentlytestingsuchcombinationsinmultipleclinicaltrials.
MRA RESEARCHERS EXPLORING A DIVERSITY OF TREATMENT STRATEGIES
Marisol Soengas
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Beyond BRAF MutationsMRA-fundedresearchersarealsoactivelypursuingnewtreatmentstrategiesthatfocusongeneticchangesinmelanomaitselfthatgobeyondBRAFgeneticmutations.Forexample,anothertumor-fuelingalterationinvolvesmoleculesthatinsteadareinvolvedinregulatinggeneactivityandtheproductionofproteinsthataffecttumorgrowth.Thereismountingevidencethatthesegene-regulating“epigenetic”factorscanplayamajorroleinfomentingcancersandthuscouldbeeffectivedrugtargetsformelanoma.
Dr.EmilyBernsteinoftheIcahnSchoolofMedicineatMountSinaireportedonanewmethodfordetectingepigeneticchangesthatpromotetumors.Usingthismethod,shediscoveredaproteincalledAMIGO2thatcouldserveasanoveldrugtarget.UnlikeBRAFandothergeneticflawsthatdrivetumorgrowth,nomutationsarefoundinthegeneencodingAMIGO2inmelanoma.Instead,melanomacellscontainmuchhigheramountsoftheAMIGO2proteincomparedtonormalcellsandthisincreasedexpressionisessentialformelanomacellsurvival.AMIGO2isatargetofagroupofexperimentaldrugscalledBETinhibitorsthatarecurrentlybeingtestedinclinicaltrials.“Theepigenomeisanimportantnewareaofbiologyandcancerthatisveryexcitingandexperimentaldrugstargetingitarerapidlymovingintotheclinic,”stressedBernstein.
Reviving an Old Drug to Treat MelanomaIncontrasttoBernstein’sreportsonnewlydeviseddrugs, LewisCantleyofWeillCornellMedicalSchoolreportedonan olddrugthatmaybeputtoanewusefightingmelanoma. Thedrugphenforminwasdevelopedasadiabetestreatmentandwasabandonedafteritprovedtootoxicinasmallsubgroupofpatients.Recognizingthatthemolecularactionsofphenformin
mightbeusefulinthetreatmentofmelanoma,CantleytesteditincombinationwithFDA-approvedtargetedtherapiesformelanoma.HefoundthecombinationofphenforminandtheBRAFinhibitorvemurafenibwassynergisticinaBRAFmutantmelanomamousemodel.Further,CantleyfoundthatphenformineffectivelykilledmelanomacellswithNRASmutationsinculturewhenitwascombinedwiththeFDA-approvedMEKinhibitortrametinib.ThisisimportantbecausenotherapiestargetingNRAS-mutantmelanomahavebeenFDAapproved.CantleyalsodiscoveredthatphenforminenhancesPD1-targetingimmunotherapiesformelanomainmousemodels.
CantleyandcolleaguesDr.PaulChapman(MemorialSloanKettering),Dr.JonathanZippin(WeillCornellMedicine)andDr.BinZheng(MassachusettsGeneralHospital)arecurrentlytestingthesafetyofphenoforminincombinationwithdabrafenibandtrametinibinpatientswithmelanoma.Sofarthisstudysuggestsphenformincanbesafelygiventopatientsatdoseslikelytobeactiveinfightingtheirtumors.Cantley’sfutureanalyseswillassesstheeffectsofphenforminonmelanomatumorbiologyandimmunecelldynamicsinpatientswithmelanoma.
Collectively,thesestudieshighlighthowresearchersareattackingmelanomaonmultiplefronts.Byfundingsuchgroundbreakingwork,MRAisdrivingcriticaldiscoveriestowardthenextgenerationofmelanomatreatments.
Robert Vonderheide
Emily Bernstein
11
Brainmetastases(mets)areafrequentandoftendeadlyprobleminpatientswithadvancedmelanoma.Nearly40%ofpatientswithmetastaticmelanomahavebrainmetsatdiagnosis,withanaveragesurvivalofonly4months,suggestingacrucialneedfortreatmentsthatcanridthebrainofthesetumors.1,2Butnewcancertreatmentsarerarelytestedinpatientswithactivebrainmets.Thisislargelyduetoconcernsaboutwhetherthesepatientswillhavesideeffectsuniquetobrainmets,andpooreroutcomesthatmaynegativelyweighagainstotherwisepositiveclinicalbenefits.Anotherpotentialconcerniswhetherthedrugswillevenpenetratethebrain,whichhasafortress-likeabilitytokeepsubstancesfromenteringit.
Fortunately,MRA-fundedresearchersaremakingheadwayinunderstandingbrainmetsandhowtobesttreatthem.Reportingfromthisexcitingresearchfrontier,threeinvestigatorsatthe2018MRAScientificRetreatpresentedtheirfindingsonhowtheuniquebiologyofthebrainsupportsbrainmets,whatpredictswhetherbrainmetswillrespondtotreatment,andwhatnewtherapiesmightbeespeciallyeffectiveatdestroyingthesetumors.
Evaluating the Effectiveness of FDA-Approved Therapies in Treating Brain MetsBecausepatientswithbrainmetsarefrequentlyexcludedfromclinicaltrials,cliniciansdonotfullyunderstandhowpatientswithbrainmetsrespondtoevenFDA-approveddrugs.Tohelpovercomethis,Dr.MichaelDaviesoftheUniversityofTexasMDAndersonCancerCenterstudiedtheresponseofmelanomapatientswithbrainmetstotreatmentwithdabrafenibplustrametinib.Thistargetedtherapycombinationblocksspecificproteinsthatfuelthegrowthoftheapproximately50%
ofmelanomasthatcontainmutationsintheBRAFenzyme.Theaverageprogression-freesurvivalofpatientsinthestudywas11months,approximatelyhalfthetimeofwhatpatientswithoutbrainmetscanexpectwhoaregiventhesametreatment.Notably,tumorsinpatients’brainsoftenprogressed,whiletumorsoutsidethebraindidnot.“Thetreatmentdidn’tworkaswellinthebrainasoutsidethebrain,”stressedDavies,whowaspuzzledbythisfinding,andconductedtwoadditionalstudiestofindoutwhythiswasso.
