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 PMID: 39561007, 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 modelTIGIT 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 microarrayCauses of death and patterns of metastatic disease at the end of life for patients with advanced melanoma in the immunotherapy era.
Lee D, Yang A, McNamara 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. Journal Of Clinical Oncology 2024, 42: e21522-e21522. DOI: 10.1200/jco.2024.42.16_suppl.e21522.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsYale Cancer CenterAdvanced melanomaMetastatic diseaseMetastatic melanomaRespiratory failureSite of metastatic diseasePattern of metastatic diseaseDied of respiratory failureAnti-CTLA4 treatmentRetrospective observational cohort studyAnti-PD1 therapyDistant lymph nodesPatients aged >Site of diseaseSurvival of patientsObservational cohort studyMulti-system involvementDiagnosis to deathImmunotherapy eraAnti-PD1Checkpoint inhibitorsInstitutional review boardMetastatic sitesMetastatic diagnosisImmunotherapy Initiation at the End of Life in Patients With Metastatic Cancer in the US
Kerekes D, Frey A, Prsic E, Tran T, Clune J, Sznol M, Kluger H, Forman H, Becher R, Olino K, Khan S. Immunotherapy Initiation at the End of Life in Patients With Metastatic Cancer in the US. JAMA Oncology 2024, 10: 342-351. PMID: 38175659, PMCID: PMC10767643, DOI: 10.1001/jamaoncol.2023.6025.Peer-Reviewed Original ResearchNon-small cell lung cancerEnd of lifeMonth of deathImmunotherapy initiationCohort studyMAIN OUTCOMEStage IV non-small cell lung cancerCharlson-Deyo comorbidity indexHigh metastatic burdenInitiation of immunotherapyNational prescribing patternsRisk-adjusted patientsImmune checkpoint inhibitorsRetrospective cohort studyStage IV melanomaPercentage of patientsHigh-volume centersLocation of metastasesLow-volume centersOdds of deathCell lung cancerNational Clinical DatabaseLow-volume facilitiesDrug Administration approvalCheckpoint inhibitors
2023
Clinical Predictors of Survival in Patients With BRAFV600-Mutated Metastatic Melanoma Treated With Combined BRAF and MEK Inhibitors After Immune Checkpoint Inhibitors
Kahn A, Perry C, Etts K, Kluger H, Sznol M. Clinical Predictors of Survival in Patients With BRAFV600-Mutated Metastatic Melanoma Treated With Combined BRAF and MEK Inhibitors After Immune Checkpoint Inhibitors. The Oncologist 2023, 29: e507-e513. PMID: 37971411, PMCID: PMC10994263, DOI: 10.1093/oncolo/oyad300.Peer-Reviewed Original ResearchBRAF/MEK inhibitorsBRAF/MEK inhibitionImmune checkpoint inhibitorsBRAFV600E/K mutationsMEK inhibitorsCheckpoint inhibitorsClinical variablesMEK inhibitionRetrospective single-institution analysisIpilimumab/nivolumabFirst-line settingFirst-line therapyFirst-line treatmentMetastatic melanoma patientsLong-term outcomesPretreatment clinical variablesSingle-institution analysisStratification of patientsK mutationCombined BRAFECOG PSMedian OSRECIST 1.1Immunotherapy regimenClinical characteristics1086MO Lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in patients (pts) with advanced mucosal melanoma after progression on immune checkpoint inhibitors (ICI): Results from the phase II C-144-01 study
Grigoleit G, Kluger H, Thomas S, Chesney J, Domingo-Musibay E, Sanmamed M, Medina T, Ziemer M, Whitman E, Finckenstein F, Chou J, Wu X, Sulur G, Shi W, Sarnaik A. 1086MO Lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in patients (pts) with advanced mucosal melanoma after progression on immune checkpoint inhibitors (ICI): Results from the phase II C-144-01 study. Annals Of Oncology 2023, 34: s654. DOI: 10.1016/j.annonc.2023.09.2220.Peer-Reviewed Original ResearchScRNA-seq defines dynamic T-cell subsets in longitudinal colon and peripheral blood samples in immune checkpoint inhibitor-induced colitis
