2025
Long-term Efficacy and Safety of Lifileucel Tumor-infiltrating Lymphocyte (TIL) Cell Therapy in Patients with Advanced Melanoma: A 5-year Analysis of the C-144-01 Study.
Medina T, Chesney J, Kluger H, Hamid O, Whitman E, Cusnir M, Thomas S, Wermke M, Domingo-Musibay E, Phan G, Kirkwood J, Larkin J, Weber J, Graf Finckenstein F, Chou J, Gastman B, Wu X, Fiaz R, Sarnaik A, Curti B, Kim K, Daniels G, Wilson M, Lee S, Puzanov I, Harker-Murray A, Logan T, Simon J, Thomas I, Schuler-Thurner B, Moritz R, Hassel J, Grigoliet G, Arance A, Rubio B, Rodriguez J, Berrocal A, de Sanmamed M, Arkenau H, Evans T, Corrie P, Dalle S, Bedane C, Olah J, Orcurto A. Long-term Efficacy and Safety of Lifileucel Tumor-infiltrating Lymphocyte (TIL) Cell Therapy in Patients with Advanced Melanoma: A 5-year Analysis of the C-144-01 Study. Journal Of Clinical Oncology 2025, 101200jco2500765. PMID: 40454684, DOI: 10.1200/jco-25-00765.Peer-Reviewed Original ResearchTumor-infiltrating lymphocytesOverall survivalLong-term efficacyCell therapyMedian duration of responseLow tumor burdenMedian overall survivalDuration of responseTumor burden reductionLong-term safety concernsBRAF/MEK inhibitorsAdvanced melanomaBrain metastasesImmune checkpointsTumor burdenMedian durationSafety profileAdverse eventsTreatment optionsInterleukin-2Follow-upLong-term benefitsOverall populationPatientsCutoff dateValidation and refinement of Society of Immunotherapy of Cancer (SITC) definitions for PD-(L)1 resistance: An analysis of more than 1,300 participants from SWOG.
Othus M, Kurzrock R, Patel S, Chae Y, Patel S, Sosman J, Snyder Charen A, Rizvi N, LaVallee T, Felquate D, Burton E, Futreal P, Sullivan R, Kluger H, Tawbi H. Validation and refinement of Society of Immunotherapy of Cancer (SITC) definitions for PD-(L)1 resistance: An analysis of more than 1,300 participants from SWOG. Journal Of Clinical Oncology 2025, 43: 2656-2656. DOI: 10.1200/jco.2025.43.16_suppl.2656.Peer-Reviewed Original ResearchOverall survivalMartingale residual plotsAdjuvant settingPD-(L)1Shorter OSNo significant differencePrimary resistanceAssociated with significantly shorter OSHazard ratioHigh-risk resected stagePD-(L)1 inhibitorsImmunotherapy of cancerSignificant differenceConfidence intervalsCox regression modelsClinical trial interpretationAdjuvant cohortAdjuvant pembrolizumabImmunotherapy resistanceLate recurrenceResected stageEarly recurrenceSWOG trialsIO agentsPatient cohortLifileucel in patients with advanced melanoma: 5-year outcomes of the C-144-01 study.