Thesefollow-upstudiescomparedtumorbiopsiestakenfromapatient’sbrainmetsandcomparedthemtoothertumorsamplesfromthesamepatient.Theresearchsuggeststhatbrainmetstendtohaveanoveractivetumor-fuelinggrowthpathwaythatisnotdirectlytargetedbydabrafenibandtrametinib.Moreover,immunesystemprofilingindicatedweakenedanti-tumorimmunityinbrainmetscomparedtothoseinothersites,suggestingthatcancerimmunotherapiesmayalsobelesseffectiveinthebrain.Altogether,Davies’studieshighlighttheneedforcontinuedresearchtoevaluatetheeffectivenessofalreadyapprovedtherapiesintreatingbrainmetsandrevealpotentialtherapeuticvulnerabilities.
Whetherimmunotherapiescanshrinkmelanomabrainmets,andwhatbiomarkersrelatetosuchaneffect,isalsoanunder-exploredterritory.InasmallstudyreportedbyDr.LuciaJilaveanuofYaleUniversity,pembrolizumabreducedthesizeofbrainmetsinapproximately25%ofmelanomapatientstreated.Thisquarterofpatientsalsoexperiencedsignificantshrinkageintumorslocatedoutsideofthebrain.Jilaveanususpectsthatusingcombinationsoftreatmentsmightimprovetherelativelylowresponserate,andthatbiomarkersmaypredictwhichpatientswillrespond,allowingclinicianstotargettreatmentstothosepatients.
TACKLING BRAIN METASTASES
Michael Davies
Lucia Jilaveanu
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Jilaveanu’steamthenexaminedbrainmetsamplesremovedfrompatientspriortotreatmentwithpembrolizumab.Comparedtopatientswhosediseaseprogressedwhileontreatment,responders’sbrainmetshadhighernumbersoftumor-fightingTcells,andtheirbrainmetsalsoproducedmorePD-L1molecules,whichispartofthemolecularpathwaytargetedbypembrolizumab.Shealsofoundthatpatientswithbrainmetswhorespondedtopembrolizumabexperiencedareductionintheamountofedema,orexcessfluidaccumulatingintheirbrains.Edemacanbedisruptive,andattimesdeadly,forpatientswithbrainmets,andtherewasconcernthatimmunotherapiesmightaggravateit.ButatleastinJilaveanu’sstudy,thisprovednottobethecase.“Thisshouldlessenconcernsofusingthesetreatmentsinthesepatients,”shesaid.
Probing the Biology of Melanoma Brain MetsDr.ManuelValienteoftheSpanishNationalCancerResearchCenterfocuseshisresearchonthecellularenvironmentsurroundingbrainmetsinanefforttounderstandhowthis‘tumormicroenvironment’allowsbrainmetstodevelopandprogress.Hesoonrealizedthatthoughmanytumorcellsarriveinthebrain,onlysomebecomemetastatictumorslargeenoughtobedetectedonascan.“Metastasisisnotjustamatterofgettingthere—therealpictureismorecomplex,”Valientesaid.Hethensetouttoexplorethiscomplexitybystudyingbothanimalmodelsofmelanomaandbrainmetbiopsies.
Thisresearchuncoveredthatstar-shapedbraincellscalledastrocytesarepresentinthetumormicroenvironmentofbrainmetsandsecretemolecularsignalsthattriggertumorgrowth.WhenValienteblockedthissignalinginmicewithmelanomaorlungcancer,hefounditreducedthenumberandsizeofbrainmets.Hethentestedanexperimentaldrugthatinhibitsthesamemolecularpathwayinasmallnumberofpatientswithbrainmets.Amajorityofthesepatientsexperiencedareductioninthetumorburdenintheirbrain,whereasnosubstantialreductionswereseeninthesizeoftumorsoutsidethebrain,highlightingthelikelydifferentunderlyingbiologyofbrainmetscomparedtoothersites.“Weareexcitedabouttheseresultsandhopetostartaclinicaltrialoftheinhibitorsoonincancerpatients,”Valientesaid.
BecausethestudiesconductedbyDavies,Jilaveanu,andValienteallincludedrelativelysmallnumbersofmelanomapatients,theirfindingswillneedtobeverifiedinlargercohortsofpatients. Buttheglimmersofinsightintobrainmetsshouldultimatelyhelp treatpatientswiththesetumors.“Ifwecanidentifymolecularpatternsinbrainmetastases,wecanexploitthemtherapeutically,” Valientestressed.
Manuel Valiente
1.GlitzaIC,HeimbergerAB,SulmanEP,etal.Prognosticfactorsforsurvivalinmelanomapatientswithbrainmetastases.In:HayatM,editor.Brainmetastasesfromprimarytumors.AcademicPress.2016.pp.267–292
2.DaviesMA,LiuP,McIntyreS,etal.Prognosticfactorsforsurvivalinmelanomapatientswithbrainmetastases.Cancer.2011.117:1687–96
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Ithasbeensaidthat“melanomawritesitsmessageontheskinwithitsowninkforallofustosee,sowhyisitsohardtodetect?”askedDr.SusanSwetterofStanfordUniversityatthe2018annualMRAretreat.Earlydetectionsaveslives,giventhe95%ten-yearsurvivalrateforpatientsdiagnosedwithveryearlystagemelanoma.3However,thatinkishardtoread.Therearevariousvisualcluesthatcanindicateacancerousskinlesion,butnotallcancerousmolessharethesefeaturesandharmlessmolescansometimeshavesimilarclinicalfeatures.It’seasytounderstandwhymisdiagnosishappens.
