2022
Coupled fibromodulin and SOX2 signaling as a critical regulator of metastatic outgrowth in melanoma
Oria VO, Zhang H, Zito CR, Rane CK, Ma XY, Provance OK, Tran TT, Adeniran A, Kluger Y, Sznol M, Bosenberg MW, Kluger HM, Jilaveanu LB. Coupled fibromodulin and SOX2 signaling as a critical regulator of metastatic outgrowth in melanoma. Cellular And Molecular Life Sciences 2022, 79: 377. PMID: 35737114, PMCID: PMC9226089, DOI: 10.1007/s00018-022-04364-5.Peer-Reviewed Original ResearchMeSH KeywordsBrain NeoplasmsFibromodulinHumansMelanomaNeoplasm MetastasisSignal TransductionSOXB1 Transcription FactorsTranscription FactorsConceptsTumor suppressor Hippo pathwayNovel regulatory mechanismTumor vasculogenic mimicryMetastatic outgrowthExtracellular matrix componentsHippo pathwayRegulatory mechanismsMolecular eventsTumor-stroma interactionsCritical regulatorMetastatic competenceProgenitor markersProliferative stateFunctional roleFunctional studiesSOX2Vasculogenic mimicryDistinct phenotypesMatrix componentsEarly developmentFmodHigh expressionCritical processOutgrowthImportant role
2021
Circulating clonally expanded T cells reflect functions of tumor-infiltrating T cells
Lucca LE, Axisa PP, Lu B, Harnett B, Jessel S, Zhang L, Raddassi K, Zhang L, Olino K, Clune J, Singer M, Kluger HM, Hafler DA. Circulating clonally expanded T cells reflect functions of tumor-infiltrating T cells. Journal Of Experimental Medicine 2021, 218: e20200921. PMID: 33651881, PMCID: PMC7933991, DOI: 10.1084/jem.20200921.Peer-Reviewed Original ResearchConceptsTumor-infiltrating T cellsT cellsUnique transcriptional patternsFeatures of exhaustionLongitudinal immune monitoringPeripheral immune environmentsT cell responsesT cell functionSingle-cell levelTranscriptional patternsTCR sharingTerminal exhaustionImmune environmentImmune monitoringCancer immunotherapyMetastatic melanomaEffector functionsCell responsesTumor tissueGene signatureTumorsCell functionImmunotherapyTCRαβBlood
2020
Melanoma brain metastases have lower T-cell content and microvessel density compared to matched extracranial metastases
Weiss SA, Zito C, Tran T, Heishima K, Neumeister V, McGuire J, Adeniran A, Kluger H, Jilaveanu LB. Melanoma brain metastases have lower T-cell content and microvessel density compared to matched extracranial metastases. Journal Of Neuro-Oncology 2020, 152: 15-25. PMID: 32974852, PMCID: PMC7910371, DOI: 10.1007/s11060-020-03619-0.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedBrain NeoplasmsFemaleHumansMaleMelanomaMicrovascular DensityMiddle AgedNeoplasm MetastasisNeovascularization, PathologicConceptsT-cell contentMelanoma brain metastasesPD-L1 expressionLower microvessel densityMicrovessel densityBrain metastasesExtracranial metastasesMacrophage contentB cellsProspective therapeutic clinical trialsTumor-infiltrating T cellsImmune-modulating drugsImmune cell subsetsTherapeutic clinical trialsExtracerebral metastasesHigh CD68Low CD3Low CD8Systemic therapyIntracerebral metastasesMetastatic sitesCell subsetsMetastatic melanomaImmune cellsClinical trialsPD-1/PD-L1 Blockers in NSCLC Brain Metastases: Challenging Paradigms and Clinical Practice
