2024
Spatially Informed Gene Signatures for Response to Immunotherapy in Melanoma.
Aung T, Warrell J, Martinez-Morilla S, Gavrielatou N, Vathiotis I, Yaghoobi V, Kluger H, Gerstein M, Rimm D. Spatially Informed Gene Signatures for Response to Immunotherapy in Melanoma. Clinical Cancer Research 2024, 30: 3520-3532. PMID: 38837895, PMCID: PMC11326985, DOI: 10.1158/1078-0432.ccr-23-3932.Peer-Reviewed Original ResearchGene signatureResistance to immunotherapyResponse to immunotherapyPrediction of treatment outcomeResistant to treatmentAccurate prediction of treatment outcomePredictive of responseImmunotherapy outcomesMelanoma patientsMelanoma specimensValidation cohortPatient stratificationDiscovery cohortTreatment outcomesImmunotherapyMelanomaTumorPatientsCohortS100BOutcomesGene expression dataGenesCD68+macrophagesExpression data
2023
Digital spatial profiling of melanoma shows CD95 expression in immune cells is associated with resistance to immunotherapy
Martinez-Morilla S, Moutafi M, Fernandez A, Jessel S, Divakar P, Wong P, Garcia-Milian R, Schalper K, Kluger H, Rimm D. Digital spatial profiling of melanoma shows CD95 expression in immune cells is associated with resistance to immunotherapy. OncoImmunology 2023, 12: 2260618. PMID: 37781235, PMCID: PMC10540659, DOI: 10.1080/2162402x.2023.2260618.Peer-Reviewed Original ResearchConceptsDigital spatial profilingImmune checkpoint inhibitor therapyShorter progression-free survivalQuantitative immunofluorescenceCheckpoint inhibitor therapyProgression-free survivalMetastatic melanoma patientsPre-treatment specimensIndependent validation cohortMetastatic melanoma casesAdjuvant settingNanoString GeoMxMultivariable adjustmentAdverse eventsImmunotherapy cohortInhibitor therapyPD-L1Immune markersMelanoma patientsUnivariable analysisValidation cohortImmune cellsMelanoma casesMultiplex immunofluorescenceCD95 expression
2020
Quantitative analysis of CMTM6 expression in tumor microenvironment in metastatic melanoma and association with outcome on immunotherapy
Martinez-Morilla S, Zugazagoitia J, Wong PF, Kluger HM, Rimm DL. Quantitative analysis of CMTM6 expression in tumor microenvironment in metastatic melanoma and association with outcome on immunotherapy. OncoImmunology 2020, 10: 1864909. PMID: 33457084, PMCID: PMC7781756, DOI: 10.1080/2162402x.2020.1864909.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsPD-L1CMTM6 expressionControl patientsLonger survivalTissue microarrayQuantitative immunofluorescenceEffectiveness of immunotherapyMetastatic melanoma patientsDeath ligand 1Like MARVEL transmembrane domainCancer Genome Atlas (TCGA) databaseExpression of CMTM6MARVEL transmembrane domainExpression of mRNAChemokine-like factorICI treatmentCheckpoint inhibitorsPretreatment biopsiesCD68 markersImmune compartmentMultivariable analysisMelanoma patientsImmune-related proteinsPredictive factors
2019
An open source automated tumor infiltrating lymphocyte algorithm for prognosis in melanoma
Acs B, Ahmed FS, Gupta S, Wong P, Gartrell RD, Sarin Pradhan J, Rizk EM, Gould Rothberg BE, Saenger YM, Rimm DL. An open source automated tumor infiltrating lymphocyte algorithm for prognosis in melanoma. Nature Communications 2019, 10: 5440. PMID: 31784511, PMCID: PMC6884485, DOI: 10.1038/s41467-019-13043-2.Peer-Reviewed Original ResearchConceptsOpen sourceOpen source softwareSource softwareTIL scoreTraining setDisease-specific overall survivalHigh TIL scorePoor prognosis cohortsSubset of patientsAlgorithmIndependent prognostic markerBroad adoptionAssessment of tumorOverall survivalFavorable prognosisMelanoma patientsMultivariable analysisValidation cohortIndependent associationPrognostic markerSeparate patientsPrognostic variablesIndependent cohortRetrospective collectionMelanomaClosed 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 cancer-associated fibroblasts and immunotherapy outcome in metastatic melanoma
Wong PF, Wei W, Gupta S, Smithy JW, Zelterman D, Kluger HM, Rimm DL. Multiplex quantitative analysis of cancer-associated fibroblasts and immunotherapy outcome in metastatic melanoma. Journal For ImmunoTherapy Of Cancer 2019, 7: 194. PMID: 31337426, PMCID: PMC6651990, DOI: 10.1186/s40425-019-0675-0.Peer-Reviewed Original ResearchConceptsProgression-free survivalBest overall responseSmooth muscle actinOverall survivalCell countQuantitative immunofluorescenceImmune markersImmunotherapy outcomesMelanoma patientsSignificant progression-free survivalAnti-PD-1 therapyAbsence of immunotherapyPretreatment tumor specimensImmune checkpoint blockadeCell death 1Cancer-associated fibroblast (CAF) populationNegative prognostic biomarkerCancer-associated fibroblastsWhole tissue sectionsOverall responseOS associationCAF parametersCheckpoint blockadeImmune dysregulationDeath-1Multiplex 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
