2023
ScRNA-seq defines dynamic T-cell subsets in longitudinal colon and peripheral blood samples in immune checkpoint inhibitor-induced colitis
Mann J, Lucca L, Austin M, Merkin R, Robert M, Al Bawardy B, Raddassi K, Aizenbud L, Joshi N, Hafler D, Abraham C, Herold K, Kluger H. ScRNA-seq defines dynamic T-cell subsets in longitudinal colon and peripheral blood samples in immune checkpoint inhibitor-induced colitis. Journal For ImmunoTherapy Of Cancer 2023, 11: e007358. PMID: 37586769, PMCID: PMC10432652, DOI: 10.1136/jitc-2023-007358.Peer-Reviewed Original ResearchMeSH KeywordsColitisHumansImmune Checkpoint InhibitorsSingle-Cell Gene Expression AnalysisSkin NeoplasmsT-Lymphocyte SubsetsConceptsImmune checkpoint inhibitorsT cell subsetsCheckpoint inhibitorsImmune environmentImmune checkpoint inhibitor-induced colitisCheckpoint inhibitor-induced colitisPeripheral immune environmentsStages of colitisTreatment of colitisMerkel cell carcinomaT cell populationsPeripheral blood samplesCourse of progressionT cell receptorMultiple tumor typesAlternative cancer therapyCommon toxicitiesICI colitisTreatment discontinuationAdverse eventsBiologic therapyImmune suppressionCell carcinomaColitisBlood samplesDeterminants of overall survival in patients with metastatic uveal melanoma
Demkowicz P, Pointdujour‐Lim R, Miguez S, Lee Y, Jones B, Barker C, Bosenberg M, Abramson D, Shoushtari A, Kluger H, Francis J, Sznol M, Bakhoum M. Determinants of overall survival in patients with metastatic uveal melanoma. Cancer 2023, 129: 3275-3286. PMID: 37382208, PMCID: PMC11149607, DOI: 10.1002/cncr.34927.Peer-Reviewed Original ResearchMeSH KeywordsFemaleHumansImmune Checkpoint InhibitorsIpilimumabMelanomaRetrospective StudiesUveal NeoplasmsConceptsAnti-PD-1 therapyMetastatic uveal melanomaDeath hazard ratioImmune checkpoint inhibitorsOverall survivalHazard ratioUveal melanomaSurvival outcomesFemale sexCheckpoint inhibitorsECOG scoreValidation cohortEastern Cooperative Oncology Group performance status scaleGood baseline performance statusMetastatic uveal melanoma patientsMetastatic UM patientsImproved overall survivalMedian overall survivalBaseline performance statusBetter survival outcomesImproved survival outcomesPotential of immunotherapyWorse survival outcomesImmune checkpoint therapyKaplan-Meier analysisResponse to "NLRC5 germline variants and their potential role in eliciting an immune response in patients with cancer treated with immune checkpoint inhibitors" by Xiang-Yu Meng
Aizenbud L, Schoenfeld D, Caulfield J, Mann J, Austin M, Perdigoto A, Herold K, Kluger H. Response to "NLRC5 germline variants and their potential role in eliciting an immune response in patients with cancer treated with immune checkpoint inhibitors" by Xiang-Yu Meng. Journal For ImmunoTherapy Of Cancer 2023, 11: e007397. PMID: 37349129, PMCID: PMC10314693, DOI: 10.1136/jitc-2023-007397.Peer-Reviewed Original ResearchSubsets 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 ResearchMeSH KeywordsB7-H1 AntigenHumansImmune Checkpoint InhibitorsIpilimumabMelanomaNivolumabTumor MicroenvironmentConceptsImmune 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 patternsSociety for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with targeted therapies