Eguren-Santamaria I, Sanmamed MF, Goldberg SB, Kluger HM, Idoate MA, Lu B, Corral J, Schalper KA, Herbst RS, Gil-Bazo I. PD-1/PD-L1 Blockers in NSCLC Brain Metastases: Challenging Paradigms and Clinical Practice. Clinical Cancer Research 2020, 26: 4186-4197. PMID: 32354698, DOI: 10.1158/1078-0432.ccr-20-0798.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerImmune checkpoint inhibitorsAnti-PD-1/PD-L1 antibodiesAdvanced non-small cell lung cancerNSCLC brain metastasesBrain metastasesPD-L1 antibodiesAnti-PD-1/PD-L1 agentsPD-1/PD-L1 blockersActive central nervous system (CNS) involvementHigh PD-L1 expressionAnti-PD-1/PD-L1 drugsCentral nervous system involvementPivotal phase III trialsActive brain metastasesCNS response ratesPD-L1 agentsPD-L1 blockersSystemic therapy combinationsNervous system involvementPD-L1 expressionPhase III trialsSubset of patientsCell lung cancerPD-L1 drugsPembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial
Goldberg SB, Schalper KA, Gettinger SN, Mahajan A, Herbst RS, Chiang AC, Lilenbaum R, Wilson FH, Omay SB, Yu JB, Jilaveanu L, Tran T, Pavlik K, Rowen E, Gerrish H, Komlo A, Gupta R, Wyatt H, Ribeiro M, Kluger Y, Zhou G, Wei W, Chiang VL, Kluger HM. Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. The Lancet Oncology 2020, 21: 655-663. PMID: 32251621, PMCID: PMC7380514, DOI: 10.1016/s1470-2045(20)30111-x.Peer-Reviewed Original ResearchConceptsBrain metastasis responseYale Cancer CenterPD-L1 expressionPhase 2 trialUntreated brain metastasesBrain metastasesAdrenal insufficiencyAdverse eventsMetastasis responseCNS diseaseCancer CenterCohort 2Cohort 1Eastern Cooperative Oncology Group performance statusTreatment-related serious adverse eventsModified Response Evaluation CriteriaStage IV NSCLCTreatment-related deathsAcute kidney injuryPD-1 blockadeSerious adverse eventsSolid Tumors criteriaPhase 2 studyProportion of patientsResponse Evaluation CriteriaSurvival after checkpoint inhibitors for metastatic acral, mucosal and uveal melanoma
Klemen ND, Wang M, Rubinstein JC, Olino K, Clune J, Ariyan S, Cha C, Weiss SA, Kluger HM, Sznol M. Survival after checkpoint inhibitors for metastatic acral, mucosal and uveal melanoma. Journal For ImmunoTherapy Of Cancer 2020, 8: e000341. PMID: 32209601, PMCID: PMC7103823, DOI: 10.1136/jitc-2019-000341.Peer-Reviewed Original ResearchMeSH KeywordsAgedFemaleHumansMaleMelanomaMiddle AgedNeoplasm MetastasisSkin NeoplasmsSurvival AnalysisUveal NeoplasmsConceptsCheckpoint inhibitorsOverall survivalMetastatic melanomaPrimary tumorLocal therapyCutaneous melanomaAnti-PD-1 antibodyAggressive multidisciplinary approachCutaneous primary tumorPrimary tumor histologyMedian overall survivalSingle institutional experienceRare melanoma subtypeMedian OSMetastatic diseaseProgressive diseaseAcral skinComplete responsePD-1PD-L1Uveal tractTumor histologyCombination therapyCTLA-4Longer survival
2019
Complications associated with immunotherapy for brain metastases.