Medina T, Chesney J, Kluger H, Hamid O, Whitman E, Cusnir M, Thomas S, Wermke M, Domingo-Musibay E, Phan G, Kirkwood J, Larkin J, Weber J, Finckenstein F, Chou J, Gastman B, Sulur G, Wu R, Fiaz R, Sarnaik A. Lifileucel in patients with advanced melanoma: 5-year outcomes of the C-144-01 study. Journal Of Clinical Oncology 2025, 43: 9515-9515. DOI: 10.1200/jco.2025.43.16_suppl.9515.Peer-Reviewed Original ResearchDuration of responseAnti-PD-1/PD-L1 therapyAdvanced melanomaFollow-upOverall survivalEastern Cooperative Oncology Group performance statusAnti-PD-1/PD-L1Autologous T-cell immunotherapyMedian duration of responseTreatment-emergent adverse eventsDoses of interleukin-2Treatment of adult patientsImmune checkpoint inhibitorsT-cell immunotherapyTumor-infiltrating lymphocytesDurability of responseLong-term safety concernsOpen-label studyStudy follow-upGroup of ptsMedian OSRefractory melanomaCheckpoint inhibitorsOS ratesRECIST v1.1Role of high-dose interleukin-2 for melanoma in the age of cellular therapy
Buchbinder E, Lotze M, Margolin K, Amaria R, Sarnaik A, Seery V, Eroglu Z, Khaddour K, Warner A, Kluger H, Sznol M, Atkins M, Mcdermott D, Silk A. Role of high-dose interleukin-2 for melanoma in the age of cellular therapy. Journal For ImmunoTherapy Of Cancer 2025, 13: e011119. PMID: 40447314, PMCID: PMC12128428, DOI: 10.1136/jitc-2024-011119.Peer-Reviewed Original ResearchConceptsTumor-infiltrating lymphocytesTIL infusionInterleukin-2Cellular therapyHigh-dose bolus IL-2High-dose interleukin-2Renal cell carcinoma patientsBolus interleukin-2Cytokine-related toxicitiesExcellent organ functionIL-2 monotherapyIL-2 toxicityLife-threatening side effectsPartial tumor regressionCell carcinoma patientsInterleukin-2 dosesT cell productionTreatment of patientsNational Cancer InstituteAdvanced melanomaTumor regressionCarcinoma patientsAdjunctive therapyInpatient administrationSide effectsPRAME is not a frequently expressed antigen in renal cell carcinoma
Yi I, Ofir Y, Mann J, Su D, Kim T, Perales O, Zhang L, Adeniran A, Kluger H, Schoenfeld D. PRAME is not a frequently expressed antigen in renal cell carcinoma. BJUI Compass 2025, 6: e70037. PMID: 40453487, PMCID: PMC12123051, DOI: 10.1002/bco2.70037.Peer-Reviewed Original ResearchMIF as an oncogenic driver of low‐heterogeneity melanomas
Tran T, Sánchez‐Zuno G, Kulkarni R, Kluger H, Bucala R. MIF as an oncogenic driver of low‐heterogeneity melanomas. Molecular Oncology 2025, 19: 1295-1298. PMID: 40131169, PMCID: PMC12077282, DOI: 10.1002/1878-0261.70031.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorImproving therapeutic outcomesMigration inhibitory factorPotential therapeutic utilityImmune landscapeMelanoma clonesImmune escapeT cellsImmunoregulatory cytokinesTumor heterogeneityTumor progressionOncogenic driversPathway inhibitorTherapeutic outcomesTumor evolutionInhibitory factorCell proliferationMelanomaTumorCellsAntagonistCytokinesMicroglial reprogramming: a potential new frontier in enhancing immunotherapy for melanoma brain metastasis
Savion‐Gaiger N, Bar‐Ziv D, Kluger H. Microglial reprogramming: a potential new frontier in enhancing immunotherapy for melanoma brain metastasis. Molecular Oncology 2025, 19: 1291-1294. PMID: 40111148, PMCID: PMC12077281, DOI: 10.1002/1878-0261.70028.Peer-Reviewed Original ResearchConceptsMelanoma brain metastasesBrain metastasesSites of metastatic disseminationHuman brain metastasesAdvanced melanomaEnhance immunotherapyMurine studiesTumor microenvironmentMetastatic disseminationMyeloid cellsMelanoma cellsMelanomaMetastasisMicroglial cellsPotential new frontiersCellsBrainImmunotherapyTumorMicroenvironmentPhase 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, 43: 1685-1694. PMID: 40048689, PMCID: PMC12058415, 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 therapyReal-world outcomes with T-VEC in patients with anti-PD-1 resistant in-transit disease from melanoma and Merkel cell carcinoma
Su D, McNamara M, Kaszycki M, Frey A, Ishizuka J, Costa P, Tran T, Kluger H, Clune J, Weiss S, Olino K. Real-world outcomes with T-VEC in patients with anti-PD-1 resistant in-transit disease from melanoma and Merkel cell carcinoma. Surgical Oncology Insight 2025, 2: 100120. DOI: 10.1016/j.soi.2024.100120.Peer-Reviewed Original ResearchMerkel cell carcinomaMerkel cell carcinoma casesT-VECCell carcinomaMedian numberAnti-PD-1 blockadeStage IIIB-IV melanomaAdvanced Merkel cell carcinomaIn-transit melanomaIn-transit diseaseICI therapyTalimogene laherparepvecAdvanced melanomaCancer immunotherapyMetastatic sitesPartial responseIn-transitRegional metastasesMedian ageGrade 3Adverse eventsTreatment cyclesDisease progressionMelanomaPatientsSurvival of patients with metastatic renal cell carcinoma with or without brain metastases.