Atkins M, Ascierto P, Feltquate D, Gulley J, Johnson D, Khushalani N, Sosman J, Yap T, Kluger H, Sullivan R, Tawbi H. Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with targeted therapies. Journal For ImmunoTherapy Of Cancer 2023, 11: e005923. PMID: 36918225, PMCID: PMC10016252, DOI: 10.1136/jitc-2022-005923.Peer-Reviewed Original ResearchMeSH KeywordsConsensusHumansImmune Checkpoint InhibitorsImmunotherapyKidney NeoplasmsMelanomaTumor MicroenvironmentConceptsImmune checkpoint inhibitorsConsensus definitionCheckpoint inhibitorsAntiangiogenic therapySingle-agent immune checkpoint inhibitorsConsensus clinical definitionSolid tumor settingTumor immune microenvironmentImmunotherapy of cancerDurable disease controlClinical trial designSignal transduction inhibitorsICI combinationsEndometrial cancerImproved survivalRandomized trialsImmune microenvironmentMechanisms of resistanceHepatocellular carcinomaClinical definitionKidney cancerImmunotherapyTumor settingsCombination treatmentTrial designSociety for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with chemotherapy
Rizvi N, Ademuyiwa F, Cao Z, Chen H, Ferris R, Goldberg S, Hellmann M, Mehra R, Rhee I, Park J, Kluger H, Tawbi H, Sullivan R. Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with chemotherapy. Journal For ImmunoTherapy Of Cancer 2023, 11: e005920. PMID: 36918220, PMCID: PMC10016262, DOI: 10.1136/jitc-2022-005920.Peer-Reviewed Original ResearchMeSH KeywordsConsensusDrug Therapy, CombinationHumansImmune Checkpoint InhibitorsImmunotherapyLung NeoplasmsConceptsImmune checkpoint inhibitorsConsensus definitionCheckpoint inhibitorsAddition of ICIsAnti-programmed cell death protein 1Combination of ICIsCell death protein 1Consensus clinical definitionProfound clinical benefitDeath protein 1Immunotherapy of cancerSolid tumor indicationsClinical trial designICI combinationsImmunotherapy combinationsRecurrent diseaseUpfront treatmentClinical benefitLung cancerMechanisms of resistanceTargeted therapyClinical definitionTumor indicationsTrial designUS FoodSociety for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors
Kluger H, Barrett J, Gainor J, Hamid O, Hurwitz M, LaVallee T, Moss R, Zappasodi R, Sullivan R, Tawbi H, Sharon E. Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors. Journal For ImmunoTherapy Of Cancer 2023, 11: e005921. PMID: 36918224, PMCID: PMC10016305, DOI: 10.1136/jitc-2022-005921.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsCheckpoint inhibitorsAnti-PD-1 immune checkpoint inhibitorTrial designConsensus definitionConsensus clinical definitionExtended disease controlNew combination regimensImmunotherapy of cancerStandard of careLong-term survivalClinical trial designICI combinationsInitial immunotherapyMetastatic settingTreatment discontinuationDurable responsesTreatment landscapeCombination regimensMechanisms of resistancePerioperative settingPrimary resistanceClinical definitionDefinition of resistanceImmunotherapyGermline genetic variants are associated with development of insulin-dependent diabetes in cancer patients treated with immune checkpoint inhibitors
