2024
TIGIT expression in renal cell carcinoma infiltrating T cells is variable and inversely correlated with PD-1 and LAG3
Perales O, Jilaveanu L, Adeniran A, Su D, Hurwitz M, Braun D, Kluger H, Schoenfeld D. TIGIT expression in renal cell carcinoma infiltrating T cells is variable and inversely correlated with PD-1 and LAG3. Cancer Immunology, Immunotherapy 2024, 73: 192. PMID: 39105820, PMCID: PMC11303630, DOI: 10.1007/s00262-024-03773-8.Peer-Reviewed Original ResearchConceptsRenal cell carcinomaRenal cell carcinoma tumorsT cellsTIGIT expressionCheckpoint inhibitorsPD-1Likelihood of response to therapyTumor-infiltrating T cellsCD3+ T cellsRenal cell carcinoma metastasisTreatment of renal cell carcinomaImmune checkpoint inhibitorsInfiltrating T cellsPurposeImmune checkpoint inhibitorsResponse to therapyT cell immunoglobulinCD3+ levelsMetastatic RCC specimensAdjacent normal renal tissuesNormal renal tissuesQuantitative immunofluorescence analysisCell carcinomaResistant diseasePotential therapeutic targetTissue microarray
2022
Longitudinal single-cell analysis of a patient receiving adoptive cell therapy reveals potential mechanisms of treatment failure
Qu R, Kluger Y, Yang J, Zhao J, Hafler D, Krause D, Bersenev A, Bosenberg M, Hurwitz M, Lucca L, Kluger H. Longitudinal single-cell analysis of a patient receiving adoptive cell therapy reveals potential mechanisms of treatment failure. Molecular Cancer 2022, 21: 219. PMID: 36514045, PMCID: PMC9749221, DOI: 10.1186/s12943-022-01688-5.Peer-Reviewed Original ResearchMeSH KeywordsCell- and Tissue-Based TherapyDisease ProgressionHumansImmunotherapy, AdoptiveLymphocytes, Tumor-InfiltratingMelanomaReceptors, Antigen, T-CellSingle-Cell AnalysisTreatment FailureConceptsAdoptive cell therapySingle-cell analysisDepth single-cell analysisSingle-cell RNAACT productsDisease progressionT-cell receptor sequencingCell therapyFamily genesFeatures of exhaustionMultiple tumor typesCell expansionGenesNew clonotypesTIL preparationsClonal cell expansionCytokine therapyTreatment failureSerial bloodClonesEffector functionsSerial samplesTumor typesCellular therapyTherapy
2021
Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma
Sarnaik AA, Hamid O, Khushalani NI, Lewis KD, Medina T, Kluger HM, Thomas SS, Domingo-Musibay E, Pavlick AC, Whitman ED, Martin-Algarra S, Corrie P, Curti BD, Oláh J, Lutzky J, Weber JS, Larkin JMG, Shi W, Takamura T, Jagasia M, Qin H, Wu X, Chartier C, Finckenstein F, Fardis M, Kirkwood JM, Chesney JA. Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma. Journal Of Clinical Oncology 2021, 39: 2656-2666. PMID: 33979178, PMCID: PMC8376325, DOI: 10.1200/jco.21.00612.Peer-Reviewed Original ResearchConceptsObjective response rateDisease control rateAdvanced melanomaPrimary refractoryControl rateMetastatic melanomaTreatment optionsInterleukin-2Investigator-assessed objective response rateHigh-dose interleukin-2Tumor-Infiltrating Lymphocyte TherapyImmune checkpoint inhibitorsPrimary end pointTumor-infiltrating lymphocytesEffective treatment optionLimited treatment optionsAdoptive cell therapyMajor unmet needLymphodepletion regimenPrior therapyCheckpoint inhibitorsAdverse eventsDurable responsesMedian durationPartial responseIntratumour microbiome associated with the infiltration of cytotoxic CD8+ T cells and patient survival in cutaneous melanoma
