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, 1-7. 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
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 analysisA Phase II Trial of the CD40 Agonist Sotigalimab (APX005M) in Combination with Nivolumab in Subjects with Metastatic Melanoma with Disease Progression on Anti-PD-1
Weiss S, Sznol M, Shaheen M, Berciano-Guerrero M, Muñoz-Couselo E, Rodríguez-Abreu D, Boni V, Schuchter L, Cao M, Fernandez A, Wei W, Ganti A, Hauke R, Berrocal A, Iannotti N, Hsu F, Kluger H. A Phase II Trial of the CD40 Agonist Sotigalimab (APX005M) in Combination with Nivolumab in Subjects with Metastatic Melanoma with Disease Progression on Anti-PD-1. Clinical Cancer Research 2023, 30: 74-81. PMID: 37535056, PMCID: PMC10767304, DOI: 10.1158/1078-0432.ccr-23-0475.Peer-Reviewed Original ResearchConceptsObjective response ratePhase II trialAdverse eventsPartial responseDisease progressionII trialGrade 3 adverse eventsAnti PD-1CD40 agonist antibodyElevated liver functionTreatment-related SAEsCommon adverse eventsActivation of CD40Subset of patientsFavorable safety profileAntigen presenting cellsStable diseaseMedian durationAdvanced melanomaAdditional patientsLiver functionSafety profileMetastatic melanomaPreclinical dataPresenting cellsCombinatorial Immunotherapy with Agonistic CD40 Activates Dendritic Cells to Express IL12 and Overcomes PD-1 Resistance.
Krykbaeva I, Bridges K, Damsky W, Pizzurro G, Alexander A, McGeary M, Park K, Muthusamy V, Eyles J, Luheshi N, Turner N, Weiss S, Olino K, Kaech S, Kluger H, Miller-Jensen K, Bosenberg M. Combinatorial Immunotherapy with Agonistic CD40 Activates Dendritic Cells to Express IL12 and Overcomes PD-1 Resistance. Cancer Immunology Research 2023, 11: 1332-1350. PMID: 37478171, DOI: 10.1158/2326-6066.cir-22-0699.Peer-Reviewed Original ResearchConceptsPD-1 resistanceDendritic cellsTumor regressionAnti-PD-1 resistanceActivates Dendritic CellsCytokine secretion profilingSystemic cytokine profileTriple therapy combinationInnate immune activationAdaptive immune responsesComplete tumor regressionMajority of miceSignificant clinical challengeMouse melanoma modelT cell activationAgonistic CD40Checkpoint inhibitorsDC subsetsTriple therapyCytokine profileImmune activationCombinatorial immunotherapyTherapy combinationsT cellsClinical challengeCase report: Metastatic Merkel cell carcinoma presenting seven years after loco-regional disease resection of primary tumor with interval in-transit and nodal metastases
Rusheen J, Clune J, Ariyan S, Baumann R, Kluger H, Olino K, Weiss S. Case report: Metastatic Merkel cell carcinoma presenting seven years after loco-regional disease resection of primary tumor with interval in-transit and nodal metastases. Frontiers In Oncology 2023, 13: 1217816. PMID: 37476373, PMCID: PMC10354444, DOI: 10.3389/fonc.2023.1217816.Peer-Reviewed Case Reports and Technical NotesMerkel cell carcinomaDuration of surveillanceLate recurrenceCell carcinomaMetastatic Merkel cell carcinomaPrimary Merkel cell carcinomaMetastases 15 monthsSuch late recurrencesPredictors of recurrenceNodal recurrenceDefinitive therapyFirst recurrenceDisease resectionNodal metastasisPhysical examinationRare tumorPrimary diagnosisPrimary tumorRisk factorsHigh riskNational guidelinesRecurrenceOptimal durationPatientsCarcinomaLenvatinib 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
389 Phase II of CD40 agonistic antibody sotigalimab (APX005M) in combination with nivolumab in subjects with metastatic melanoma with confirmed disease progression on anti-PD-1 therapy