Thatmaysoonchange,giventhepromisingresultsofanewcomputer-basedsystemfordistinguishingmalignantfrombenignmolesorothernon-cancerousskinconditions,suchaspsoriasis.Withtheadventofartificialintelligencecombinedwithlarge
imagedatabasesand“deeplearning”algorithms,SwetterandherStanfordDermatologyandComputerSciencecolleagueswereinspiredtocreateacomputerprogramthatcouldlearntherelevantpatternsofvariousskinconditionsandaidthediagnosisofearlymelanoma.“Wefiguredifartificialintelligencecandifferentiatebetweenhundredsofdogbreedsinpictures,itcouldmakeagreatcontributiontodermatology,”Swettersaid.
Initialresultsofthesystemtheresearcherscreatedarepromising.Afterbeingtrainedonadatabaseofnearly130,000imagesspanningthebreadthofskindiseases,thesystemperformedatleastaswellas21board-certifieddermatologistsindistinguishingskinmelanomasfrombenignmoles.“Thisisanastoundingresultthatacomputersystemtrainedoveramatterofweekscouldoutperformhumanexpertswhohadspentyearsintraining,”Swettersaid,addingthatovertimeasthecomputersystemcontinueslearning,itsdiagnosticperformanceisalsolikely toimprove.
Butmoretestsneedtobedonetoverifytheaccuracyofthesystem.Swetterexpectsthecomputerprogramtobereadyforlarge-scaleclinicaltestswithinanotheryear,includinganappversionthatcanbeusedonasmartphone.Thisappmayalsoenableearlydetectionofmelanomaandotherskincancersinremote,underservedpopulations,Swetternoted.Butneithertheappnorcomputerprogramarereadyformolesurveillance,sincetheydon’tyetlookatsequentialchangesinmoles,Swettersaid.
Shestressedthatartificialintelligencesystems,suchastheoneshehelpedtocreate,aredecisionsupporttoolsandwon’treplacedermatologistsinthediagnosisofmelanoma.Butsheadded“IfAIcanbedemonstratedtoperformrobustlyinprospectiveclinicalsettings,Iamwillingtoincorporateitsresultsintomymedicaldecision-making.”Shegaveanexampleofanimageofapatient’smolewhosefeatureswereambiguousenoughthatherresearchcolleaguewasonthefenceaboutwhethertobiopsyit.“Ourcomputersystemweighedinonthesideofmalignancy(asdidtheclinician),andlowandbeholditwasasubtleearlymelanoma,sotheproofisinthepudding,”Swettersaid.
APPLYING ARTIFICIAL INTELLIGENCE TO MELANOMA DETECTION
Susan Swetter
3https://www.cancer.org/cancer/melanoma-skin-cancer/detection-diagnosis-staging/survival-rates-for-melanoma-skin-cancer-by-stage.html
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ThereisnodoubtthattreatmentsformetastaticmelanomahavechangeddramaticallyinthedecadesinceMRA’sfoundingin2007.Targetedtherapyandimmunotherapyhavebecomemainstaysoftreatmentandhaveextendedpatientlives.Inaddition,newapproachestothediagnosticworkupforpatientshavebeenrecentlyannouncedandmultipletreatmentstokeepmelanomafromreturningaftersurgeryarenowavailable.Specifically:
• Eleventreatments4forpatientswithmetastaticmelanomagarneredFDAapprovalsince2011including:a)targeteddrugsforBRAFandMEK;and,b)immunotherapywithcheckpointblockade,cytokinesoroncolyticviraltherapy.Over400melanomainterventionaltrialsarerecruitingpatientsonwww.clinicaltrials.gov,5
• Treatmentcontinuestoevolvewiththelate2017approvalofnivolumabformelanomaadjuvanttherapy,theApril30,2018,approvalofadjuvantdabrafenibandtrametinib,andencouragingdataforotherdrugs,6
• Newmelanomastagingguidelinesandrecommendationsoncompletelymphnodedissection(CLND)haverecentlybeenpublished,7,8
• Companiondiagnostics9forbothtargetedandimmunotherapyhavegainedapprovalandbiomarkerdevelopmentremainsatoppriority.
Thesechangesinthestandardofcareformelanomabringwiththemtheneedtoconsiderwhattheirimpactisonhowevennewertreatmentsaredevelopedfromthestandpointofacademicandgovernmentresearchers,biopharmascientistsandregulators.
Over50thoughtleaderscametogetheratanannual,invitation-onlyIndustryRoundtabletoidentifyanddiscusscross-cuttingissuesfacingmelanomatreatmentanddiagnosticdevelopment.Participantsincludedrepresentativesfromacademia,FDA,
industry,NCIandMRA.ThesessionwasmoderatedbyDr.Antoni(Toni)RibasandMRAChiefScienceOfficer,Dr.LouisePerkins.Amongthetopicsdiscussedwerea)clinicaltrials;b)endpoints;and,c)biomarkers.
Ribasaskedaprovocativequestiontokickoffdiscussion,“Aretheretoomanyclinicaltrialsbeingconductedinmelanoma?”Giventheneedforimprovedoutcomesandtherationalesupportingmosttrials,theoverwhelmingmajorityofparticipantsfeltthattheanswerwasaresounding“No,therearenottoomanytrials.”Whatfollowedwasanuanceddiscussionthatexploredbothefficiencyimprovementsandmobilizingthepreciousresourceofpatientswhoareableandwillingtoparticipateinsuchtrials.MRA,alongwithexternalpartners,recentlylaunchedMelanoma>Exchange tobolstereducationaboutclinicaltrialsandanonlineplatformthatmakesiteasierforpatientstofindatrial.
Onewaytoimprovetheefficiencyofmelanomaclinicaltrialswouldbethedevelopmentofendpointstomoreaccuratelypredictwhethertreatmentsareworkingascomparedtothoseincommonusetoday.Forexample,tumorshrinkage,progressionaftertreatmentandoverallsurvivalarecommonendpoints.Butwhatifabloodtest,animagingendpointorapathologymeasurementcouldaccuratelyshedlightonwhetheryourtreatmentisworkingorisfailingearlierthancurrenttechnologiescandetermine?Thereisgreatinterestinthisareaanditspotentialtomorerapidlyandaccuratelyinformdrugdevelopment.