Tran TT, Jilaveanu LB, Omuro A, Chiang VL, Huttner A, Kluger HM. Complications associated with immunotherapy for brain metastases. Current Opinion In Neurology 2019, 32: 907-916. PMID: 31577604, PMCID: PMC7398556, DOI: 10.1097/wco.0000000000000756.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic AgentsBrain NeoplasmsHumansImmunologic FactorsImmunotherapyNeoplasm MetastasisNeoplasm Recurrence, LocalNeurotoxicity SyndromesConceptsBrain metastasesNeurologic toxicityImmune therapyPhase 2 clinical trialCheckpoint inhibitor therapyImmune checkpoint inhibitorsMultiple phase 2 clinical trialsTreatment-related morbidityBrain metastatic diseaseSymptomatic edemaCheckpoint inhibitorsAdverse eventsDurable responsesMedian survivalMetastatic diseaseInhibitor therapyMore patientsIntracranial activityPatient groupRadiation necrosisClinical trialsTherapy trialsMultidisciplinary teamMetastasisPatients
2018
A Serum Protein Signature Associated with Outcome after Anti–PD-1 Therapy in Metastatic Melanoma
Weber JS, Sznol M, Sullivan RJ, Blackmon S, Boland G, Kluger HM, Halaban R, Bacchiocchi A, Ascierto PA, Capone M, Oliveira C, Meyer K, Grigorieva J, Asmellash SG, Roder J, Roder H. A Serum Protein Signature Associated with Outcome after Anti–PD-1 Therapy in Metastatic Melanoma. Cancer Immunology Research 2018, 6: 79-86. PMID: 29208646, DOI: 10.1158/2326-6066.cir-17-0412.Peer-Reviewed Original ResearchConceptsAcute phase reactantsCheckpoint inhibitorsOverall survivalPhase reactantsIpilimumab-treated patientsPD-1 blockadeTrials of nivolumabBetter overall survivalIndependent patient cohortsPretreatment serumPD-1Melanoma patientsValidation cohortMetastatic melanomaMultipeptide vaccinePatient cohortPooled analysisWorse outcomesClinical dataPatientsMultivariate analysisComplement cascadeMass spectrometry analysisNivolumabCohort
2017
Efficacy and Safety of Pembrolizumab in Patients Enrolled in KEYNOTE-030 in the United States
Gangadhar TC, Hwu WJ, Postow MA, Hamid O, Daud A, Dronca R, Joseph R, O’Day S, Hodi FS, Pavlick AC, Kluger H, Oxborough RP, Yang A, Gazdoiu M, Kush DA, Ebbinghaus S, Salama AKS. Efficacy and Safety of Pembrolizumab in Patients Enrolled in KEYNOTE-030 in the United States. Journal Of Immunotherapy 2017, 40: 334-340. PMID: 29028788, PMCID: PMC5647109, DOI: 10.1097/cji.0000000000000186.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedAged, 80 and overAntibodies, Monoclonal, HumanizedAntineoplastic AgentsClinical Trials as TopicDrug Resistance, NeoplasmDrug-Related Side Effects and Adverse ReactionsExanthemaFatigueFemaleHumansMaleMelanomaMiddle AgedNeoplasm MetastasisNeoplasm StagingTreatment OutcomeUnited StatesYoung AdultConceptsTreatment-related adverse eventsAdverse eventsAdvanced melanomaGrade 3/4 treatment-related adverse eventsNational Cancer Institute Common Terminology CriteriaUnresectable stage III/IV melanomaStage III/IV melanomaImmune-related response criteriaDeath-1 antibodySafety of pembrolizumabTreatment-related deathsUse of pembrolizumabCommon Terminology CriteriaObjective response rateSubcutaneous tissue disordersAccess programEvaluable patientsTerminology CriteriaCare therapyComplete responseInvestigator reviewGastrointestinal disordersDisease progressionTissue disordersBRAF inhibitorsNuclear IRF-1 expression as a mechanism to assess “Capability” to express PD-L1 and response to PD-1 therapy in metastatic melanoma