Caulfield J, Aizenbud L, Perdigoto A, Meffre E, Jilaveanu L, Michalek D, Rich S, Aizenbud Y, Adeniran A, Herold K, Austin M, Kluger H. Germline genetic variants are associated with development of insulin-dependent diabetes in cancer patients treated with immune checkpoint inhibitors. Journal For ImmunoTherapy Of Cancer 2023, 11: e006570. PMID: 36898736, PMCID: PMC10008335, DOI: 10.1136/jitc-2022-006570.Peer-Reviewed Original ResearchMeSH KeywordsDiabetes Mellitus, Type 1Germ CellsGerm-Line MutationHumansImmune Checkpoint InhibitorsInsulinsIntracellular Signaling Peptides and ProteinsNeoplasmsConceptsImmune-related adverse eventsInsulin-dependent diabetesImmune checkpoint inhibitorsType 1 diabetesCheckpoint inhibitorsControl patientsSevere immune-related adverse eventsImmunotherapy-treated patientsCheckpoint inhibitor therapyIslet cell destructionPotential predictive biomarkersIslet cell functionWhole-exome sequencingICI exposureAdverse eventsGermline genetic variantsInhibitor therapyPatient selectionTreatment regimensCancer patientsPredictive biomarkersGeneral populationPatientsDiabetesSame drug
2022
Mortality after acute kidney injury and acute interstitial nephritis in patients prescribed immune checkpoint inhibitor therapy
Baker ML, Yamamoto Y, Perazella MA, Dizman N, Shirali AC, Hafez N, Weinstein J, Simonov M, Testani JM, Kluger HM, Cantley LG, Parikh CR, Wilson FP, Moledina DG. Mortality after acute kidney injury and acute interstitial nephritis in patients prescribed immune checkpoint inhibitor therapy. Journal For ImmunoTherapy Of Cancer 2022, 10: e004421. PMID: 35354588, PMCID: PMC8968986, DOI: 10.1136/jitc-2021-004421.Peer-Reviewed Original ResearchMeSH KeywordsAcute Kidney InjuryCreatinineHumansImmune Checkpoint InhibitorsKidneyNephritis, InterstitialConceptsAcute interstitial nephritisAcute kidney injuryImmune checkpoint inhibitor therapyCheckpoint inhibitor therapyICI therapyKidney injuryInhibitor therapyInterstitial nephritisTime-varying Cox proportional hazards modelsHigher peak serum creatinineSevere acute kidney injuryCancer typesCox proportional hazards modelAssociations of biopsyBaseline laboratory valuesObservational cohort studyPeak serum creatinineFavorable treatment responseProportional hazards modelAKI patientsTherapy initiationCohort studySerum creatinineUnivariable analysisImmune activationInhibition of renalase drives tumour rejection by promoting T cell activation
Guo X, Jessel S, Qu R, Kluger Y, Chen TM, Hollander L, Safirstein R, Nelson B, Cha C, Bosenberg M, Jilaveanu LB, Rimm D, Rothlin CV, Kluger HM, Desir GV. Inhibition of renalase drives tumour rejection by promoting T cell activation. European Journal Of Cancer 2022, 165: 81-96. PMID: 35219026, PMCID: PMC8940682, DOI: 10.1016/j.ejca.2022.01.002.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsHumansImmune Checkpoint InhibitorsImmunotherapyMelanomaMiceMonoamine OxidaseTumor MicroenvironmentConceptsPD-1 inhibitorsMurine melanoma modelMelanoma-bearing miceMelanoma modelTumor microenvironmentTumor rejectionCell death protein 1 (PD-1) inhibitorsAnti-PD-1 activityEnhanced T cell infiltrationT cell-dependent fashionMelanoma cellsMelanoma tumor regressionPreclinical melanoma modelsT cell infiltrationNatural killer cellsForkhead box P3Expression of IFNγWild-type miceProtein 1 inhibitorT cell activationTumor cell contentWild-type melanoma cellsCD4 cellsAdvanced melanomaAntibody treatment
2021
A Phase I Study of APX005M and Cabiralizumab with or without Nivolumab in Patients with Melanoma, Kidney Cancer, or Non–Small Cell Lung Cancer Resistant to Anti-PD-1/PD-L1
