2023
Subsets of IFN Signaling Predict Response to Immune Checkpoint Blockade in Patients with Melanoma.
Horowitch B, Lee D, Ding M, Martinez-Morilla S, Aung T, Ouerghi F, Wang X, Wei W, Damsky W, Sznol M, Kluger H, Rimm D, Ishizuka J. Subsets of IFN Signaling Predict Response to Immune Checkpoint Blockade in Patients with Melanoma. Clinical Cancer Research 2023, 29: 2908-2918. PMID: 37233452, PMCID: PMC10524955, DOI: 10.1158/1078-0432.ccr-23-0215.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsHuman melanoma cell linesMelanoma cell linesPD-L1Validation cohortYale-New Haven HospitalCombination of ipilimumabPD-L1 markersImmune checkpoint blockadePD-L1 biomarkerNew Haven HospitalSTAT1 levelsCell linesWestern blot analysisCheckpoint inhibitorsCheckpoint blockadeClinical responseOverall survivalImproved survivalResistance of cancersMetastatic melanomaMelanoma responsePredict responseTreatment responseDistinct patterns
2019
Closed system RT-qPCR as a potential companion diagnostic test for immunotherapy outcome in metastatic melanoma
Gupta S, McCann L, Chan YGY, Lai EW, Wei W, Wong PF, Smithy JW, Weidler J, Rhees B, Bates M, Kluger HM, Rimm DL. Closed system RT-qPCR as a potential companion diagnostic test for immunotherapy outcome in metastatic melanoma. Journal For ImmunoTherapy Of Cancer 2019, 7: 254. PMID: 31533832, PMCID: PMC6751819, DOI: 10.1186/s40425-019-0731-9.Peer-Reviewed Original ResearchMeSH KeywordsAgedAntineoplastic Agents, ImmunologicalB7-H1 AntigenBiomarkers, TumorCD8 AntigensFemaleFollow-Up StudiesGene Expression ProfilingHumansInterferon Regulatory Factor-1MaleMelanomaMiddle AgedMonitoring, ImmunologicPrognosisProgrammed Cell Death 1 Ligand 2 ProteinProgression-Free SurvivalReal-Time Polymerase Chain ReactionRetrospective StudiesReverse Transcriptase Polymerase Chain ReactionRNA, MessengerSkin NeoplasmsConceptsCompanion diagnostic testsImmunotherapy outcomesMelanoma patientsClinical benefitAnti-PD-1 therapyImmune checkpoint inhibitor therapyMRNA expressionQuantitative immunofluorescenceDiagnostic testsCheckpoint inhibitor therapyReal-time quantitative reverse transcription polymerase chain reactionMetastatic melanoma patientsQuantitative reverse transcription polymerase chain reactionReverse transcription-polymerase chain reactionTranscription-polymerase chain reactionYale Pathology archivesParaffin-embedded tissue sectionsAdjuvant settingICI therapyOS associationInhibitor therapyBaseline variablesMetastatic melanomaPredictive biomarkersPolymerase chain reactionMultiplex Quantitative Analysis of Tumor-Infiltrating Lymphocytes and Immunotherapy Outcome in Metastatic Melanoma
Wong PF, Wei W, Smithy JW, Acs B, Toki MI, Blenman K, Zelterman D, Kluger HM, Rimm DL. Multiplex Quantitative Analysis of Tumor-Infiltrating Lymphocytes and Immunotherapy Outcome in Metastatic Melanoma. Clinical Cancer Research 2019, 25: 2442-2449. PMID: 30617133, PMCID: PMC6467753, DOI: 10.1158/1078-0432.ccr-18-2652.Peer-Reviewed Original ResearchMeSH KeywordsAgedAged, 80 and overAntineoplastic Agents, ImmunologicalBiomarkersBiomarkers, TumorFemaleFluorescent Antibody TechniqueHumansImmunohistochemistryImmunotherapyKaplan-Meier EstimateLymphocytes, Tumor-InfiltratingMaleMelanomaMiddle AgedMolecular Targeted TherapyNeoplasm StagingROC CurveT-Lymphocyte SubsetsConceptsCell countTIL activationQuantitative immunofluorescenceLymphocytic infiltrationMelanoma patientsMetastatic melanomaAnti-PD-1 responseAnti-PD-1 therapyCell death 1 (PD-1) inhibitionAbsence of immunotherapyDeath-1 (PD-1) inhibitionDisease control rateProgression-free survivalCD8 cell countsTumor-Infiltrating LymphocytesNew predictive biomarkersWhole tissue sectionsRECIST 1.1Progressive diseaseDurable responsesObjective responsePartial responseImmunotherapy outcomesLymphocyte profilesMultivariable analysis
2017
Quantitative spatial profiling of PD-1/PD-L1 interaction and HLA-DR/IDO1 to predict outcomes to anti-PD-1 in metastatic melanoma (MM).