Weiss S, Sznol M, Shaheen M, Berciano-Guerrero M, Felip E, Rodríguez-Abreu D, Arance A, Boni V, Linette G, Schuchter L, Gonzalez-Cao M, Iannotti N, Ganti A, Hauke R, Berrocal A, Filbert E, Kluger H. 389 Phase II of CD40 agonistic antibody sotigalimab (APX005M) in combination with nivolumab in subjects with metastatic melanoma with confirmed disease progression on anti-PD-1 therapy. Journal For ImmunoTherapy Of Cancer 2021, 9: a422-a422. DOI: 10.1136/jitc-2021-sitc2021.389.Peer-Reviewed Original ResearchAnti-PD-1 therapyMelanoma patientsMetastatic melanomaTumor PD-L1 expressionEffective anti-tumor immunityArm phase II trialCD40 agonist antibodyRefractory melanoma patientsRefractory metastatic melanomaAdvanced melanoma patientsPD-1 blockadePD-L1 expressionPhase II trialAnti-tumor immunitySubset of patientsOverall safety profileMajority of AEsOptimal therapeutic applicationReceptor binding profileInstitutional review boardClinical study teamNebraska Medical CenterOpen labelII trialTolerability profileIncidence and characteristics of metastatic intracranial lesions in stage III and IV melanoma: a single institute retrospective analysis
Sandhu MRS, Chiang VL, Tran T, Yu JB, Weiss S, Goldberg S, Aboian M, Kluger HM, Mahajan A. Incidence and characteristics of metastatic intracranial lesions in stage III and IV melanoma: a single institute retrospective analysis. Journal Of Neuro-Oncology 2021, 154: 197-203. PMID: 34351544, DOI: 10.1007/s11060-021-03813-8.Peer-Reviewed Original ResearchConceptsStage IV melanomaMetastatic brain lesionsStage IIIInitial diagnosisTumor RegistryOverall incidenceBrain lesionsBM incidenceSingle-institute retrospective analysisBM developmentBrain metastases incidenceIncidence of BMInstitution's tumor registryStage III patientsTime of diagnosisMetastatic intracranial lesionsCommon genetic mutationsTumor genetic profileGenetic profileBM occurrenceMedian durationAdvanced melanomaSurveillance regimenIII patientsMedian time
2020
Melanoma brain metastases have lower T-cell content and microvessel density compared to matched extracranial metastases
Weiss SA, Zito C, Tran T, Heishima K, Neumeister V, McGuire J, Adeniran A, Kluger H, Jilaveanu LB. Melanoma brain metastases have lower T-cell content and microvessel density compared to matched extracranial metastases. Journal Of Neuro-Oncology 2020, 152: 15-25. PMID: 32974852, PMCID: PMC7910371, DOI: 10.1007/s11060-020-03619-0.Peer-Reviewed Original ResearchConceptsT-cell contentMelanoma brain metastasesPD-L1 expressionLower microvessel densityMicrovessel densityBrain metastasesExtracranial metastasesMacrophage contentB cellsProspective therapeutic clinical trialsTumor-infiltrating T cellsImmune-modulating drugsImmune cell subsetsTherapeutic clinical trialsExtracerebral metastasesHigh CD68Low CD3Low CD8Systemic therapyIntracerebral metastasesMetastatic sitesCell subsetsMetastatic melanomaImmune cellsClinical trials19. PLEKHA5 REGULATES TUMOR GROWTH IN METASTATIC MELANOMA
Oria V, Zhang H, Zhu H, Deng G, Zito C, Rane C, Zhang S, Weiss S, Tran T, Adeniran A, Zhang F, Zhou J, Kluger Y, Bosenberg M, Kluger H, Jilaveanu L. 19. PLEKHA5 REGULATES TUMOR GROWTH IN METASTATIC MELANOMA. Neuro-Oncology Advances 2020, 2: ii3-ii3. PMCID: PMC7401364, DOI: 10.1093/noajnl/vdaa073.009.Peer-Reviewed Original ResearchMelanoma brain metastasesBrain metastasesTumor growthPI3K/Akt/mTORCell cycle transitionAkt/mTORGrowth of tumorsS cell cycle transitionPhosphorylation of AktMelanoma patientsPoor prognosisNovel drug targetsPatient populationRegulation of PDCD4Metastatic melanomaUnique cohortXenograft modelClinical relevanceNude miceMetastasisCycle transitionMelanomaBrain developmentKey mediatorMelanoma cellsSystemic Therapy for Brain Metastases: Melanoma