Hurwitz M, Considine B, Hasson N, Savion Gaiger N, Nelson M, Chiang V, Kluger H, Braun D, Schoenfeld D, Sznol M, Leapman M. Survival of patients with metastatic renal cell carcinoma with or without brain metastases. Journal Of Clinical Oncology 2025, 43: 476-476. DOI: 10.1200/jco.2025.43.5_suppl.476.Peer-Reviewed Original ResearchMetastatic renal cell carcinomaImmune checkpoint inhibitorsClear cell RCCRenal cell carcinomaImmune checkpoint inhibitor therapyMetastatic clear cell RCCBrain metastasesOverall survivalCell carcinomaImmune checkpoint inhibitor eraPrevalence of brain metastasesMultivariate Cox proportional hazards modelAssociated with poor survivalMedian overall survivalAssociated with poor prognosisCompare overall survivalImproved overall survivalAdverse prognostic indicatorDevelopment of BMSurvival of patientsKaplan-Meier analysisYale Cancer CenterRetrospective cohort studyCox proportional hazards modelsProportional hazards model
2024
Nivolumab plus relatlimab and nivolumab plus ipilimumab for patients with advanced renal cell carcinoma: results from the open-label, randomised, phase II FRACTION-RCC trial
Choueiri T, Kuzel T, Tykodi S, Verzoni E, Kluger H, Nair S, Perets R, George S, Gurney H, Pachynski R, Folefac E, Castonguay V, Lee C, Vaishampayan U, Miller W, Bhagavatheeswaran P, Wang Y, Gupta S, DeSilva H, Lee C, Escudier B, Motzer R. Nivolumab plus relatlimab and nivolumab plus ipilimumab for patients with advanced renal cell carcinoma: results from the open-label, randomised, phase II FRACTION-RCC trial. ESMO Open 2024, 9: 104073. PMID: 39642635, PMCID: PMC11667034, DOI: 10.1016/j.esmoop.2024.104073.Peer-Reviewed Original ResearchConceptsAdvanced renal cell carcinomaNivolumab + ipilimumabProgression-free survivalDuration of responseMedian duration of responseProgression-free survival ratesProgrammed death-ligand 1Renal cell carcinomaImmuno-oncologyOpen-labelCell carcinomaPatients treated with nivolumabTyrosine kinase inhibitor therapyTreatment-related adverse eventsLymphocyte activation gene-3Death-ligand 1Kinase inhibitor therapyAssessment of combination therapyEffective combination regimenImmuno-oncology studiesCombination regimenInhibitor therapyLAG-3Combination therapySecondary endpointsCirculating tumor-reactive KIR+CD8+ T cells suppress anti-tumor immunity in patients with melanoma
Lu B, Lucca L, Lewis W, Wang J, Nogueira C, Heer S, Rayon-Estrada V, Axisa P, Reeves S, Buitrago-Pocasangre N, Pham G, Kojima M, Wei W, Aizenbud L, Bacchiocchi A, Zhang L, Walewski J, Chiang V, Olino K, Clune J, Halaban R, Kluger Y, Coyle A, Kisielow J, Obermair F, Kluger H, Hafler D. Circulating tumor-reactive KIR+CD8+ T cells suppress anti-tumor immunity in patients with melanoma. Nature Immunology 2024, 26: 82-91. PMID: 39609626, DOI: 10.1038/s41590-024-02023-4.Peer-Reviewed Original ResearchCD8+ T cellsAnti-tumor immunityRegulatory T cellsT cellsSubpopulation of CD8+ T cellsCytotoxic CD8+ T cellsHuman CD8+ T cellsTumor antigen-specific CD8Impaired anti-tumor immunityTumor antigen-specificPoor overall survivalTumor rejectionKIR expressionOverall survivalTumor antigensImmune evasionCellular mediatorsHuman cancersCD8MelanomaTumorTranscriptional programsFunctional heterogeneityImmunityPatientsDecoy-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 model16S rRNA target sequencing of human tumors validates findings of Lachnoclostridium abundance in human melanomas that are heavily CD8+ T-cell infiltrated
Lu L, Johnson C, Khan S, Kluger H. 16S rRNA target sequencing of human tumors validates findings of Lachnoclostridium abundance in human melanomas that are heavily CD8+ T-cell infiltrated. European Journal Of Cancer 2024, 213: 115084. PMID: 39477777, DOI: 10.1016/j.ejca.2024.115084.Peer-Reviewed Original Research1102P Immune checkpoint inhibitor rechallenge after treatment with tumor-infiltrating lymphocytes in unresectable melanoma
