2023
A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better
Djureinovic D, Weiss S, Krykbaeva I, Qu R, Vathiotis I, Moutafi M, Zhang L, Perdigoto A, Wei W, Anderson G, Damsky W, Hurwitz M, Johnson B, Schoenfeld D, Mahajan A, Hsu F, Miller-Jensen K, Kluger Y, Sznol M, Kaech S, Bosenberg M, Jilaveanu L, Kluger H. A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better. Molecular Cancer 2023, 22: 182. PMID: 37964379, PMCID: PMC10644655, DOI: 10.1186/s12943-023-01884-x.Peer-Reviewed Original ResearchConceptsStable diseasePartial responseMacrophage populationsThree-drug regimenUnconfirmed partial responsePhase I trialLimited treatment optionsMonocyte/macrophage populationNon-classical monocytesMurine melanoma modelTreatment-related changesResultsThirteen patientsWorse survivalI trialInflammatory tumorPatient populationTreatment optionsImmune cellsDisease progressionMurine studiesPreclinical modelsResistant melanomaAntigen presentationMurine modelCyTOF analysis1070 ‘Decoy-resistant’ IL-18 in combination with CTLA-4 blockade enhances anti-tumor efficacy in preclinical models of renal cell carcinoma
Schoenfeld D, Djureinovic D, Zhang L, Mann J, Huck J, Jilaveanu L, Ring A, Kluger H. 1070 ‘Decoy-resistant’ IL-18 in combination with CTLA-4 blockade enhances anti-tumor efficacy in preclinical models of renal cell carcinoma. 2023, a1177-a1179. DOI: 10.1136/jitc-2023-sitc2023.1070.Peer-Reviewed Original ResearchA modified IL-18 drug in combination with CTLA-4 blockade enhances anti-tumor efficacy in preclinical models of renal cell carcinoma
Schoenfeld D, Djureinovic D, Zhang L, Mann J, Huck J, Jilaveanu L, Ring A, Kluger H. A modified IL-18 drug in combination with CTLA-4 blockade enhances anti-tumor efficacy in preclinical models of renal cell carcinoma. The Oncologist 2023, 28: s7-s7. PMCID: PMC10445567, DOI: 10.1093/oncolo/oyad216.010.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsRenal cell carcinomaImmune cell depletion studiesCell depletion studiesT cellsAnti-tumor activityPreclinical modelsRENCA modelTumor growthNK cellsIL-18IL-18BPCell carcinomaAnti-PD-1/CTLAAnti-PD-1 therapyIntra-tumoral T cellsModest anti-tumor activityAnti-tumor immune responseCytokine/chemokine levelsCytokine/chemokine profilingDepletion studiesEarly phase clinical trialsDecoy receptor proteinEnrichment of CD8PD-1 blockadeImmune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases
Schoenfeld D, Moutafi M, Martinez S, Djureinovic D, Merkin R, Adeniran A, Braun D, Signoretti S, Choueiri T, Parisi F, Hurwitz M, Rimm D, Wei W, Jilaveanu L, Kluger H. Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases. Journal For ImmunoTherapy Of Cancer 2023, 11: e007240. PMID: 37586773, PMCID: PMC10432651, DOI: 10.1136/jitc-2023-007240.Peer-Reviewed Original ResearchConceptsRenal cell carcinomaBrain metastasesPrimary tumorTumor microenvironmentDigital spatial profilingCell carcinomaActivation protein expressionInflammatory macrophage markersRCC brain metastasesInnate immune activatorsNormal kidney samplesProgressive stagesExtracranial metastasesTim-3Immune checkpointsImmune dysfunctionImmune activationRCC metastasisLonger survivalImmune activatorsMacrophage markersTreatment responseSeparate cohortTissue microarrayMetastatic samplesPeripheral blood immune cell and cytokine profiling of patients receiving corticosteroids for immune checkpoint inhibitor-related adverse events: Steroid dose and duration.
Merkin R, Schoenfeld D, Djureinovic D, Austin M, Wang M, Qu R, Zhang L, Mann J, Wei W, Sun L, Aizenbud L, Destina J, Kluger H. Peripheral blood immune cell and cytokine profiling of patients receiving corticosteroids for immune checkpoint inhibitor-related adverse events: Steroid dose and duration. Journal Of Clinical Oncology 2023, 41: e14694-e14694. DOI: 10.1200/jco.2023.41.16_suppl.e14694.Peer-Reviewed Original ResearchImmune-related adverse eventsImmune checkpoint inhibitorsSevere immune-related adverse eventsPeripheral blood immune cellsBlood immune cellsSteroid therapyDose levelsSteroid taperAdverse eventsIL-6Immune cellsImmune checkpoint inhibitor-related adverse eventsSeverity of irAEsMultiple immune-related adverse eventsAnti-PD-1 therapyT effector memory cellsPeripheral blood mononuclear cellsYale Cancer CenterSerum cytokine concentrationsEffector memory cellsPathogenic T cellsBlood mononuclear cellsConcentrations of TNFαBiomarkers of responseT cell subtypesLenvatinib or anti-VEGF in combination with anti-PD-1 differentially augments anti-tumor activity in melanoma
Tran T, Caulfield J, Zhang L, Schoenfeld D, Djureinovic D, Chiang V, Oria V, Weiss S, Olino K, Jilaveanu L, Kluger H. Lenvatinib or anti-VEGF in combination with anti-PD-1 differentially augments anti-tumor activity in melanoma. JCI Insight 2023, 8: e157347. PMID: 36821392, PMCID: PMC10132152, DOI: 10.1172/jci.insight.157347.Peer-Reviewed Original ResearchConceptsTumor microenvironmentAnti-VEGFCytokine/chemokine signalingCytokine/chemokine profilingBlood-brain barrier modelBlood vesselsLeukocyte transmigrationTumor-associated blood vesselsTumor-associated macrophagesIntratumoral blood vesselsAnti-angiogenesis effectAnti-tumor activityExtracranial diseasePlasmacytoid DCsImmune checkpointsPD-1Melanoma murine modelImmune infiltrationBBB modelChemokine profilingEndothelial stabilizationMurine modelLenvatinibCombined targetingMelanoma model
2021
Agonistic CD40 Antibodies in Cancer Treatment
Djureinovic D, Wang M, Kluger HM. Agonistic CD40 Antibodies in Cancer Treatment. Cancers 2021, 13: 1302. PMID: 33804039, PMCID: PMC8000216, DOI: 10.3390/cancers13061302.Peer-Reviewed Original ResearchAgonistic CD40 antibodyCD40 antibodyDendritic cellsAntigen presentationClinical developmentEarly phase clinical trialsAgonist CD40 antibodyActivation of CD8Pro-inflammatory effectsAntigen-presenting cellsT cell functionRenal cell carcinomaAnti-tumor effectsPhase clinical trialsAnti-tumor activityT cell activationCancer Genome AtlasSystemic therapyCell carcinomaCostimulatory moleculesCD40 expressionClinical trialsPancreatic adenocarcinomaPreclinical modelsT cells
2025
Phase II Trial of Pembrolizumab in Combination With Bevacizumab for Untreated Melanoma Brain Metastases.