Weiss S, Kluger H. Systemic Therapy for Brain Metastases: Melanoma. 2020, 235-244. DOI: 10.1007/978-3-030-42958-4_16.Peer-Reviewed Original ResearchMelanoma brain metastasesIntracranial response ratesBrain metastasesClinical trialsResponse rateAnti-PD-1 monotherapyCentral nervous system metastasesExtracranial metastatic sitesNervous system metastasesSystemic therapy approachesMultiple clinical trialsSystemic therapySystemic treatmentAdvanced melanomaImmune checkpointsMetastatic sitesTherapeutic challengePatient survivalMetastatic melanomaExtracranial sitesStereotactic radiosurgeryMetastasisMutant BRAFSignificant causeMEK inhibitionNeoadjuvant anti–programmed cell death 1 therapy for locally advanced basal cell carcinoma in treatment-naive patients: A case series
Ligtenberg KG, Hu JK, Damsky W, Olino K, Kluger H, Clune J, Cowper SE, Panse G, Leventhal J, Weiss SA. Neoadjuvant anti–programmed cell death 1 therapy for locally advanced basal cell carcinoma in treatment-naive patients: A case series. JAAD Case Reports 2020, 6: 628-633. PMID: 32613057, PMCID: PMC7317689, DOI: 10.1016/j.jdcr.2020.05.010.Peer-Reviewed Case Reports and Technical NotesSurvival after checkpoint inhibitors for metastatic acral, mucosal and uveal melanoma
Klemen ND, Wang M, Rubinstein JC, Olino K, Clune J, Ariyan S, Cha C, Weiss SA, Kluger HM, Sznol M. Survival after checkpoint inhibitors for metastatic acral, mucosal and uveal melanoma. Journal For ImmunoTherapy Of Cancer 2020, 8: e000341. PMID: 32209601, PMCID: PMC7103823, DOI: 10.1136/jitc-2019-000341.Peer-Reviewed Original ResearchConceptsCheckpoint inhibitorsOverall survivalMetastatic melanomaPrimary tumorLocal therapyCutaneous melanomaAnti-PD-1 antibodyAggressive multidisciplinary approachCutaneous primary tumorPrimary tumor histologyMedian overall survivalSingle institutional experienceRare melanoma subtypeMedian OSMetastatic diseaseProgressive diseaseAcral skinComplete responsePD-1PD-L1Uveal tractTumor histologyCombination therapyCTLA-4Longer survival
2019
PLEKHA5 regulates tumor growth in metastatic melanoma
Zhang H, Zhu H, Deng G, Zito CR, Oria VO, Rane CK, Zhang S, Weiss SA, Tran T, Adeniran A, Zhang F, Zhou J, Kluger Y, Bosenberg MW, Kluger HM, Jilaveanu LB. PLEKHA5 regulates tumor growth in metastatic melanoma. Cancer 2019, 126: 1016-1030. PMID: 31769872, PMCID: PMC7147081, DOI: 10.1002/cncr.32611.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAnimalsApoptosis Regulatory ProteinsBiomarkers, TumorBrain NeoplasmsCell ProliferationFemaleFollow-Up StudiesGene Expression Regulation, NeoplasticHumansIntracellular Signaling Peptides and ProteinsMaleMelanomaMiceMice, NudeMiddle AgedPhosphatidylinositol 3-KinasesPrognosisProto-Oncogene Proteins c-aktTOR Serine-Threonine KinasesTumor Cells, CulturedXenograft Model Antitumor AssaysYoung AdultConceptsTumor growthDisseminated melanomaExtracranial melanoma metastasesPI3K/AKT/mTOR pathwayMelanoma brain metastasesBetter overall survivalPI3K/Akt/mTORAKT/mTOR pathwayCell proliferationAkt/mTORMelanoma xenograft modelGrowth of tumorsS cell cycle transitionBrain metastasesOverall survivalPoor prognosisMetastatic melanomaMAPK/ERKSubcutaneous inoculationMelanoma metastasesXenograft modelClinical relevanceMelanoma growthNude miceCerebral specimensRBTT-07. A PHASE 2 TRIAL OF PEMBROLIZUMAB AND BEVACIZUMAB IN MELANOMA BRAIN MET PATIENTS
Kluger H, Forsyth P, Khushalani N, Eroglu Z, Sznol M, Tran T, Jilaveanu L, Cohen J, Hegde U, Wei W, Mahajan A, Goldberg S, Chiang V, Weiss S. RBTT-07. A PHASE 2 TRIAL OF PEMBROLIZUMAB AND BEVACIZUMAB IN MELANOMA BRAIN MET PATIENTS. Neuro-Oncology 2019, 21: vi220-vi220. PMCID: PMC6847787, DOI: 10.1093/neuonc/noz175.919.Peer-Reviewed Original ResearchVEGF inhibitorsPrimary endpointPD-1/PD-L1Anti-PD-1 activityGrade 3 ALT elevationPre-specified primary endpointPhase 2 studyPhase 2 trialUnconfirmed PRALT elevationDiverticular perforationMetS patientsCerebral edemaPD-L1Wound dehiscencePembroToxicity profileEdemaFurther studiesPromising activityEndpointBRAFmtPembrolizumabMucositisULNPatterns 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-L1Ophthalmic Immune-Related Adverse Events of Immunotherapy: A Single-Site Case Series