Johnson D, Bordeaux J, Kim J, Vaupel C, Rimm D, Ho T, Joseph R, Daud A, Conry R, Gaughan E, Dimou A, Balko J, Smithy J, Witte J, McKee S, Dominiak N, Dabbas B, Hall J, Dakappagari N. Quantitative spatial profiling of PD-1/PD-L1 interaction and HLA-DR/IDO1 to predict outcomes to anti-PD-1 in metastatic melanoma (MM). Journal Of Clinical Oncology 2017, 35: 9517-9517. DOI: 10.1200/jco.2017.35.15_suppl.9517.Peer-Reviewed Original ResearchHLA-DRValidation cohortMetastatic melanomaPD-1/PD-L1Anti-PD-1 therapyPD-1/L1Pre-treatment tumor biopsiesPD-1/PD-L1 interactionPD-1 monotherapyPD-L1 expressionProgression-free survivalBiomarkers of responseFuture clinical trialsMultiple immune markersPD-L1 interactionImmune suppression mechanismsPrior therapyFree survivalDurable responsesOverall survivalPD-L1Immune markersClinical trialsTreatment responseTumor biopsiesNuclear 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 response
2015
Characterization of PD-L1 Expression and Associated T-cell Infiltrates in Metastatic Melanoma Samples from Variable Anatomic Sites
Kluger HM, Zito CR, Barr ML, Baine MK, Chiang VL, Sznol M, Rimm DL, Chen L, Jilaveanu LB. Characterization of PD-L1 Expression and Associated T-cell Infiltrates in Metastatic Melanoma Samples from Variable Anatomic Sites. Clinical Cancer Research 2015, 21: 3052-3060. PMID: 25788491, PMCID: PMC4490112, DOI: 10.1158/1078-0432.ccr-14-3073.Peer-Reviewed Original ResearchConceptsPD-L1 expressionT-cell contentPD-1/PD-L1 inhibitorsHigher T-cell contentT-cell infiltratesPD-L1 inhibitorsAnatomic sitesBrain metastasesMetastatic melanomaTissue microarrayHigh PD-L1 expressionLess PD-L1 expressionLow PD-L1 expressionTumor PD-L1 expressionHigher TIL contentImproved overall survivalT cell infiltrationLess T cellsMetastatic melanoma samplesExtracerebral metastasesCerebral metastasesOverall survivalDermal metastasesImproved survivalPD-L1
2007
The X-linked inhibitor of apoptosis protein (XIAP) is up-regulated in metastatic melanoma, and XIAP cleavage by Phenoxodiol is associated with Carboplatin sensitization
Kluger HM, McCarthy MM, Alvero AB, Sznol M, Ariyan S, Camp RL, Rimm DL, Mor G. The X-linked inhibitor of apoptosis protein (XIAP) is up-regulated in metastatic melanoma, and XIAP cleavage by Phenoxodiol is associated with Carboplatin sensitization. Journal Of Translational Medicine 2007, 5: 6. PMID: 17257402, PMCID: PMC1796544, DOI: 10.1186/1479-5876-5-6.Peer-Reviewed Original ResearchConceptsMetastatic melanomaXIAP expressionCell linesCy5-conjugated antibodiesMechanism of actionMelanoma cell linesPrimary lesionOvarian cancerTherapeutic approachesTissue microarrayDisease aggressionCarboplatin sensitivityChemotherapy resistanceMalignant progressionClinical specimensBenign counterpartsCarboplatinMelanomaChemotherapy sensitizationPrimary specimensPhenoxodiolResistant cellsMelanoma cellsHigh expressionMelanoma resistance