Zhu G, Su H, Johnson CH, Khan SA, Kluger H, Lu L. Intratumour microbiome associated with the infiltration of cytotoxic CD8+ T cells and patient survival in cutaneous melanoma. European Journal Of Cancer 2021, 151: 25-34. PMID: 33962358, PMCID: PMC8184628, DOI: 10.1016/j.ejca.2021.03.053.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedAged, 80 and overBacteriaBacterial LoadBacterial TranslocationChemokinesClostridialesCytotoxicity, ImmunologicFemaleGastrointestinal MicrobiomeHumansLymphocyte CountLymphocytes, Tumor-InfiltratingMaleMelanomaMiddle AgedPrognosisSkin NeoplasmsT-Lymphocytes, CytotoxicTumor MicroenvironmentYoung AdultConceptsT cellsCutaneous melanomaPatient survivalGut microbiomeAdjusted hazard ratioT cell infiltrationChemokine gene expressionChemokine levelsCytotoxic CD8Hazard ratioSystemic inflammationShorter survivalCCL5 expressionPatient outcomesCD8Immune responseMortality riskGut microbiotaSurvival analysisMelanomaTumor nicheHuman cancersSurvivalSignificant correlationPositive associationCirculating 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 functionImmunotherapyTCRαβBloodAutomated digital TIL analysis (ADTA) adds prognostic value to standard assessment of depth and ulceration in primary melanoma
Moore MR, Friesner ID, Rizk EM, Fullerton BT, Mondal M, Trager MH, Mendelson K, Chikeka I, Kurc T, Gupta R, Rohr BR, Robinson EJ, Acs B, Chang R, Kluger H, Taback B, Geskin LJ, Horst B, Gardner K, Niedt G, Celebi JT, Gartrell-Corrado RD, Messina J, Ferringer T, Rimm DL, Saltz J, Wang J, Vanguri R, Saenger YM. Automated digital TIL analysis (ADTA) adds prognostic value to standard assessment of depth and ulceration in primary melanoma. Scientific Reports 2021, 11: 2809. PMID: 33531581, PMCID: PMC7854647, DOI: 10.1038/s41598-021-82305-1.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overBiopsyChemotherapy, AdjuvantClinical Decision-MakingDeep LearningFemaleFollow-Up StudiesHumansImage Processing, Computer-AssistedKaplan-Meier EstimateLymphocytes, Tumor-InfiltratingMaleMelanomaMiddle AgedNeoplasm StagingPatient SelectionPrognosisRetrospective StudiesRisk AssessmentROC CurveSkinSkin NeoplasmsYoung AdultConceptsTumor-infiltrating lymphocytesDisease-specific survivalEarly-stage melanomaOpen-source deep learningCutoff valueMultivariable Cox proportional hazards analysisCox proportional hazards analysisDeep learningLow-risk patientsProportional hazards analysisKaplan-Meier analysisAccurate prognostic biomarkersEosin imagesAccuracy of predictionAdjuvant therapyRisk patientsSpecific survivalPrognostic valueValidation cohortReceiver operating curvesTraining cohortTIL analysisClinical trialsPrimary melanomaPrognostic biomarker
2020
Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02)
Diab A, Tannir NM, Bentebibel SE, Hwu P, Papadimitrakopoulou V, Haymaker C, Kluger HM, Gettinger SN, Sznol M, Tykodi SS, Curti BD, Tagliaferri MA, Zalevsky J, Hannah AL, Hoch U, Aung S, Fanton C, Rizwan A, Iacucci E, Liao Y, Bernatchez C, Hurwitz ME, Cho DC. Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02). Cancer Discovery 2020, 10: 1158-1173. PMID: 32439653, DOI: 10.1158/2159-8290.cd-19-1510.