2024
Digital spatial proteomic profiling reveals immune checkpoints as biomarkers in lymphoid aggregates and tumor microenvironment of desmoplastic melanoma
Su D, Schoenfeld D, Ibrahim W, Cabrejo R, Djureinovic D, Baumann R, Rimm D, Khan S, Halaban R, Kluger H, Olino K, Galan A, Clune J. Digital spatial proteomic profiling reveals immune checkpoints as biomarkers in lymphoid aggregates and tumor microenvironment of desmoplastic melanoma. Journal For ImmunoTherapy Of Cancer 2024, 12: e008646. PMID: 38519058, PMCID: PMC10961546, DOI: 10.1136/jitc-2023-008646.Peer-Reviewed Original ResearchMeSH KeywordsActinsBiomarkers, TumorCTLA-4 AntigenHumansMelanomaProgrammed Cell Death 1 ReceptorProteomicsTumor MicroenvironmentConceptsCTLA-4 expression levelsCancer-associated fibroblastsAssociated with worse survivalExpression of immune checkpointsLAG-3 expressionDesmoplastic melanomaLymphoid aggregatesCTLA-4PD-1Immune checkpointsIntratumoral leukocytesLAG-3Tumor compartmentsWorse survivalCD20+B cellsIncreased expression of immune checkpointsProgrammed cell death protein 1Macrophage/monocyte markerSentinel lymph node positivityCell death protein 1Associated with poor prognosisLymph node positivityDense fibrous stromaPotential prognostic significanceCore of tumors
2019
Patterns of failure after immunotherapy with checkpoint inhibitors predict durable progression-free survival after local therapy for metastatic melanoma
Klemen ND, Wang M, Feingold PL, Cooper K, Pavri SN, Han D, Detterbeck FC, Boffa DJ, Khan SA, Olino K, Clune J, Ariyan S, Salem RR, Weiss SA, Kluger HM, Sznol M, Cha C. Patterns of failure after immunotherapy with checkpoint inhibitors predict durable progression-free survival after local therapy for metastatic melanoma. Journal For ImmunoTherapy Of Cancer 2019, 7: 196. PMID: 31340861, PMCID: PMC6657062, DOI: 10.1186/s40425-019-0672-3.Peer-Reviewed Original ResearchConceptsThree-year progression-free survivalProgression-free survivalDisease-specific survivalFive-year disease-specific survivalPatterns of failureDurable progression-free survivalLocal therapyStereotactic body radiotherapyMetastatic melanomaNew metastasesPatient selectionIndependent radiological reviewOngoing complete responseResultsFour hundred twentyEvidence of diseaseCNS metastasisCPI treatmentImmunotherapy failureCheckpoint inhibitorsMost patientsProgressive diseaseRadiological reviewComplete responsePD-1PD-L1
2018
Early B cell changes predict autoimmunity following combination immune checkpoint blockade
Das R, Bar N, Ferreira M, Newman AM, Zhang L, Bailur JK, Bacchiocchi A, Kluger H, Wei W, Halaban R, Sznol M, Dhodapkar MV, Dhodapkar KM. Early B cell changes predict autoimmunity following combination immune checkpoint blockade. Journal Of Clinical Investigation 2018, 128: 715-720. PMID: 29309048, PMCID: PMC5785243, DOI: 10.1172/jci96798.Peer-Reviewed Original ResearchConceptsCombination checkpoint blockadeB cell changesB cellsCheckpoint blockadeCell changesCombination immune checkpoint blockadeB-cell receptor sequencingRisk of irAEsImmune checkpoint blockadeCell receptor sequencingB cell activationTreatment-induced changesCCB therapyAdverse eventsPD1 expressionPD1 receptorGrade 3PatientsCell activationEarly changesSingle-cell RNA sequencingTherapyPreemptive strategyCancer therapyIrAEsA Serum Protein Signature Associated with Outcome after Anti–PD-1 Therapy in Metastatic Melanoma
Weber JS, Sznol M, Sullivan RJ, Blackmon S, Boland G, Kluger HM, Halaban R, Bacchiocchi A, Ascierto PA, Capone M, Oliveira C, Meyer K, Grigorieva J, Asmellash SG, Roder J, Roder H. A Serum Protein Signature Associated with Outcome after Anti–PD-1 Therapy in Metastatic Melanoma. Cancer Immunology Research 2018, 6: 79-86. PMID: 29208646, DOI: 10.1158/2326-6066.cir-17-0412.Peer-Reviewed Original ResearchConceptsAcute phase reactantsCheckpoint inhibitorsOverall survivalPhase reactantsIpilimumab-treated patientsPD-1 blockadeTrials of nivolumabBetter overall survivalIndependent patient cohortsPretreatment serumPD-1Melanoma patientsValidation cohortMetastatic melanomaMultipeptide vaccinePatient cohortPooled analysisWorse outcomesClinical dataPatientsMultivariate analysisComplement cascadeMass spectrometry analysisNivolumabCohort
