2024
Patterns of brain metastases response to immunotherapy with pembrolizumab
Mahajan A, Goldberg S, Weiss S, Tran T, Singh K, Joshi K, Aboian M, Kluger H, Chiang V. Patterns of brain metastases response to immunotherapy with pembrolizumab. Journal Of Neuro-Oncology 2024, 169: 555-561. PMID: 38963658, DOI: 10.1007/s11060-024-04754-8.Peer-Reviewed Original ResearchNon-small cell lung cancerBrain metastasesComplete resolutionLung cancerMedian time to CNS progressionLesion progressionNon-small cell lung cancer patientsModified RECIST criteriaPD-1 inhibitorsTrial of pembrolizumabEffective systemic treatmentResponse to immunotherapyPhase II trialCell lung cancerMethodsThis retrospective studyLocal treatment decisionsPurposeCentral nervous systemCNS progressionRECIST criteriaPD-1Local therapySystemic treatmentMRI evaluationResponse assessmentRetrospective study
2022
Location matters: LAG3 levels are lower in renal cell carcinoma metastatic sites compared to primary tumors, and expression at metastatic sites only may have prognostic importance
Schoenfeld D, Merkin R, Moutafi M, Martinez S, Adeniran A, Kumar D, Jilaveanu L, Hurwitz M, Rimm D, Kluger H. Location matters: LAG3 levels are lower in renal cell carcinoma metastatic sites compared to primary tumors, and expression at metastatic sites only may have prognostic importance. Frontiers In Oncology 2022, 12: 990367. PMID: 36313654, PMCID: PMC9608089, DOI: 10.3389/fonc.2022.990367.Peer-Reviewed Original ResearchRenal cell carcinomaImmune checkpoint inhibitorsMetastatic sitesBrain metastasesPrimary tumorMechanisms of resistancePD-1/PD-L1Anti-PD-1 therapyHigh-risk clinical characteristicsLarger primary tumor sizeAdvanced renal cell carcinomaAlternative immune checkpointsCertain drug regimensPoor-risk diseasePD-1 inhibitorsMinority of patientsPrimary tumor sizeLonger overall survivalGrade 4 tumorsProtein levelsPrimary RCC tumorsAttractive therapeutic targetIdentification of subgroupsCheckpoint inhibitorsUpfront therapyInhibition 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 ResearchConceptsPD-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
Prolonged Complete Response of Early Stage Primary Adenocarcinoma of the Lung to Nivolumab Monotherapy.
Unlu S, Grant MJ, Gettinger S, Adeniran A, Kluger HM. Prolonged Complete Response of Early Stage Primary Adenocarcinoma of the Lung to Nivolumab Monotherapy. Clinical Oncology Case Reports 2021, 4 PMID: 34382032, PMCID: PMC8353529.Peer-Reviewed Original ResearchMultiple primary malignant tumorsNivolumab monotherapyCheckpoint inhibitorsLung cancerHigh Programmed-Death Ligand 1 (PD-L1) expressionProgrammed Death Ligand 1 ExpressionNon-small cell lung cancerMultiple regional lymph nodesImmune checkpoint inhibitorsPD-1 inhibitorsLigand 1 expressionPrimary lung cancerEarly-stage diseaseRegional lymph nodesCell lung cancerPrimary malignant tumorsHigh-risk natureSystemic immunotherapyDurable responsesAdvanced melanomaComplete responseEffective immunotherapyLymph nodesMore patientsPrimary adenocarcinoma
2019
1375TiP Pembrolizumab (pembro) plus lenvatinib (len) for first-line treatment of patients (pts) with advanced melanoma: Phase III LEAP-003 study