Warner A, Smithy J, Los C, Kalvin H, Hasson N, Amaria R, Czapla J, Schollenberger M, furness A, Hassel J, Wermke M, Gallegos J, Lutzky J, Lipson E, Sullivan R, Kluger H, Panageas K, Klobuch S, Haanen J, Shoushtari A. 1102P Immune checkpoint inhibitor rechallenge after treatment with tumor-infiltrating lymphocytes in unresectable melanoma. Annals Of Oncology 2024, 35: s730-s731. DOI: 10.1016/j.annonc.2024.08.1170.Peer-Reviewed Original ResearchTIGIT expression in renal cell carcinoma infiltrating T cells is variable and inversely correlated with PD-1 and LAG3
Perales O, Jilaveanu L, Adeniran A, Su D, Hurwitz M, Braun D, Kluger H, Schoenfeld D. TIGIT expression in renal cell carcinoma infiltrating T cells is variable and inversely correlated with PD-1 and LAG3. Cancer Immunology, Immunotherapy 2024, 73: 192. PMID: 39105820, PMCID: PMC11303630, DOI: 10.1007/s00262-024-03773-8.Peer-Reviewed Original ResearchConceptsRenal cell carcinomaRenal cell carcinoma tumorsT cellsTIGIT expressionCheckpoint inhibitorsPD-1Likelihood of response to therapyTumor-infiltrating T cellsCD3+ T cellsRenal cell carcinoma metastasisTreatment of renal cell carcinomaImmune checkpoint inhibitorsInfiltrating T cellsPurposeImmune checkpoint inhibitorsResponse to therapyT cell immunoglobulinCD3+ levelsMetastatic RCC specimensAdjacent normal renal tissuesNormal renal tissuesQuantitative immunofluorescence analysisCell carcinomaResistant diseasePotential therapeutic targetTissue microarrayGP100 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 productsExpressionTebentafuspImmunohistochemistryCauses of death and patterns of metastatic disease at the end of life for patients with advanced melanoma in the immunotherapy era
Lee D, McNamara M, Yang A, Yaskolko M, Kluger H, Tran T, Olino K, Clune J, Sznol M, Ishizuka J. Causes of death and patterns of metastatic disease at the end of life for patients with advanced melanoma in the immunotherapy era. Pigment Cell & Melanoma Research 2024, 37: 847-853. PMID: 39073002, PMCID: PMC11809125, DOI: 10.1111/pcmr.13188.Peer-Reviewed Original ResearchSite of metastasisPattern of metastatic diseaseMelanoma mortalityRetrospective observational cohort studyCause of cancer mortalityDistant lymph nodesObservational cohort studyDiagnosis to deathImmunotherapy eraAdvanced melanomaMetastatic diagnosisMetastatic diseaseMetastatic melanomaImmunotherapy treatmentRespiratory failureCause of deathMedian timeLymph nodesTherapeutic advancesCohort studyMelanomaImmunotherapyMechanism of deathPatientsEnd of lifePatterns 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 studySpatially Informed Gene Signatures for Response to Immunotherapy in Melanoma.
Aung T, Warrell J, Martinez-Morilla S, Gavrielatou N, Vathiotis I, Yaghoobi V, Kluger H, Gerstein M, Rimm D. Spatially Informed Gene Signatures for Response to Immunotherapy in Melanoma. Clinical Cancer Research 2024, 30: 3520-3532. PMID: 38837895, PMCID: PMC11326985, DOI: 10.1158/1078-0432.ccr-23-3932.Peer-Reviewed Original ResearchGene signatureResistance to immunotherapyResponse to immunotherapyPrediction of treatment outcomeResistant to treatmentAccurate prediction of treatment outcomePredictive of responseImmunotherapy outcomesMelanoma patientsMelanoma specimensValidation cohortPatient stratificationDiscovery cohortTreatment outcomesImmunotherapyMelanomaTumorPatientsCohortS100BOutcomesGene expression dataGenesCD68+macrophagesExpression data
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