Biomarkerdevelopmentisarelatedsubjectthatattemptstomeasurethingslikeproteinsorcelltypestohelpidentifywhichpatientswillbenefitfromwhichtreatment.Agreatdealofeffortinresearchisbeinginvestedtodevelopthesebiomarkersformelanomaandtousethemtoidentifywhichpatientsareinneedofmoreaggressiveorearliertherapycomparedtothosewhowilldofinewithstandardsurgeryorexistingdrugs.
Anothertopicthatwasdiscussedrelatedtobringingpotentiallylife-savingtreatmentstopatientsmorequicklybyincludingpatientsintrialswhoaretypicallyexcluded.Forexample,patientswithbrainmetastaseshavehistoricallybeenexcludedfromclinicaltrialseventhougharound15%ofnewlydiagnosedmelanomapatientshaveexistingbrainmets.Recentworkbyamulti-stakeholdergroupmadethecaseformodernizingclinicaltrialeligibility,includingtreatingcertainpatientswithbrainmets,10toachieveseveralobjectivesincludingunderstandingthesafetyandefficacyinreal-worldpopulationsandalsotopotentiallyenrollmorepatientsontrialsmorequickly.
Inconclusion,therapidityofchangeinmelanomasincethefirstwaveofnewtreatmentscametomarketin2011hasbeenastounding.ThroughdialogueamongexpertssuchasatthisIndustryRoundtable,problemsandsolutionscanemergethataddressproblemsthatnowexistduetotherelativesuccessin thefield.
MAINTAINING THE PACE OF MELANOMA INNOVATION IN THE ERA OF AN EVOLVING STANDARD OF CARE
Louise Perkins and Antoni Ribas
4https://www.curemelanoma.org/about-mra/mra-overview/5 https://clinicaltrials.gov/ct2/results?cond=melanoma&Search=Apply&recrs=a&age_v=&gndr=&type=Intr&rslt6https://www.uptodate.com/contents/adjuvant-therapy-for-cutaneous-melanoma#H934565933&https://www.novartis.com/news/media-releases/novartis-combination-adjuvant-therapy-tafinlarr-mekinistr-receives-fda
7 http://onlinelibrary.wiley.com/doi/10.3322/caac.21409/full8 https://www.nccn.org/professionals/physician_gls/pdf/melanoma_blocks.pdf
9https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm
10 http://ascopubs.org/doi/full/10.1200/JCO.2017.74.0761
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AGENDA
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Wednesday, February 28th 1:30-5:30 pm Melanoma Advocates & Foundations Forum (invitation only)……………………….………Salon II
4:00-8:00pm Registrationopen……………………….…………………………………………….……..FoyerofSalonIII
6:00-7:30 pm Opening Reception………………………………………………………….…...……………….... Salon III
Thursday, March 1st6:30am-6:00pm Registration..…………………………………………………………...........…..OutsideofSalonBallroom7:00-8:15am GeneralBreakfast…………………………………..…………………………………………………SalonIII7:00-8:15am YoungInvestigatorsBreakfast(byinvitationonly)……………………..………....……….PlazaBallroom8:30-8:45 am Opening Remarks Day 1……………………………………………………………………….Salon I & II MichaelKaplan,MRAPresident&CEO LouisePerkins,MRAChiefScienceOfficer SamanthaStinchcomb,WayneStinchcombBigOrangeFoundation
8:45-9:15 am Lecture Suzanne Topalian, Johns Hopkins University: A decade of progress in melanoma
9:15-11:10 am Session 1: New approaches and tools for predicting efficacy: immunotherapy and beyond Chair:JenniferWargo9:15-9:40 Kai Wucherpfennig, Dana-Farber Cancer Institute:Humananti-MICAmonoclonalantibodiesfor
melanomaimmunotherapy9:40-10:05 Marisol Soengas, Spanish National Cancer Research Center (CNIO):Imagingandtargeting
dormantandpro-metastaticmelanomalesionsinvivo10:05-10:25 Iwei Yeh, University of California, San Francisco:Activatingß-cateninmutationscooperatewith
BRAFV600Etopromoteinvasion10:25-10:45am Break10:45-11:10 Yvonne Saenger, Columbia University:Combinationimmunotherapyleadstodecreasedtumor
growth,improvedsurvivalandintratumoralimmuneinfiltrationintransgenicmurinemodelofmelanoma
11:10 am-12:00 pm Session 2: Microbial influences on immunotherapy efficacy Chair:MarisolSoengas
11:10-11:35 Tom Gajewski, University of Chicago:Thecommensalmicrobiotaasanewvariableimpactingcancerimmunotherapy
11:35-12:00 Jennifer Wargo, MD Anderson Cancer Center:Profilingthemicrobiometopredictimmunotherapyefficacy
AGENDA
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12:00-12:10pm Transitiontolunch12:10-1:15pm Lunch and Panel Discussion………………………..……………………….…….....….....….... Salon III The changing landscape of melanoma Moderator:ElliottSigal,MRABoardofDirectors
Panelist:RichardPazdur,OncologyCenterofExcellence,FDA Panelist:MarcTheoret,OncologyCenterofExcellence,FDA Panelist:NageatteIbrahim,Merck Panelist:DavidFeltquate,Bristol-MyersSquibb Panelist:CarolineRobert,InstitutGustaveRoussy1:15-1:30pm Transitiontoroom
1:30-3:00 pm Session 3: Melanoma metastasis……………………………..………………….……….…. Salon I & II
Chair:RobertVonderheide1:30-1:55 Michael Davies, MD Anderson Cancer Center:TargetingBRAFmutantbrainmetastases1:55-2:15 Manuel Valiente, Spanish National Cancer Research Center (CNIO):Blockingbrainmetastasis
bytargetingthemicroenvironment2:15-2:35 Lucia Jilaveanu, Yale University:ResponsetoPD-1inhibitorsinmelanomapatientswithbrain
metastases2:35-3:00 Robert Vonderheide, University of Pennsylvania:Radiationandimmunecheckpointblockade
frommechanismtopatients3:00-3:20pm Break3:20-5:00 pm Session 4: New targets for melanoma…………………………………………………….….Salon I & II Chair:IdoAmit
3:20-3:45 F. Stephen Hodi, Dana-Farber Cancer Institute:CombinedCTLA-4andangiopoietin-2blockadeinadvancedmelanomapatients
3:45-4:05 Niroshana Anandasabapathy, Weill Cornell Medical School:Tissueimmunedifferentiationrevealsnewpathwaysofmelanomaescape
4:05-4:30 Michal Lotem, Hadassah Medical Organization:MechanismofactionofSLAMF6anditspotentialroleinimmunotherapy
4:30-4:55 Ido Amit, Weizmann Institute of Science:Singlecellanalysisandperturbationofthetumor-immuneecosystem
4:55-5:00 Closing Remarks Day 1 KristenMueller,MRAScientificProgramDirector
6:30-9:00 pm Reception and Dinner…………………………………………..………..………Teddy & the Bully Bar* Dress:Casual120019thStreet,NW,(202)872-8700 Reception:6:30-7:00pm;Dinner:7:15pm*6:15-7:00pm:TransportationprovidedtoTeddy&BullyBar;Shuttleswilldepartfromthecirculardriveoutsidethehotellobby.Uponexitingthehotel,beartoyourrightandshuttleswillbestationedinthebreezewaybetweenthehotelandartgalleryontheproperty.