Eggermont A, Carlino M, Hauschild A, Ascierto P, Arance A, Daud A, O’Day S, Taylor M, Smith A, Rodgers A, Moreno B, Diede S, Kluger H. 1375TiP Pembrolizumab (pembro) plus lenvatinib (len) for first-line treatment of patients (pts) with advanced melanoma: Phase III LEAP-003 study. Annals Of Oncology 2019, 30: v561. DOI: 10.1093/annonc/mdz255.063.Peer-Reviewed Original ResearchBlinded independent central reviewPD-1 inhibitorsAdvanced melanomaSanofi GenzymeSubsidiary of MerckArray BioPharmaDohme Corp.Pierre FabreRoche-GenentechEnd pointMerck SharpBaseline tumor samplesNCI CTCAE v4.0Performance status 0/1Antitumor activityPrimary end pointSecondary end pointsFirst-line standardFirst-line treatmentUntreated stage IIIIndependent central reviewMurine tumor modelsPDGF receptor αEligible ptsQd poFrequent Use of Local Therapy Underscores Need for Multidisciplinary Care in the Management of Patients With Melanoma Brain Metastases Treated With PD-1 Inhibitors
Qian JM, Yu JB, Mahajan A, Goldberg SB, Kluger HM, Chiang VLS. Frequent Use of Local Therapy Underscores Need for Multidisciplinary Care in the Management of Patients With Melanoma Brain Metastases Treated With PD-1 Inhibitors. International Journal Of Radiation Oncology • Biology • Physics 2019, 105: 1113-1118. PMID: 31479702, DOI: 10.1016/j.ijrobp.2019.08.053.Peer-Reviewed Original ResearchConceptsBrain metastasesLocal therapyNeurologic safetyMelanoma patientsProspective phase 2 trialProgressive brain metastasesSerial brain imagingMelanoma brain metastasesPD-1 inhibitorsPhase 2 trialRapid disease progressionManagement of patientsNeurologic symptomsMultidisciplinary careTrial enrollmentCystic changesClinical trialsDisease progressionPatientsLesion sizeMetastasisMultidisciplinary teamTumor growthTherapyClinical decisionB cell depletion or absence does not impede anti-tumor activity of PD-1 inhibitors
Damsky W, Jilaveanu L, Turner N, Perry C, Zito C, Tomayko M, Leventhal J, Herold K, Meffre E, Bosenberg M, Kluger HM. B cell depletion or absence does not impede anti-tumor activity of PD-1 inhibitors. Journal For ImmunoTherapy Of Cancer 2019, 7: 153. PMID: 31200747, PMCID: PMC6567557, DOI: 10.1186/s40425-019-0613-1.Peer-Reviewed Original ResearchConceptsPD-1 inhibitorsB cell contentB-cell depletionAnti-tumor activityB cellsMuMT miceCell depletionAnti-PD-1 inhibitorsAnti-PD-1 responseB-cell depleting drugsTumor-infiltrating B cellsImpaired B-cell functionT cell-dependent tumor rejectionPD-1 inhibitionMC38 colon cancerB cell functionAnti-tumor effectsB-cell malignanciesMurine cancer modelsCell contentOverall survivalTumor rejectionCD20 antibodyAutoimmune disordersTumor shrinkageLenvatinib (len) plus pembrolizumab (pembro) in patients (pts) with advanced melanoma previously exposed to anti–PD-1/PD-L1 agents: Phase 2 LEAP-004 study.
Arance Fernandez A, Ascierto P, Carlino M, Daud A, Eggermont A, Hauschild A, Kluger H, Taylor M, Smith A, Chen K, Krepler C, Diede S, O'Day S. Lenvatinib (len) plus pembrolizumab (pembro) in patients (pts) with advanced melanoma previously exposed to anti–PD-1/PD-L1 agents: Phase 2 LEAP-004 study. Journal Of Clinical Oncology 2019, 37: tps9594-tps9594. DOI: 10.1200/jco.2019.37.15_suppl.tps9594.Peer-Reviewed Original ResearchPD-1/PD-L1 inhibitor therapyPD-L1 inhibitor therapyPD-1 inhibitorsRECIST v1.1Advanced melanomaLast doseInhibitor therapyAnti-PD-1/PD-L1 agentsKey secondary end pointPrimary efficacy end pointEnd pointActive autoimmune diseaseAdequate organ functionBaseline tumor samplesECOG PS 0/1Exploratory biomarker analysisNCI CTCAE v4.0PD-L1 agentsUnresectable stage IIIAntitumor activityEfficacy end pointSecondary end pointsWeeks of therapyPhase 2 trialKey inclusion criteria
2018
Anti‐PD‐1 Therapy‐Associated Perforating Colitis