Weiss S, Djureinovic D, Wei W, Tran T, Austin M, Markowitz J, Eroglu Z, Khushalani N, Hegde U, Cohen J, Sznol M, Anderson G, Johnson B, Piteo C, Mahajan A, Adeniran A, Jilaveanu L, Goldberg S, Chiang V, Forsyth P, Kluger H. Phase II Trial of Pembrolizumab in Combination With Bevacizumab for Untreated Melanoma Brain Metastases. Journal Of Clinical Oncology 2025, jco2402219. PMID: 40048689, DOI: 10.1200/jco-24-02219.Peer-Reviewed Original ResearchMelanoma brain metastasesOverall survivalBrain metastasesAnti-vascular endothelial growth factor therapyMedian intracranial progression-free survivalFour-year OS ratesIntracranial progression-free survivalResponse rateCirculating angiopoietin-2Median overall survivalTrial of pembrolizumabYears of pembrolizumabDose of bevacizumabProgression-free survivalPhase II trialGrowth factor therapyAdverse event ratesAssociated with responseOS ratesPD-1Radiation necrosisLocal therapyOn-therapyMetastatic tumorsFactor therapy
2024
Decoy-resistant IL-18 reshapes the tumor microenvironment and enhances rejection by anti-CTLA-4 in renal cell carcinoma
Schoenfeld D, Djureinovic D, Su D, Zhang L, Lu B, Kamga L, Mann J, Huck J, Hurwitz M, Braun D, Jilaveanu L, Ring A, Kluger H. Decoy-resistant IL-18 reshapes the tumor microenvironment and enhances rejection by anti-CTLA-4 in renal cell carcinoma. JCI Insight 2024, 10: e184545. PMID: 39561007, PMCID: PMC11721305, DOI: 10.1172/jci.insight.184545.Peer-Reviewed Original ResearchAnti-CTLA-4Renal cell carcinomaIL-18IL-18BPCell carcinomaTumor microenvironmentTumor typesPatients treated with immune checkpoint inhibitorsRegulatory T cell levelsAnti-PD-1 treatmentCD8+ T cellsAnti-PD-1Immune checkpoint inhibitorsCell renal cell carcinomaNon-responder patientsMyeloid cell populationsT cell levelsCytokine interleukin-18Anti-cancer efficacySecreted binding proteinCheckpoint inhibitorsResponding patientsPreclinical modelsT cellsMurine modelGP100 expression is variable in intensity in melanoma
Mann J, Hasson N, Su D, Adeniran A, Smalley K, Djureinovic D, Jilaveanu L, Schoenfeld D, Kluger H. GP100 expression is variable in intensity in melanoma. Cancer Immunology, Immunotherapy 2024, 73: 191. PMID: 39105816, PMCID: PMC11303354, DOI: 10.1007/s00262-024-03776-5.Peer-Reviewed Original ResearchConceptsGp100 expressionCutaneous melanomaTreatment of cutaneous melanomaAdvanced cutaneous melanomaT-cell engagersImprove patient selectionMetastatic melanomaUveal melanomaMetastatic samplesPatient selectionClinical trialsMelanomaQuantitative immunofluorescence methodGp100Improve outcomesImmunofluorescence methodTherapeutic intentDrugCellular productsExpressionTebentafuspImmunohistochemistryMelanocortin-1 Receptor Expression as a Marker of Progression in Melanoma
Su D, Djureinovic D, Schoenfeld D, Marquez-Nostra B, Olino K, Jilaveanu L, Kluger H. Melanocortin-1 Receptor Expression as a Marker of Progression in Melanoma. JCO Precision Oncology 2024, 8: e2300702. PMID: 38662983, PMCID: PMC11513442, DOI: 10.1200/po.23.00702.Peer-Reviewed Original ResearchConceptsMC1R expressionMelanoma progressionAssociated with shorter survivalStages of melanoma progressionCases of benign neviChronic sun exposureMarkers of progressionHuman melanoma tissuesBreslow thicknessMelanocortin-1Metastatic melanomaOverall survivalPrimary melanomaMetastatic tumorsMelanoma cohortReceptor expressionPredictive biomarkersAggressive melanomaPrimary lesionTissue microarrayShorter survivalMale sexQuantitative immunofluorescenceBenign neviClinical trialsDigital 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 ResearchConceptsCTLA-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
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