Kim J, Materin MA, Sznol M, Kluger H, Weiss S, Chow J, Stoessel K, Kombo N, Del Priore L, Pointdujour-Lim R. Ophthalmic Immune-Related Adverse Events of Immunotherapy: A Single-Site Case Series. Ophthalmology 2019, 126: 1058-1062. PMID: 30735682, PMCID: PMC6933747, DOI: 10.1016/j.ophtha.2019.01.031.Peer-Reviewed Original Research
2018
Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial
Kluger HM, Chiang V, Mahajan A, Zito CR, Sznol M, Tran T, Weiss SA, Cohen JV, Yu J, Hegde U, Perrotti E, Anderson G, Ralabate A, Kluger Y, Wei W, Goldberg SB, Jilaveanu LB. Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial. Journal Of Clinical Oncology 2018, 37: 52-60. PMID: 30407895, PMCID: PMC6354772, DOI: 10.1200/jco.18.00204.Peer-Reviewed Original ResearchConceptsBrain metastasis responseBrain metastasesMetastasis responseAdverse eventsAnti-programmed cell death-1 (PD-1) agentsDeath ligand 1 (PD-L1) expressionModified Response Evaluation CriteriaPhase II clinical trialActive brain metastasesAsymptomatic brain metastasesCD8 cell densityNeurologic adverse eventsPembrolizumab-treated patientsUse of pembrolizumabMelanoma brain metastasesPrimary end pointLigand 1 expressionPhase II trialResponse Evaluation CriteriaT-cell infiltratesUntreated brain metastasesDeath ligand 1Two-year survivalOverall survival timeResult of progressionCollateral Damage: Insulin-Dependent Diabetes Induced With Checkpoint Inhibitors
Stamatouli AM, Quandt Z, Perdigoto AL, Clark PL, Kluger H, Weiss SA, Gettinger S, Sznol M, Young A, Rushakoff R, Lee J, Bluestone JA, Anderson M, Herold KC. Collateral Damage: Insulin-Dependent Diabetes Induced With Checkpoint Inhibitors. Diabetes 2018, 67: dbi180002. PMID: 29937434, PMCID: PMC6054443, DOI: 10.2337/dbi18-0002.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Agents, ImmunologicalAutoimmune DiseasesB7-H1 AntigenDiabetes Mellitus, Type 1Genetic Predisposition to DiseaseGenotypeHLA-DR4 AntigenHumansHypoglycemic AgentsInsulinInsulin SecretionIsoantibodiesKetosisModels, ImmunologicalNeoplasmsPancreasPancreatitisProgrammed Cell Death 1 ReceptorConceptsInsulin-dependent diabetesCheckpoint inhibitorsAdverse eventsHLA-DR4Classic type 1 diabetesPD-L1 checkpoint inhibitorsEvidence of pancreatitisImmune adverse eventsSolid organ cancersType 1 diabetesPeridiagnosis periodPositive autoantibodiesL1 antibodyInsulin-DependentHigh riskPatientsDiabetesCancerInhibitorsKetoacidosisAutoimmuneAutoantibodiesPancreatitisComplicationsSyndromeTumor Microvessel Density as a Prognostic Marker in High-Risk Renal Cell Carcinoma Patients Treated on ECOG-ACRIN E2805
Jilaveanu LB, Puligandla M, Weiss SA, Wang X, Zito C, Flaherty KT, Boeke M, Neumeister V, Camp RL, Adeniran A, Pins M, Manola J, DiPaola RS, Haas N, Kluger HM. Tumor Microvessel Density as a Prognostic Marker in High-Risk Renal Cell Carcinoma Patients Treated on ECOG-ACRIN E2805. Clinical Cancer Research 2018, 24: 217-223. PMID: 29066509, PMCID: PMC5904512, DOI: 10.1158/1078-0432.ccr-17-1555.Peer-Reviewed Original ResearchConceptsHigher microvessel densityDisease-free survivalRenal cell carcinomaHigh-risk RCC patientsImproved overall survivalOverall survivalMicrovessel densityRCC patientsAdjuvant therapy trialsClear cell histologyHigh-risk patientsBiomarkers of outcomeTumor microvessel densityLower microvessel densityAbsence of necrosisFuhrman grade 1Clin Cancer ResAdjuvant sunitinibProlonged OSCell histologyLymphovascular invasionSarcomatoid featuresMultivariable analysisTreatment armsEntire cohort