Weiss SA, Djureinovic D, Jessel S, Krykbaeva I, Zhang L, Jilaveanu L, Ralabate A, Johnson B, Levit NS, Anderson G, Zelterman D, Wei W, Mahajan A, Trifan O, Bosenberg M, Kaech SM, Perry CJ, Damsky W, Gettinger S, Sznol M, Hurwitz M, Kluger HM. A Phase I Study of APX005M and Cabiralizumab with or without Nivolumab in Patients with Melanoma, Kidney Cancer, or Non–Small Cell Lung Cancer Resistant to Anti-PD-1/PD-L1. Clinical Cancer Research 2021, 27: 4757-4767. PMID: 34140403, PMCID: PMC9236708, DOI: 10.1158/1078-0432.ccr-21-0903.Peer-Reviewed Original ResearchConceptsAnti-PD-1/PD-L1Non-small cell lung cancerCell lung cancerRenal cell carcinomaPD-L1Lung cancerDisease progressionCommon treatment-related adverse eventsPD-1/PD-L1 inhibitorsTreatment-related adverse eventsPhase 2 doseSubstantial clinical challengeUnconfirmed partial responseDose-limiting toxicityPD-L1 inhibitorsPhase I trialDose-escalation designPro-inflammatory cytokinesMultiple tumor typesAsymptomatic elevationStable diseaseIntolerable toxicityAdverse eventsMedian durationPartial responseImmune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of immunosuppressants and association with outcome: ECOG-ACRIN E1609 study analysis
Tarhini AA, Kang N, Lee SJ, Hodi FS, Cohen GI, Hamid O, Hutchins LF, Sosman JA, Kluger HM, Eroglu Z, Koon HB, Lawrence DP, Kendra KL, Minor DR, Lee CB, Albertini MR, Flaherty LE, Petrella TM, Streicher H, Sondak VK, Kirkwood JM. Immune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of immunosuppressants and association with outcome: ECOG-ACRIN E1609 study analysis. Journal For ImmunoTherapy Of Cancer 2021, 9: e002535. PMID: 33963015, PMCID: PMC8108687, DOI: 10.1136/jitc-2021-002535.Peer-Reviewed Original ResearchConceptsImmune-related adverse eventsRelapse-free survivalUse of immunosuppressantsAdjuvant ipilimumabGrade 3Grade 1Significant associationAdverse eventsPrognostic factorsSpecific immune-related adverse eventsTerms of RFSEndocrine immune-related adverse eventsBetter relapse-free survivalHigh-dose corticosteroidsImmune adverse eventsHigh-risk melanomaIndependent prognostic factorOverall survival outcomesDose corticosteroidsImmunosuppressant useRFS benefitsImproved OSBetter prognosisAdjuvant useSurvival outcomesThree-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma
Nghiem P, Bhatia S, Lipson EJ, Sharfman WH, Kudchadkar RR, Brohl AS, Friedlander PA, Daud A, Kluger HM, Reddy SA, Boulmay BC, Riker A, Burgess MA, Hanks BA, Olencki T, Kendra K, Church C, Akaike T, Ramchurren N, Shinohara MM, Salim B, Taube JM, Jensen E, Kalabis M, Fling SP, Moreno B, Sharon E, Cheever MA, Topalian SL. Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma. Journal For ImmunoTherapy Of Cancer 2021, 9: e002478. PMID: 33879601, PMCID: PMC8061836, DOI: 10.1136/jitc-2021-002478.Peer-Reviewed Original ResearchConceptsProgression-free survivalMerkel cell carcinomaSalvage therapyStable diseaseCell carcinomaBaseline Eastern Cooperative Oncology Group performance statusEastern Cooperative Oncology Group performance statusAnti-programmed death-1 therapyCell death-1 pathway inhibitorsDeath-1 pathway inhibitorsDurable progression-free survivalFirst-line pembrolizumab therapyMedian progression-free survivalMulticenter phase II trialRefractory Merkel cell carcinomaTumor progressionAdvanced Merkel cell carcinomaMedian response durationFirst-line pembrolizumabPhase II trialProportion of patientsInitial disease progressionThree-year survivalDurable tumor regressionOverall response rateAdverse events induced by immune checkpoint inhibitors