2018
Quantitative Spatial Profiling of PD-1/PD-L1 Interaction and HLA-DR/IDO-1 Predicts Improved Outcomes of Anti–PD-1 Therapies in Metastatic Melanoma
Johnson DB, Bordeaux J, Kim J, Vaupel C, Rimm DL, Ho TH, Joseph RW, Daud AI, Conry RM, Gaughan EM, Hernandez-Aya LF, Dimou A, Funchain P, Smithy J, Witte JS, McKee SB, Ko J, Wrangle J, Dabbas B, Tangri S, Lameh J, Hall J, Markowitz J, Balko JM, Dakappagari N. Quantitative Spatial Profiling of PD-1/PD-L1 Interaction and HLA-DR/IDO-1 Predicts Improved Outcomes of Anti–PD-1 Therapies in Metastatic Melanoma. Clinical Cancer Research 2018, 24: 5250-5260. PMID: 30021908, PMCID: PMC6214750, DOI: 10.1158/1078-0432.ccr-18-0309.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntineoplastic Agents, ImmunologicalB7-H1 AntigenBiomarkers, TumorBiopsyCell Line, TumorFemaleHLA-DR AntigensHumansImmunohistochemistryIndoleamine-Pyrrole 2,3,-DioxygenaseMaleMelanomaMiddle AgedModels, BiologicalNeoplasm MetastasisNeoplasm StagingPrognosisProgrammed Cell Death 1 ReceptorProtein BindingRetreatmentTreatment OutcomeConceptsAnti-PD-1 responseHLA-DRValidation cohortPD-1/PD-L1PD-1 blockersPD-1 monotherapyPD-L1 expressionPretreatment tumor biopsiesProgression-free survivalSubset of patientsAcademic cancer centerBiomarkers of responseIndependent validation cohortClin Cancer ResImmunosuppression mechanismsClinical responseOverall survivalPD-L1Melanoma patientsCancer CenterTreatment outcomesTumor biopsiesDiscovery cohortPatientsIndividual biomarkers
2017
PD-L1 Studies Across Tumor Types, Its Differential Expression and Predictive Value in Patients Treated with Immune Checkpoint Inhibitors
Kluger HM, Zito CR, Turcu G, Baine M, Zhang H, Adeniran A, Sznol M, Rimm DL, Kluger Y, Chen L, Cohen JV, Jilaveanu LB. PD-L1 Studies Across Tumor Types, Its Differential Expression and Predictive Value in Patients Treated with Immune Checkpoint Inhibitors. Clinical Cancer Research 2017, 23: 4270-4279. PMID: 28223273, PMCID: PMC5540774, DOI: 10.1158/1078-0432.ccr-16-3146.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerPD-L1 expressionRenal cell carcinomaPD-1 inhibitorsCell carcinomaImmune-infiltrating cellsMelanoma patientsPD-L1Tumor cellsTumor typesTumor-associated inflammatory cellsCTLA-4 inhibitorsCell lung cancerRenal cell carcinoma cellsHigh response rateClin Cancer ResCell linesMelanoma tumor cellsPD-1Multivariable analysisNSCLC specimensInflammatory cellsLung cancerTissue microarrayResponse rate
2014
Correlation of Somatic Mutations and Clinical Outcome in Melanoma Patients Treated with Carboplatin, Paclitaxel, and Sorafenib
Wilson MA, Zhao F, Letrero R, D'Andrea K, Rimm DL, Kirkwood JM, Kluger HM, Lee SJ, Schuchter LM, Flaherty KT, Nathanson KL. Correlation of Somatic Mutations and Clinical Outcome in Melanoma Patients Treated with Carboplatin, Paclitaxel, and Sorafenib. Clinical Cancer Research 2014, 20: 3328-3337. PMID: 24714776, PMCID: PMC4058354, DOI: 10.1158/1078-0432.ccr-14-0093.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorCarboplatinDouble-Blind MethodFemaleFollow-Up StudiesGenotypeGTP PhosphohydrolasesHumansMaleMelanomaMembrane ProteinsMiddle AgedMutationNeoplasm StagingNiacinamidePaclitaxelPhenylurea CompoundsPrognosisProto-Oncogene Proteins B-rafSkin NeoplasmsSorafenibSurvival RateConceptsProgression-free survivalNRAS-mutant melanomaPlatelet-derived growth factor receptorPerformance statusClinical outcomesNRAS mutationsCox proportional hazards modelVEGF receptorsSomatic mutationsWorse performance statusGood performance statusImproved clinical responseKaplan-Meier methodClinical trial populationsPretreatment tumor samplesSite of diseaseProportional hazards modelEffect of sorafenibBRAF-mutant melanomaFisher's exact testGrowth factor receptorClinical responseOverall survivalClinicopathologic featuresMelanoma patients
2013
Construction and Analysis of Multiparameter Prognostic Models for Melanoma Outcome
Rothberg BE, Rimm DL. Construction and Analysis of Multiparameter Prognostic Models for Melanoma Outcome. Methods In Molecular Biology 2013, 1102: 227-258. PMID: 24258982, PMCID: PMC3912557, DOI: 10.1007/978-1-62703-727-3_13.Peer-Reviewed Original ResearchConceptsAdjuvant regimensNegative sentinel lymph node biopsyAdverse risk-benefit ratioPrognostic modelStage II melanoma patientsSentinel lymph node biopsyConventional clinicopathologic criteriaLymph node biopsyStage II melanomaMelanoma-specific survivalWide local excisionRisk-benefit ratioKi-67 assaysTumor molecular profilesComposite prognostic indicesMost patientsNode biopsyLocal excisionMelanoma patientsPrognostic indexRisk stratificationClinicopathologic criteriaMelanoma outcomesPrognostic biomarkerIndependent cohort
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