Smithy JW, Moore LM, Pelekanou V, Rehman J, Gaule P, Wong PF, Neumeister VM, Sznol M, Kluger HM, Rimm DL. Nuclear IRF-1 expression as a mechanism to assess “Capability” to express PD-L1 and response to PD-1 therapy in metastatic melanoma. Journal For ImmunoTherapy Of Cancer 2017, 5: 25. PMID: 28331615, PMCID: PMC5359951, DOI: 10.1186/s40425-017-0229-2.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedB7-H1 AntigenBiomarkers, PharmacologicalDisease-Free SurvivalFemaleGene Expression Regulation, NeoplasticHumansImmunotherapyInterferon Regulatory Factor-1IpilimumabMaleMelanomaMiddle AgedNeoplasm MetastasisNeoplasms, Second PrimaryNivolumabProgrammed Cell Death 1 ReceptorConceptsProgression-free survivalObjective radiographic responsePD-L1 expressionPD-L1IRF-1 expressionMetastatic melanomaAnti-PD-1 therapyCombination ipilimumab/nivolumabHigh PD-L1 expressionAnti-PD-1 immunotherapyYale-New Haven HospitalIpilimumab/nivolumabPD-1 therapyPR/CRPre-treatment formalinRECIST v1.1 criteriaDeath ligand 1Valuable predictive biomarkerMajor unmet needNew Haven HospitalInterferon regulatory factor 1Combination ipilimumabProgressive diseaseRadiographic responseComplete responsePhase II randomised discontinuation trial of the MET/VEGF receptor inhibitor cabozantinib in metastatic melanoma
Daud A, Kluger HM, Kurzrock R, Schimmoller F, Weitzman AL, Samuel TA, Moussa AH, Gordon MS, Shapiro GI. Phase II randomised discontinuation trial of the MET/VEGF receptor inhibitor cabozantinib in metastatic melanoma. British Journal Of Cancer 2017, 116: 432-440. PMID: 28103611, PMCID: PMC5318966, DOI: 10.1038/bjc.2016.419.Peer-Reviewed Original ResearchConceptsObjective response rateStable diseaseWeek 12Metastatic melanomaEvaluable patientsDiscontinuation trialUveal melanomaCommon grade 3/4 adverse eventsGrade 3/4 adverse eventsTreatment-related deathsMedian overall survivalProgression-free survivalResponse Evaluation CriteriaCohort of patientsStudy days 1Further clinical investigationPhase IIAbdominal painDiverticular perforationPrimary endpointAdverse eventsOverall survivalTarget lesionsClinical activityClinical investigation
2015
The transcription factor ATF2 promotes melanoma metastasis by suppressing protein fucosylation
Lau E, Feng Y, Claps G, Fukuda MN, Perlina A, Donn D, Jilaveanu L, Kluger H, Freeze HH, Ronai ZA. The transcription factor ATF2 promotes melanoma metastasis by suppressing protein fucosylation. Science Signaling 2015, 8: ra124. PMID: 26645581, PMCID: PMC4818095, DOI: 10.1126/scisignal.aac6479.Peer-Reviewed Original ResearchConceptsProtein fucosylationFucose salvage pathwayTranscription factor ATF2Tumor microarray analysisProtein kinase CεTranscription factor 2Human melanoma specimensTranscriptional repressionPrimary melanoma growthPrimary melanocytesGenetic manipulationActive ATF2Cell motilityElucidation of mechanismsMicroarray analysisSalvage pathwayATF2Cell adhesionHigh abundanceCellular adhesionReduced motilityInvasive behaviorCell linesFactor 2Melanoma specimensMET Expression in Primary and Metastatic Clear Cell Renal Cell Carcinoma: Implications of Correlative Biomarker Assessment to MET Pathway Inhibitors