Celli R, Kluger HM, Zhang X. Anti‐PD‐1 Therapy‐Associated Perforating Colitis. Case Reports In Gastrointestinal Medicine 2018, 2018: 3406437. PMID: 29955400, PMCID: PMC6000840, DOI: 10.1155/2018/3406437.Peer-Reviewed Original ResearchAnti-PD-1/PD-L1PD-L1T-lymphocyte-associated antigen 4Immune-related adverse effectsCell death protein 1PD-1 inhibitorsDeath protein 1T-cell regulatory moleculesAdvanced malignanciesColonic perforationAntigen-4Metastatic melanomaTimely diagnosisColitisAdverse effectsProtein 1PerforationCell regulatory moleculesRegulatory moleculesPembrolizumabDiarrheaPatientsMalignancyMelanomaDiagnosis
2017
Sarcoidosis Following Anti-PD-1 and Anti-CTLA-4 Therapy for Metastatic Melanoma
Reddy SB, Possick JD, Kluger HM, Galan A, Han D. Sarcoidosis Following Anti-PD-1 and Anti-CTLA-4 Therapy for Metastatic Melanoma. Journal Of Immunotherapy 2017, 40: 307-311. PMID: 28737620, DOI: 10.1097/cji.0000000000000181.Peer-Reviewed Case Reports and Technical NotesMeSH KeywordsAdrenal Cortex HormonesAntibodies, MonoclonalAntineoplastic Combined Chemotherapy ProtocolsAutoimmunityCTLA-4 AntigenDrug-Related Side Effects and Adverse ReactionsFemaleHumansImmunotherapyIpilimumabLungMelanomaMiddle AgedNivolumabProgrammed Cell Death 1 ReceptorSarcoidosisSkinSkin NeoplasmsTreatment OutcomeConceptsAnti-PD-1 therapyImmune checkpoint inhibitorsStage IV melanomaCheckpoint inhibitorsOncologic responseSevere immune-related adverse effectsImmune checkpoint inhibitor therapyImmune-related adverse effectsAnti PD-1Severe pulmonary manifestationsCheckpoint inhibitor therapyPD-1 inhibitorsDevelopment of sarcoidosisAutoimmune tendencyCorticosteroid treatmentLast dosePulmonary manifestationsCutaneous sarcoidosisRare complicationInhibitor therapyRadiologic findingsPatient's symptomsMetastatic melanomaPotential complicationsSarcoidosisPD-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
2016
Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial
Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, Tsiouris AJ, Cohen J, Vortmeyer A, Jilaveanu L, Yu J, Hegde U, Speaker S, Madura M, Ralabate A, Rivera A, Rowen E, Gerrish H, Yao X, Chiang V, Kluger HM. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. The Lancet Oncology 2016, 17: 976-983. PMID: 27267608, PMCID: PMC5526047, DOI: 10.1016/s1470-2045(16)30053-5.Peer-Reviewed Original ResearchConceptsProgressive brain metastasesUntreated brain metastasesBrain metastasis responseYale Cancer CenterBrain metastasesPhase 2 trialCell lung cancerAdverse eventsMetastasis responseCancer CenterLung cancerMelanoma cohortGrade 3 colitisGrade 3 fatigueGrade 3 pneumonitisPD-1 axisAcute kidney injuryNeurological adverse eventsPD-1 inhibitorsAcceptable safety profilePD-L1 expressionSystemic immunotherapyKidney injuryPrimary endpointNSCLC cohort
2014
PD-L1 Expression in Clear Cell Renal Cell Carcinoma: An Analysis of Nephrectomy and Sites of Metastases
Jilaveanu LB, Shuch B, Zito CR, Parisi F, Barr M, Kluger Y, Chen L, Kluger HM. PD-L1 Expression in Clear Cell Renal Cell Carcinoma: An Analysis of Nephrectomy and Sites of Metastases. Journal Of Cancer 2014, 5: 166-172. PMID: 24563671, PMCID: PMC3931264, DOI: 10.7150/jca.8167.Peer-Reviewed Original ResearchPD-L1 expressionMetastatic sitesPD-L1Tissue microarrayMetastatic specimensTumor PD-L1 expressionClear cell renal cell carcinomaPD-1 inhibitorsAutomated Quantitative AnalysisMetastatic RCC patientsCell renal cell carcinomaSite of metastasisRenal cell carcinomaClear cell RCCRenal cell carcinoma cellsInter-tumor heterogeneityRCC patientsCell carcinomaNephrectomy specimensTumor expressionCore biopsyImmune escapeCell RCCBiopsy coresClinical development