2005
Automated Quantitative Analysis of Activator Protein-2α Subcellular Expression in Melanoma Tissue Microarrays Correlates with Survival Prediction
Berger AJ, Davis DW, Tellez C, Prieto VG, Gershenwald JE, Johnson MM, Rimm DL, Bar-Eli M. Automated Quantitative Analysis of Activator Protein-2α Subcellular Expression in Melanoma Tissue Microarrays Correlates with Survival Prediction. Cancer Research 2005, 65: 11185-11192. PMID: 16322269, DOI: 10.1158/0008-5472.can-05-2300.Peer-Reviewed Original ResearchConceptsAP-2 expressionM.D. Anderson Cancer CenterCytoplasmic expression levelsAnderson Cancer CenterAP-2 levelsProgression of melanomaMelanoma tissue microarrayClinicopathologic factorsRetrospective cohortMetastatic groupPrognostic significanceBreslow depthCancer CenterNevi groupPoor prognosisMetastatic melanomaPrimary tumorPrimary melanomaDiagnosis groupsTissue microarrayTumor growthMelanoma specimensMalignant transformationHuman melanomaMelanoma progression
2004
Automated Quantitative Analysis of Tissue Microarrays Reveals an Association between High Bcl-2 Expression and Improved Outcome in Melanoma
DiVito KA, Berger AJ, Camp RL, Dolled-Filhart M, Rimm DL, Kluger HM. Automated Quantitative Analysis of Tissue Microarrays Reveals an Association between High Bcl-2 Expression and Improved Outcome in Melanoma. Cancer Research 2004, 64: 8773-8777. PMID: 15574790, DOI: 10.1158/0008-5472.can-04-1387.Peer-Reviewed Original ResearchConceptsBcl-2 expressionHigh Bcl-2 expressionTissue microarrayMetastatic specimensResponse rateSmall cohortProgression-free survivalImproved response ratesLarge patient cohortMelanoma patientsClark levelEntire cohortBreslow depthClinical variablesPatient cohortMetastatic melanomaContinuous index scoreBetter outcomesIndex scoreMelanoma specimensCohortMelanomaBcl-2PatientsOutcomesHer2/neu is not a commonly expressed therapeutic target in melanoma – a large cohort tissue microarray study
Kluger HM, DiVito K, Berger AJ, Halaban R, Ariyan S, Camp RL, Rimm DL. Her2/neu is not a commonly expressed therapeutic target in melanoma – a large cohort tissue microarray study. Melanoma Research 2004, 14: 207-210. PMID: 15179190, DOI: 10.1097/01.cmr.0000130874.33504.2f.Peer-Reviewed Original ResearchConceptsHER2/neu expressionHER2/neuNeu expressionMelanoma specimensNeu stainingMelanoma patientsLarge cohortPositive HER2/neu expressionChemotherapy-resistant malignancyPrimary cutaneous lesionNumerous new agentsTissue microarray studyMonoclonal antibody trastuzumabAdjuvant therapyCutaneous specimensTrastuzumab therapyMetastatic lesionsBreslow depthClark levelClinicopathological dataCutaneous lesionsPrimary lesionTumor stageMetastatic melanomaBreast cancer