Shuch B, Falbo R, Parisi F, Adeniran A, Kluger Y, Kluger HM, Jilaveanu LB. MET Expression in Primary and Metastatic Clear Cell Renal Cell Carcinoma: Implications of Correlative Biomarker Assessment to MET Pathway Inhibitors. BioMed Research International 2015, 2015: 192406. PMID: 26448928, PMCID: PMC4584049, DOI: 10.1155/2015/192406.Peer-Reviewed Original ResearchConceptsClear cell renal cell carcinomaCell renal cell carcinomaMetastatic sitesRenal cell carcinomaMET expressionCell carcinomaPredictive biomarkersPrimary tumorMetastatic clear cell renal cell carcinomaMetastatic kidney cancerAppropriate patient selectionDistant metastatic sitesPatient selectionMetastatic tissuesKidney cancerMET pathwayTissue microarrayBiomarker assessmentNumber of casesPrimary siteModerate concordancePathway inhibitorTumorsDistant tissuesNephrectomyCharacterization of tumor infiltrating lymphocytes in paired primary and metastatic renal cell carcinoma specimens
Baine MK, Turcu G, Zito CR, Adeniran AJ, Camp RL, Chen L, Kluger HM, Jilaveanu LB. Characterization of tumor infiltrating lymphocytes in paired primary and metastatic renal cell carcinoma specimens. Oncotarget 2015, 6: 24990-25002. PMID: 26317902, PMCID: PMC4694809, DOI: 10.18632/oncotarget.4572.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedB7-H1 AntigenCarcinoma, Renal CellCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesFemaleFluorescent Antibody TechniqueForkhead Transcription FactorsHumansKidney NeoplasmsLymphocytes, Tumor-InfiltratingMaleMiddle AgedNeoplasm MetastasisTissue Array AnalysisYoung AdultConceptsRenal cell carcinomaT cell ratioMetastatic specimensPD-L1Cell carcinomaPD-1/PD-L1 blockadePD-1/PD-L1 statusPD-1/PD-L1 pathwayMetastatic renal cell carcinomaHigh PD-L1PD-L1 blockadeUnfavorable tumor characteristicsPD-L1 expressionPD-L1 statusPD-L1 pathwayT-cell contentPre-treatment tumorsLow CD8TIL subsetsCharacterization of tumorsTIL densitySuch patientsTumor characteristicsImmune activationPatient survival
2014
PAX-8 expression in renal tumours and distant sites: A useful marker of primary and metastatic renal cell carcinoma?
Barr ML, Jilaveanu LB, Camp RL, Adeniran AJ, Kluger HM, Shuch B. PAX-8 expression in renal tumours and distant sites: A useful marker of primary and metastatic renal cell carcinoma? Journal Of Clinical Pathology 2014, 68: 12. PMID: 25315900, PMCID: PMC4429054, DOI: 10.1136/jclinpath-2014-202259.Peer-Reviewed Original ResearchConceptsRenal cell carcinomaPAX-8 expressionMetastatic renal cell carcinomaRenal tumorsMetastatic sitesCell carcinomaClear cell renal cell carcinomaPAX-8 stainingCell renal cell carcinomaPAX-8Distant sitesNormal renal tissueUseful diagnostic markerAdjacent normal kidneyHistological typePrimary tumorDistant tumorsLack of expressionRenal originImmunohistochemical stainsChromophobe tumorsClear cellsRenal tissueNormal kidneyTissue microarrayNY-ESO-1 as a potential immunotherapeutic target in renal cell carcinoma
Giesen E, Jilaveanu LB, Parisi F, Kluger Y, Camp RL, Kluger HM. NY-ESO-1 as a potential immunotherapeutic target in renal cell carcinoma. Oncotarget 2014, 5: 5209-5217. PMID: 24970819, PMCID: PMC4170640, DOI: 10.18632/oncotarget.2101.Peer-Reviewed Original ResearchConceptsNY-ESO-1 expressionNY-ESO-1Renal cell carcinomaCell carcinomaMetastatic sitesRenal tissueCancer-testis antigen NY-ESO-1Antigen NY-ESO-1Adjacent normal renal tissuesClear cell renal cell carcinomaRCC specimensMetastatic RCC specimensPapillary renal cell carcinomaCell renal cell carcinomaPotential immunotherapeutic targetAdoptive cell therapySubset of RCCTumor-specific antigensClear cell carcinomaNovel immune therapiesPrimary RCC specimensBenign renal tissueNormal renal tissueDifferent tumor sitesImmune therapyMEK targeting in N-RAS mutated metastatic melanoma