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Friday, March 2nd6:30-10:00am Registrationopen……………………………………………………....…OutsideSalonBallroom7:00-8:30am GeneralBreakfast……………………………………………………………..…………….SalonIII7:00-8:30am IndustryRoundtableBreakfast(byinvitationonly)………………………....…...PlazaBallroom8:40-8:45 am Opening Remarks Day 2 ……………………………………………………………...Salon I & II KristenMueller,MRAScientificProgramDirector8:45-11:25 am Session 5: New strategies in preventing and treating melanoma Chair:LewisCantley8:45-9:10 Georgina Long, Melanoma Institute Australia, University of Sydney:Adjuvanttherapy
formelanoma9:10-9:30 Steve Barthel, Brigham and Women’s Hospital:Melanomacell-intrinsicTim-3:An
unexpectedvariableincancerimmunotherapy?9:30-9:50 Amanda Lund, Oregon Health & Science University:LymphaticvesselsandT
cell-inflammationinmelanoma9:50-10:15 Boris Bastian, University of California, San Francisco:Structureandexpression
levelofBRAFfusionkinasesaffectdrugresponse10:15-10:35am Break10:35-11:00 Susan Swetter, Stanford University:Artificialintelligence(AI)forcutaneous
melanomadetection11:00-11:25 Emily Bernstein, Icahn School of Medicine at Mount Sinai:Harnessingtheepigenome
formelanomaoncogenediscovery11:25-11:55 Lecture Lewis Cantley, Weill Cornell Medical School:DevelopmentofAMPKactivatorsfor
treatmentofmelanoma
11:55-12:35pm Panel Discussion
A decade of MRA: Funding for the future Moderator:MargaretAnderson,MRABoardofDirectors Panelist:DebraBlack,MRABoardChairandCo-founder Panelist:GeorginaLong,MelanomaInstituteAustralia,UniversityofSydney Panelist:RichardMarais,CancerResearchUKManchesterInstitute Panelist:SuzanneTopalian,JohnsHopkinsUniversity,MRABoardofDirectors Panelist:JeddWolchok,MemorialSloanKetteringCancerCenter
12:35-12:45 pm Closing Remarks
MichaelKaplan,MRAPresidentandCEO LouisePerkins,MRAChiefScienceOfficer
12:45-2:00 pm Lunch and Departures…………………………………………………………………Salon III
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Sama Ahsan Clinical Director Merck & Co., Inc. [email protected]
Alexandre Alencar Program Manager Rising Tide Foundation for Clinical Cancer Research [email protected]
Ido Amit Professor Weizmann Institute of Science [email protected]
Niroshana Anandapathy Attending Physician, Assistant Professor Weill Cornell Medicine [email protected]
Ana AndersonAssociate ProfessorHarvard Medical [email protected]
Margaret AndersonBoard Member, MRAManaging DirectorDeloitte
Steve AnrederPresident & CEOAnreder & [email protected]
Andrew AplinAssociate DirectorThomas Jefferson [email protected]
Charlotte AriyanAssociate [email protected]
Julia ArnoldProgram DirectorNIH/[email protected]
Maryam AsgariAssociate ProfessorMassachusetts General [email protected]
Michael AtkinsDeputy DirectorGeorgetown Lombardi Cancer [email protected]
Alex AvilaIO Medical Lead, GU and MelanomaBristol-Myers [email protected]
Anand BalasubramaniAssociate EditorScience [email protected]
Cody BarnettDirector of CommunicationsMelanoma Research [email protected]
Steven BarthelInstructorBrigham & Women’s [email protected]
Boris Bastian Professor UCSF [email protected] BernsteinAssociate ProfessorIcahn School of Medicine at Mount [email protected]
Nina BhardwajDirector of ImmunotherapyIcahn School of Medicine at Mount [email protected] BigganePresidentMollie Biggane Melanoma [email protected] BigganePresidentMollie Biggane Melanoma [email protected] BlackBoard Member, MRAVice PresidentOCV PartnersDebra BlackCo-Founder & Chair, MRABroadway ProducerLeon BlackCo-Founder, MRAChairman & CEOApollo Global Management, LLC
Christian BlankMolecular Oncology & ImmunologyNetherlands Cancer [email protected]
PARTICIPANTS
Michael Kaplan
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Kim BlenmanAssociate Research ScientistYale [email protected]
Paul BlieseDirector of PhotographyCreative Services, Milken [email protected] BoikoAssistant ProfessorUC [email protected] BorrelloAssociate Professor of OncologyJohns Hopkins [email protected] BosenbergProfessor of Dermatology and PathologyYale [email protected] BrodyPartnerO’Melveny & Myers [email protected]
Peter BrossOncology Branch Team LeadUS/FDA/CBER/[email protected] BrownDevelopment AssociateMelanoma Research [email protected] BrownPatient Engagement & Operations AssociateMelanoma Research [email protected] BullockAssociate Professor, Immune Therapy CenterUniversity of [email protected] BurdAssistant ProfessorOhio [email protected] Burstyn-CohenPrincipal InvestigatorThe Hebrew University of [email protected]
Lisa ButterfieldProfessor of Medicine, Surgery and ImmunologyUniversity of [email protected] ByrnesExecutive DirectorSkin of [email protected] [email protected] CantorAssistant [email protected] CarinoExecutive [email protected] CarvajalAssociate Professor of MedicineColumbia University Medical [email protected]
Nageatte Ibrahim, David Feltquate, Marc Theoret, Richard Pazdur, Caroline Robert, Elliott Sigal
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Jonathan CebonMedical DirectorOlivia Newton-John Cancer Research [email protected] ChapmanAttending [email protected] ChenAssistant ProfessorYale [email protected] ChenAssistant [email protected] ChiouMedical [email protected] ChitaleDigital [email protected] ClaycombDirector, Business DevelopmentNewLink [email protected] CohanMedical DirectorAmgen, [email protected]