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 complicationsSarcoidosisStereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTLA-4 treatment is associated with improved intracranial control
An Y, Jiang W, Kim BYS, Qian JM, Tang C, Fang P, Logan J, D'Souza NM, Haydu LE, Wang XA, Hess KR, Kluger H, Glitza IC, Mahajan A, Welsh JW, Lin SH, Yu JB, Davies MA, Hwu P, Sulman EP, Brown PD, Chiang VLS, Li J. Stereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTLA-4 treatment is associated with improved intracranial control. Radiotherapy And Oncology 2017, 125: 80-88. PMID: 28916225, DOI: 10.1016/j.radonc.2017.08.009.Peer-Reviewed Original ResearchConceptsIntracranial disease controlNew brain metastasesIntracranial controlStereotactic radiosurgeryBrain metastasesOverall survivalDisease controlLymphocyte countMulti-institutional retrospective analysisYale-New Haven HospitalMD Anderson cohortMelanoma brain metastasesAbsolute lymphocyte countAntitumor immune responseImmune checkpoint blockadeMetastatic melanoma patientsComplete blood countTumor-specific antigensIndependent validation cohortMulti-institutional studyIpilimumab therapyMedian followLast doseCheckpoint blockadeIntracranial recurrence
2016
Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery
Qian JM, Yu JB, Kluger HM, Chiang VL. Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery. Cancer 2016, 122: 3051-3058. PMID: 27285122, PMCID: PMC5030143, DOI: 10.1002/cncr.30138.Peer-Reviewed Original ResearchConceptsMedian percent reductionImmune checkpoint therapyLesional responseStereotactic radiosurgeryCheckpoint therapyLesion volumeAnti-cytotoxic T-lymphocyte-associated protein 4Anti-programmed cell death protein 1T-lymphocyte-associated protein 4Anti-PD-1 therapyGreater median percent reductionsCell death protein 1Administration of immunotherapyWeeks of immunotherapyMelanoma brain metastasesDeath protein 1Type of immunotherapyWilcoxon rank sum testRank sum testNonconcurrent therapyBrain metastasesMelanoma patientsTreatment of cancerSingle institutionPercent reduction
2015
Combination 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
2013
Nivolumab plus Ipilimumab in Advanced Melanoma
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus Ipilimumab in Advanced Melanoma. New England Journal Of Medicine 2013, 369: 122-133. PMID: 23724867, PMCID: PMC5698004, DOI: 10.1056/nejmoa1302369.Peer-Reviewed Original ResearchConceptsObjective response ratePhase 1 trialAdverse eventsConcurrent therapyAdvanced melanomaTumor regressionClinical activityGrade 3Distinct immunologic mechanismsManageable safety profileProlongs overall survivalDurable tumor regressionSupportive preclinical dataRegimen groupImmunologic mechanismsObjective responseOverall survivalIntravenous dosesSafety profileTumor reductionPreclinical dataIpilimumabNivolumabPatientsMaximum doses
2010
Ipilimumab: a promising immunotherapy for melanoma.
Thumar JR, Kluger HM. Ipilimumab: a promising immunotherapy for melanoma. Oncology 2010, 24: 1280-8. PMID: 21294471.Peer-Reviewed Original ResearchConceptsMetastatic melanomaClinical trialsCytotoxic T-lymphocyte antigen-4Recent phase III trialsT-lymphocyte antigen-4Overall survival benefitPhase III trialsDrug-related toxicityAntibody-based targetingIII trialsSurvival benefitPromising immunotherapyAntigen-4Immune modulationTreatment responseTherapeutic benefitMelanomaIpilimumabTrialsImmunotherapyUnique challengesCancerClinicians
2008
Toxicity and Activity of a Twice Daily High-dose Bolus Interleukin 2 Regimen in Patients With Metastatic Melanoma and Metastatic Renal Cell Cancer
Acquavella N, Kluger H, Rhee J, Farber L, Tara H, Ariyan S, Narayan D, Kelly W, Sznol M. Toxicity and Activity of a Twice Daily High-dose Bolus Interleukin 2 Regimen in Patients With Metastatic Melanoma and Metastatic Renal Cell Cancer. Journal Of Immunotherapy 2008, 31: 569-576. PMID: 18528297, DOI: 10.1097/cji.0b013e318177a4ba.Peer-Reviewed Original ResearchConceptsIL-2 regimenMetastatic melanomaNormal saline fluid bolusesMetastatic renal cell cancerNew immune modulatorsTreatment-related deathsObjective response ratePercent of patientsRetrospective chart reviewSubset of patientsIL-2 dosesIntensive care unitRenal cell cancerRenal cancer patientsSubstantial acute toxicityDevelopment of combinationsChart reviewCare unitCell cancerMelanoma patientsOncology wardFluid bolusCancer patientsImmune modulatorsMedian number