Thumar J, Shahbazian D, Aziz SA, Jilaveanu LB, Kluger HM. MEK targeting in N-RAS mutated metastatic melanoma. Molecular Cancer 2014, 13: 45. PMID: 24588908, PMCID: PMC3945937, DOI: 10.1186/1476-4598-13-45.Peer-Reviewed Original ResearchConceptsN-RASShort-term cultureMelanoma patientsMelanoma culturesYale Cancer CenterMetastatic melanoma patientsTime of presentationOngoing clinical trialsProtein kinase pathway activationN-RAS mutationsB-RafPan-RAF inhibitorTerm cultureKinase pathway activationConclusionsThe prognosisBrain metastasesClinical characteristicsMetastatic diseasePathologic dataWorse prognosisCancer CenterMetastatic melanomaClinical trialsMutant melanomaMelanoma cell cultures
2013
Vascularity of primary and metastatic renal cell carcinoma specimens
Aziz SA, Sznol J, Adeniran A, Colberg JW, Camp RL, Kluger HM. Vascularity of primary and metastatic renal cell carcinoma specimens. Journal Of Translational Medicine 2013, 11: 15. PMID: 23316728, PMCID: PMC3561185, DOI: 10.1186/1479-5876-11-15.Peer-Reviewed Original ResearchConceptsRenal cell carcinomaMicrovessel areaMetastatic samplesCell carcinomaMetastatic sitesPrimary tumorMetastatic renal cell carcinomaRenal cell carcinoma tumorsClear cell tumorsClear cell carcinomaPredictive biomarker studiesAnti-angiogenic drugsAnti-angiogenic therapyTypes of tumorsHigh response ratePrimary nephrectomyHistologic subtypeCell tumorsDifferent histologyPapillary histologyCD 34Variable histologyClinical studiesClear cellsTumor vascularity
2012
Immunotherapy for metastatic melanoma
Zito CR, Kluger HM. Immunotherapy for metastatic melanoma. Journal Of Cellular Biochemistry 2012, 113: 725-734. PMID: 22006439, DOI: 10.1002/jcb.23402.Peer-Reviewed Original ResearchMeSH KeywordsAntibodiesCancer VaccinesCytokinesHumansImmunotherapyImmunotherapy, AdoptiveMelanomaNeoplasm MetastasisConceptsMetastatic melanomaPromising investigational approachesTreatment of melanomaImmunogenic tumorsAntitumor immunityCTLA-4Interleukin-2First cytokineInvestigational approachesProlonged responseMelanomaMonoclonal antibodiesImmunotherapyTreatmentIpilimumabPatientsCytokinesTumorsSmall subsetDiseaseImmunityAntibodies
2011
Plasma Markers for Identifying Patients with Metastatic Melanoma
Kluger HM, Hoyt K, Bacchiocchi A, Mayer T, Kirsch J, Kluger Y, Sznol M, Ariyan S, Molinaro A, Halaban R. Plasma Markers for Identifying Patients with Metastatic Melanoma. Clinical Cancer Research 2011, 17: 2417-2425. PMID: 21487066, PMCID: PMC3415234, DOI: 10.1158/1078-0432.ccr-10-2402.Peer-Reviewed Original ResearchMeSH KeywordsAgedAntigens, CDBiomarkers, TumorCell Adhesion MoleculesEnzyme-Linked Immunosorbent AssayExtracellular Matrix ProteinsFemaleGlycoproteinsGrowth Differentiation Factor 15HumansIntercellular Adhesion Molecule-1L-Lactate DehydrogenaseMaleMelanomaMiddle AgedNeoplasm MetastasisNeoplasm ProteinsNeoplasm Recurrence, LocalNeoplasm StagingNerve Growth FactorsPrognosisReproducibility of ResultsS100 Calcium Binding Protein beta SubunitS100 ProteinsSensitivity and SpecificityTissue Inhibitor of Metalloproteinase-1ConceptsGenome-wide gene expression dataGene expression dataHigh expression levelsLevels of proteinExpression dataExpression levelsProteinMelanoma cellsStage I/II diseaseEqual-sized trainingMarkersGenesDisease recurrencePlasma markersMetastatic melanomaTIMP-1Lactate dehydrogenaseCEACAMsStage I/II patientsDehydrogenaseOsteopontinStage IV diseaseStage IV patientsMetastatic melanoma patientsGender-matched patients