Sara CulverMarketingLoxo [email protected] DanielsProgram DirectorAmerican Cancer [email protected] DanielsenManaging DirectorSolCarib [email protected] DaviesAssociate ProfessorMD Anderson Cancer [email protected] DavisBoard Member, MRAPrincipalMakana BeveragesScott DiedeSenior Clinical DirectorMerck & Co., [email protected] DimmittMedical Affairs-Advocacy ManagerProvectus [email protected] D’OrazioProfessor of PediatricsUniversity of [email protected] DorosMedical [email protected] DouganAssistant ProfessorDana-Farber Cancer [email protected] DuludeCEODefeat [email protected]
Shelton EarpDirectorUNC Lineberger Comprehensive Cancer [email protected] ErezLab Head, Department ChairTel Aviv [email protected] Marie FarroPresidentMoving for Melanoma of [email protected] FayehunMarketing [email protected] FeltquateHead of Early Clinical DevelopmentBristol-Myers [email protected] FestaExecutive DirectorLive SunSmart [email protected] FisherChief of DermatologyMassachusetts General [email protected] FlahertyDirector of Developmental TherapeuticsMassachusetts General [email protected] FlattoExecutive DirectorPershing Square Sohn Cancer Research [email protected] FuchsRebecca C. Lancefield ProfessorThe Rockefeller [email protected]
PARTICIPANTS
Benjamin Black and Xu Wu
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Thomas GajewskiProfessorUniversity of [email protected] GarrisonPresidentThe White Aisle [email protected] GarrisonBoard MemberThe White Aisle [email protected] GavathiotisAssociate ProfessorAlbert Einstein College of [email protected] GazzerroAssociate Director, Development& Information ManagementMelanoma Research [email protected] GershenwaldProfessorThe University of Texas MD Anderson Cancer [email protected] GoldbergAssistant ProfessorDana-Farber Cancer [email protected] GormanPatient AdvocateLee GrinbergPortfolio ManagerElliott [email protected] GrinbergVolunteerMelanoma Research [email protected] GuildPresidentAIM at [email protected]
Piyush GuptaAssociate ProfessorWhitehead Institute/[email protected] HalabanSenior Research ScientistYale [email protected] [email protected] HamidDir, Melanoma Oncology; Chief, Clinical ResearchThe Angeles Clinic and Research [email protected] HanksAssistant ProfessorDuke [email protected] HaqAssistant ProfessorDana-Farber Cancer [email protected] HarbourDirector, Ocular OncologyVice Chairman, TranslatUniversity of [email protected] HazarikaSenior Medical [email protected] HerlynProfessor and Program DirectorThe Wistar [email protected] HernandoAssociate ProfessorNew York University Medical [email protected]
Jack HidaryChairmanSarcos [email protected] HoAssistant ProfessorUniversity of Lausanne/Ludwig Lausanne [email protected]. Stephen HodiDirector, Melanoma Disease Center & Center for Immuno-OncologyDana-Farber Cancer [email protected] HolmenProfessorUniversity of [email protected] HoonDirectorJohn Wayne Cancer [email protected] HornyakAssociate Chief of Staff for Research & Development , VA Maryland Health Care SystemUniversity of Maryland/[email protected] HugoAssistant Adjunct [email protected] Hu-LieskovanAssistant Professor of [email protected] HuntingtonImmunotherapy [email protected] HwuHead, Division of Cancer [email protected]
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Nageatte IbrahimExecutive Director, Clinical Research, MelanomaMerck & Co., [email protected] IbrahimVP Clinical DevelopmentParker Institute for Cancer [email protected] ItoAssociate Professor of SurgeryRoswell Park Cancer [email protected]
Burkhard JansenChief Medical [email protected] JilaveanuAssistant ProfessorYale [email protected] JohnsonAssistant Professor of MedicineVanderbilt [email protected]
Barinder KangExecutive Director Clinical [email protected] KaplanPresident & CEOMelanoma Research [email protected] KarrethAssistant MemberMoffitt Cancer [email protected]
Tibor KelerExecutive VP & CSOCelldex Therapeutics, [email protected] KellyEditorAAAS/[email protected] KirkwoodUsher Professor of Medicine, Dermatology,and Translational ScienceUPMC Hillman Cancer [email protected]
Libby KistlerFounderKistler & [email protected] KlowdenBoard Member, MRAChief Executive OfficerMilken InstituteDavid KnorrClinical ScholarRockefeller [email protected] KoboldAttending Physician, Assistant ProfessorKlinikum der Universität Mü[email protected] KorteExecutive Director, Medical Affairs/IML OGMAMerck & Co., [email protected] KrauthammerAssociate ProfessorYale [email protected] KreplerDirector, Clinical ResearchMerck & Co., [email protected] KriegChief Executive OfficerCheckmate [email protected] KulkarniAssistant ProfessorUniversity of Massachusetts [email protected] KulkarniAssistant [email protected]
PARTICIPANTS
David Cohen
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Trip LaneBoard MemberSkin of [email protected] LarimerInstructorMassachusetts General [email protected] LeachmanProfessor & Chair, Department of DermatologyOregon Health & Science [email protected] LegosSenior VP & Franchise [email protected] LemeryAssociate Division Directory, [email protected] LipsonAssistant Professor, Medical OncologyJohns Hopkins [email protected] Liu-SmithAssistant ProfessorUC [email protected] LoProfessor & Attending [email protected] LombardAssociate Professor of PathologyUniversity of [email protected] LongConjoint Medical DirectorMelanoma Institute Australia,The University of [email protected]