Perdigoto AL, Kluger H, Herold KC. Adverse events induced by immune checkpoint inhibitors. Current Opinion In Immunology 2021, 69: 29-38. PMID: 33640598, PMCID: PMC8122053, DOI: 10.1016/j.coi.2021.02.002.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAutoantibodiesAutoantigensAutoimmune DiseasesAutoimmunityCytotoxicity, ImmunologicDrug-Related Side Effects and Adverse ReactionsGene-Environment InteractionGenetic Predisposition to DiseaseHumansImmune Checkpoint InhibitorsImmunotherapyLymphocyte ActivationNeoplasmsT-LymphocytesConceptsImmune checkpoint inhibitorsCheckpoint inhibitorsAdverse eventsT cellsImmune related adverse eventsEmergence of autoantibodiesRelated adverse eventsAnti-tumor responseAutoreactive T cellsActivated T cellsAutoimmune mechanismsTreatment of cancerAutoimmune diseasesInflammatory responsePredictive valueHost factorsToxic effectsInhibitorsDirect effectOngoing investigationAutoantibodiesCellsAutoimmunityPathogenesisCancerLeft ventricular myocardial strain and tissue characterization by cardiac magnetic resonance imaging in immune checkpoint inhibitor associated cardiotoxicity
Higgins AY, Arbune A, Soufer A, Ragheb E, Kwan JM, Lamy J, Henry M, Cuomo JR, Charifa A, Gallegos C, Hull S, Coviello JS, Bader AS, Peters DC, Huber S, Mojibian HR, Sinusas AJ, Kluger H, Baldassarre LA. Left ventricular myocardial strain and tissue characterization by cardiac magnetic resonance imaging in immune checkpoint inhibitor associated cardiotoxicity. PLOS ONE 2021, 16: e0246764. PMID: 33606757, PMCID: PMC7895343, DOI: 10.1371/journal.pone.0246764.Peer-Reviewed Original ResearchConceptsGlobal longitudinal strainImmune checkpoint inhibitorsLate gadolinium enhancementRecovery of LVEFLake Louise criteriaCheckpoint inhibitorsNormal LVEFAverage global longitudinal strainPresence of LGEAbnormal global longitudinal strainCardiac magnetic resonance imagingCorrect clinical contextEvaluation of myocarditisLeft ventricular dysfunctionVentricular ejection fractionDiagnosis of myocarditisLeft ventricular strainCardiac magnetic resonanceLeft ventricular myocardial strainOvert left ventricular dysfunctionVentricular myocardial strainMagnetic resonance imagingAtrial strainVentricular dysfunctionVentricular strainBiomarker Discovery in Patients with Immunotherapy-Treated Melanoma with Imaging Mass CytometryMultiplex Discovery with Imaging Mass Cytometry
Martinez-Morilla S, Villarroel-Espindola F, Wong PF, Toki MI, Aung TN, Pelekanou V, Bourke-Martin B, Schalper KA, Kluger HM, Rimm DL. Biomarker Discovery in Patients with Immunotherapy-Treated Melanoma with Imaging Mass CytometryMultiplex Discovery with Imaging Mass Cytometry. Clinical Cancer Research 2021, 27: 1987-1996. PMID: 33504554, PMCID: PMC8026677, DOI: 10.1158/1078-0432.ccr-20-3340.Peer-Reviewed Original ResearchMeSH KeywordsBeta 2-MicroglobulinBiomarkers, TumorHumansImage CytometryImmune Checkpoint InhibitorsMelanomaRNA, MessengerTissue Array AnalysisTumor Microenvironment
2020
PD-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 ResearchMeSH KeywordsB7-H1 AntigenBrain NeoplasmsCarcinoma, Non-Small-Cell LungCentral Nervous System NeoplasmsHumansImmune Checkpoint InhibitorsNeoplasm MetastasisProgrammed Cell Death 1 ReceptorConceptsNon-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 drugsBempegaldesleukin (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