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntineoplastic Agents, ImmunologicalAntineoplastic Combined Chemotherapy ProtocolsCarcinoma, Non-Small-Cell LungCarcinoma, Renal CellFemaleGene Expression Regulation, NeoplasticHumansImmune Checkpoint InhibitorsImmunotherapyInterleukin-2Kidney NeoplasmsLung NeoplasmsLymphocyte CountLymphocytes, Tumor-InfiltratingMaleMelanomaMiddle AgedNivolumabPolyethylene GlycolsProgrammed Cell Death 1 ReceptorTreatment OutcomeYoung AdultConceptsTreatment-related adverse eventsAdvanced solid tumorsPD-L1 statusSolid tumorsGrade 3/4 treatment-related adverse eventsPD-1/PD-L1 blockadeCommon treatment-related adverse eventsPhase I dose-escalation trialPoor prognostic risk factorsTotal objective response rateI dose-escalation studyI dose-escalation trialLongitudinal tumor biopsiesPD-L1 blockadeT-cell enhancementTreatment-related deathsObjective response ratePhase II doseDose-escalation studyDose-escalation trialDose-limiting toxicityFlu-like symptomsPrognostic risk factorsTumor-infiltrating lymphocytesCytotoxicity of CD8
2019
High-Plex Predictive Marker Discovery for Melanoma Immunotherapy–Treated Patients Using Digital Spatial Profiling
Toki MI, Merritt CR, Wong PF, Smithy JW, Kluger HM, Syrigos KN, Ong GT, Warren SE, Beechem JM, Rimm DL. High-Plex Predictive Marker Discovery for Melanoma Immunotherapy–Treated Patients Using Digital Spatial Profiling. Clinical Cancer Research 2019, 25: 5503-5512. PMID: 31189645, PMCID: PMC6744974, DOI: 10.1158/1078-0432.ccr-19-0104.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic Agents, ImmunologicalBiomarkers, TumorFemaleFluorescent Antibody TechniqueHumansImmunohistochemistryImmunotherapyLymphocytes, Tumor-InfiltratingMaleMelanomaMolecular Diagnostic TechniquesMolecular Targeted TherapyPrognosisProportional Hazards ModelsTissue Array AnalysisTreatment OutcomeConceptsNon-small cell lung cancerProlonged progression-free survivalDigital spatial profilingOverall survivalPD-L1Predictive markerPD-L1 expressionProgression-free survivalProtein expressionCell lung cancerNovel predictive markerCD68-positive cellsStromal CD3Melanoma immunotherapyImmune markersImmune therapyPrognostic valueLung cancerAntibody cocktailTissue microarrayQuantitative fluorescenceOutcome assessmentTumor cellsHigh concordanceMultiple biomarkersMultiplex 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
2015
Characterization 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 survivalCharacterization 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-L1Combination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo
Das R, Verma R, Sznol M, Boddupalli CS, Gettinger SN, Kluger H, Callahan M, Wolchok JD, Halaban R, Dhodapkar MV, Dhodapkar KM. Combination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo. The Journal Of Immunology 2015, 194: 950-959. PMID: 25539810, PMCID: PMC4380504, DOI: 10.4049/jimmunol.1401686.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalAntigens, SurfaceAntineoplastic Combined Chemotherapy ProtocolsCTLA-4 AntigenCytokinesGene Expression ProfilingGene Expression Regulation, NeoplasticHumansImmunophenotypingIpilimumabLymphocytes, Tumor-InfiltratingNeoplasmsNivolumabProgrammed Cell Death 1 ReceptorSignal TransductionT-Lymphocyte SubsetsConceptsPD-1T cellsCTLA-4Checkpoint blockadeCombination therapyReceptor occupancyCombination immune checkpoint blockadeCTLA-4 immune checkpointsPD-1 receptor occupancyTransitional memory T cellsAnti-PD-1 therapyAnti CTLA-4Immune-based combinationsPD-1 blockadeSoluble IL-2RImmune checkpoint blockadeNK cell functionMemory T cellsTherapy-induced changesT cell activationTumor T cellsHuman T cellsRemarkable antitumor effectImmunologic changesImmunologic effects