A. Thomas LookPrincipal Investigator/Professor of PediatricsDana-Farber Cancer [email protected] LotemHead, Center for MelanomaHadassah Medical [email protected] LukeAssistant Professor of MedicineUniversity of [email protected] LundAssistant ProfessorOregon Health & Science [email protected] MaraisDirectorCancer Research UK Manchester [email protected] MargolinClinical ProfessorCity of Hope National Medical [email protected] MasoudSchool of MedicineDuke [email protected] McLaughlinProfessorWest Virginia [email protected] McMahonHuntsman Cancer Institute & Dept. of DermatologyUniversity of [email protected] MehnertRegional Phase I Clinical Program Director; Medical OncologistRutgers Cancer [email protected]
Thorsten MempelAssociate ProfessorMassachusetts General [email protected] MercierDirector, Medical AffairsNewLink [email protected] MerlinoScientific Director for Basic ResearchDHHS/NIH/NCI/[email protected] MihmProfessor, Pathology and DermatologyBrigham & Women’s [email protected] MillerCo-FounderTara Miller Melanoma [email protected] MillerCo-FounderTara Miller Melanoma [email protected] MillerCo-FounderTara Miller Melanoma [email protected] MillerCo-FounderTara Miller Melanoma [email protected] MitsiadesAssociate ProfessorBaylor College of [email protected] MonteiroEditor-in-ChiefNature [email protected]
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Federico MonzonChief Medical OfficerCastle [email protected] MoonJohn Gideon Searle Assistant ProfessorUniversity of [email protected] Gerardo MorosChief of Medical PhysicsH. Lee Moffitt Cancer Center& Research [email protected] MorrisSenior Director, ResearchCheckmate [email protected] MorseAssociate MemberH. Lee Moffitt Cancer Center & Research [email protected] MossClinical Program Lead, MelanomaBristol-Myers [email protected] MuellerScientific Program DirectorMelanoma Research [email protected] NathansonProfessor, Dept. of Medicine, Translational Medicine & Human GeneticsUniversity of [email protected] NoonanChief Science OfficerWindMIL Therapeutics, [email protected] NusinovichSenior EditorScience Translational Medicine/[email protected]
Christy OsgoodMedical [email protected] OttClinical DirectorDana Farber Cancer [email protected] OverwijkProfessorMD Anderson Cancer [email protected] PanAssociate ProfessorJohns Hopkins [email protected] PanditAdvocacy & Professional AffairsMerck & Co., [email protected] PardollProfessor of Oncology, Director Cancer ImmunologyJohns Hopkins [email protected] PascavageMedical Marketing, [email protected] PatelPhysicianMD Anderson Cancer [email protected] PatlakScience WriterMargie Patlak [email protected] PattonProgramme Leader and ReaderMRC Human Genetics Unit,The University of [email protected]
Anna PavlickProfessor of Medicine and DermatologyNYU Cancer [email protected] PazdurDirector, Office of Oncology Drugs [email protected] PengProfessorSaint Louis [email protected] PerkinsChief Science OfficerMelanoma Research [email protected] PolskyProfessorNYU Langone [email protected] M. PoolePresident & FounderMelanoma International [email protected] PoulikakosAssistant ProfessorIcahn School of Medicine at Mount [email protected] PowellMD/MPH studentUNC-Chapel Hill School of [email protected] PratilasAssistant ProfessorJohns Hopkins [email protected] PrinceScientific Program ManagerMelanoma Research [email protected]
PARTICIPANTS
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Raj PuriDivision Director of Cellular and Gene [email protected] PuzaDuke [email protected] RahimianMedical DirectorIdera [email protected] RaiAssistant ProfessorMD Anderson Cancer [email protected] RetzlaffChief Policy Officer, & VP, Science Policy & Government [email protected] RibasProfessor of [email protected] RichVP Principal PartnershipsAmerican Cancer [email protected]
David RicklesChief Scientific OfficerRadimmune [email protected] RidkyAssistant ProfessorUniversity of [email protected] RileyPatient [email protected] RitchingsAssociate Director, Immuno-Oncology Medical ScientistBristol-Myers [email protected]
Rocio RiveraScientific Communications DirectorL’Oréal Paris, USACaroline RobertHead of Dermatology UnitGustave [email protected] Jo RogersBoard Member, MRAZe’ev RonaiCo-Director, TICCTechnicon Israel Institute of [email protected] RosenMember, Dept. of Medicine and MPCMemorial Sloan-Kettering Cancer [email protected] RosenbergChief, Surgery BranchNational Cancer [email protected] RowbottomBoard Member, MRAManaging DirectorPSP Investments USAAlicia RowellVice-PresidentAIM at [email protected] RowinskiDirectorBristol-Myers [email protected] RubinsteinAssistant ProfessorThe Medical University of South [email protected] RushSenior Director Medical Affairs OperationsArray BioPharma [email protected]
Joan RussoChief Development OfficerMelanoma Research [email protected] SaengerDirector, Melanoma ImmunotherapyColumbia [email protected] SamsSpokespersonMitsy’s [email protected] SamuelsAssociate ProfessorWeizmann Institute of [email protected] SanjanaCore Faculty MemberNew York Genome Center & [email protected] Satchi-FainaroChair, Department of Physiology and PharmacologyTel Aviv [email protected] SchuchterChief, Hematology/Oncology DivisionUniveristy of [email protected] SchwartzChief, Hematology and OncologyColumbia [email protected] ScofieldHQ Medical Lead, Adjuvant MelanomaBristol-Myers [email protected] ShackletonDirector of Oncology, Alfred HealthMonash [email protected]
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William SharfmanDirector of Cutaneous OncologyJohns Hopkins [email protected] SharonSenior InvestigatorNational Cancer [email protected] SharpeCancer BloggerStarfish Harbor [email protected] SigalBoard Member, MRASenior Advisor/Venture PartnerNew Enterprise AssociatesSteve SilversteinBoard ChairMelanoma Research [email protected] Simms BoothSenior Director for Patient and Public EngagementBiden Cancer [email protected] SimonsBoard Member, MRAPresident & CEOProstate Cancer FoundationAnurag SinghAssistant ProfessorBoston [email protected] SlingluffProfessor of Surgery; Director, Human Immune Therapy CenterUniversity of [email protected] SmalleyProfessor and DirectorMoffitt Cancer [email protected]
Jacqueline SmithPolicy and Advocacy ManagerSociety for Immunotherapy of [email protected] SnodgrassExecutive [email protected] SoengasHead, Melanoma GroupSpanish National Cancer Research [email protected] SolitMember, HOPP; Director, CMO; Attending Physician, Genitourinary Oncology ServiceMemorial Sloan Kettering Cancer [email protected] SosaAssistant ProfessorMount [email protected] SosmanDirector, Melanoma ProgramNorthwestern [email protected] SpieglerExecutive DirectorPeggy Spiegler Melanoma Research [email protected] StacyUS Oncology Advocacy PharmD FellowBristol-Myers [email protected] SteppExecutive Director Medical [email protected]
Mark StewartSenior Science Policy AnalystFriends of Cancer [email protected] StinchcombPresidentWayne Stinchcomb Big Orange [email protected] StinchcombWayne Stinchcomb Big Orange [email protected] StoneAssistant ProfessorThe Wistar [email protected] SullivanInstructorMassachusetts General [email protected] SullivanBoard ChairSkin of [email protected] SunwooAssociate ProfessorStanford [email protected] SuplickNewLink [email protected] SwetterProfessor of Dermatology; Director, Pigmented Lesion and Melanoma Program,Stanford University, Stanford Cancer [email protected] TabachSchool of Medicine-IMRIC-Developmental Biology and Cancer ResearchHebrew [email protected]
PARTICIPANTS
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Mary TagliaferriSVP, Clinical Development & CMONektar [email protected] TanSenior Scientific EditorCell [email protected] TaubeDirector of DermatopathologyJohns Hopkins [email protected] TheoretAssociate Director (Acting) Immuno-Oncology [email protected] ThompsonMedical [email protected] ThurinProgram [email protected] TopalianBoard Member, MRAProfessor of Surgery and OncologyJohns Hopkins UniversityCheryl TrockePresidentGraham’s [email protected] TroilPatient [email protected] UselmannPresidentMDSolarSciences [email protected] ValienteJunior Group [email protected]
Navin VaradarajanAssociate ProfessorUniversity of [email protected] VillanuevaAssistant ProfessorThe Wistar [email protected] VoiVP, Global Program [email protected] VonderheideDirector, Abramson Cancer CenterUniversity of [email protected] WachterChief Technology OfficerProvectus [email protected] WalkerPatient AdvocateLi WangAssociate ProfessorMedical College of [email protected]
Ashley WardActing Clinical Team [email protected] WareVolunteerPatient [email protected] WargoAssistant Professor, Dept. of Surgical OncologyMD Anderson Cancer [email protected] WashkauMedical [email protected] WatsonAssistant ProfessorMcGill [email protected] WeberDirector Emeritus, Cancer CenterUniversity of [email protected] WeeraratnaProfessorWistar [email protected]
Nicholas Huntington and Jonathan Simons
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Fred WeinerBoard MemberPeggy Spiegler Melanoma Research [email protected] WhiteAssistant [email protected] WichmanVice PresidentAnreder & [email protected] WilliamsPrincipal ScientistJohnson & [email protected] WilsonAssistant ProfessorVanderbilt [email protected] WilsonAssistant Professor of MedicinePerlmutter Cancer Center, NYU Langone Medical [email protected]
Tara WithingtonExecutive DirectorSociety for Immunotherapy of [email protected] WolchokChief, Melanoma & ImmunotherapeuticsMemorial Sloan Kettering Cancer [email protected] WoodmanAssistant ProfessorMD Anderson Cancer [email protected] WuAssociate ProfessorMassachusetts General [email protected] WucherpfennigProfessorDana-Farber Cancer [email protected] YangDevelopment Lead, Melanoma/GenitourinaryBristol-Myers [email protected]
Iwei YehAssistant [email protected] YellinVice President, Clinical [email protected] Yennu-NandaAssistant ProfessorM.D. Anderson Cancer [email protected] ZarourProfessorUniversity of [email protected] ZhangAssociate ProfessorNorthwestern [email protected] ZhengAssistant ProfessorMassachusetts General [email protected] ZhouAssistant ScientistHenry Ford Health [email protected] ZippinAssistant ProfessorWeill Cornell [email protected] ZonGrousbeck Professor of PediatricsBoston Children’s [email protected]
PARTICIPANTS
Maria Soledad Sosa and Kristen Mueller
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SPONSORSPresenting Sponsors
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Melanoma Research AllianceCureMelanoma.org1101 New York Avenue, NW Suite 620Washington, DC 20005