Mann J, Lucca L, Austin M, Merkin R, Robert M, Al Bawardy B, Raddassi K, Aizenbud L, Joshi N, Hafler D, Abraham C, Herold K, Kluger H. ScRNA-seq defines dynamic T-cell subsets in longitudinal colon and peripheral blood samples in immune checkpoint inhibitor-induced colitis. Journal For ImmunoTherapy Of Cancer 2023, 11: e007358. PMID: 37586769, PMCID: PMC10432652, DOI: 10.1136/jitc-2023-007358.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsT cell subsetsCheckpoint inhibitorsImmune environmentImmune checkpoint inhibitor-induced colitisCheckpoint inhibitor-induced colitisPeripheral immune environmentsStages of colitisTreatment of colitisMerkel cell carcinomaT cell populationsPeripheral blood samplesCourse of progressionT cell receptorMultiple tumor typesAlternative cancer therapyCommon toxicitiesICI colitisTreatment discontinuationAdverse eventsBiologic therapyImmune suppressionCell carcinomaColitisBlood samplesCombinatorial 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 challengeDeterminants of overall survival in patients with metastatic uveal melanoma
Demkowicz P, Pointdujour‐Lim R, Miguez S, Lee Y, Jones B, Barker C, Bosenberg M, Abramson D, Shoushtari A, Kluger H, Francis J, Sznol M, Bakhoum M. Determinants of overall survival in patients with metastatic uveal melanoma. Cancer 2023, 129: 3275-3286. PMID: 37382208, PMCID: PMC11149607, DOI: 10.1002/cncr.34927.Peer-Reviewed Original ResearchConceptsAnti-PD-1 therapyMetastatic uveal melanomaDeath hazard ratioImmune checkpoint inhibitorsOverall survivalHazard ratioUveal melanomaSurvival outcomesFemale sexCheckpoint inhibitorsECOG scoreValidation cohortEastern Cooperative Oncology Group performance status scaleGood baseline performance statusMetastatic uveal melanoma patientsMetastatic UM patientsImproved overall survivalMedian overall survivalBaseline performance statusBetter survival outcomesImproved survival outcomesPotential of immunotherapyWorse survival outcomesImmune checkpoint therapyKaplan-Meier analysisResponse to "NLRC5 germline variants and their potential role in eliciting an immune response in patients with cancer treated with immune checkpoint inhibitors" by Xiang-Yu Meng
Aizenbud L, Schoenfeld D, Caulfield J, Mann J, Austin M, Perdigoto A, Herold K, Kluger H. Response to "NLRC5 germline variants and their potential role in eliciting an immune response in patients with cancer treated with immune checkpoint inhibitors" by Xiang-Yu Meng. Journal For ImmunoTherapy Of Cancer 2023, 11: e007397. PMID: 37349129, PMCID: PMC10314693, DOI: 10.1136/jitc-2023-007397.Peer-Reviewed Original ResearchSubsets of IFN Signaling Predict Response to Immune Checkpoint Blockade in Patients with Melanoma.
Horowitch B, Lee D, Ding M, Martinez-Morilla S, Aung T, Ouerghi F, Wang X, Wei W, Damsky W, Sznol M, Kluger H, Rimm D, Ishizuka J. Subsets of IFN Signaling Predict Response to Immune Checkpoint Blockade in Patients with Melanoma. Clinical Cancer Research 2023, 29: 2908-2918. PMID: 37233452, PMCID: PMC10524955, DOI: 10.1158/1078-0432.ccr-23-0215.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsHuman melanoma cell linesMelanoma cell linesPD-L1Validation cohortYale-New Haven HospitalCombination of ipilimumabPD-L1 markersImmune checkpoint blockadePD-L1 biomarkerNew Haven HospitalSTAT1 levelsCell linesWestern blot analysisCheckpoint inhibitorsCheckpoint blockadeClinical responseOverall survivalImproved survivalResistance of cancersMetastatic melanomaMelanoma responsePredict responseTreatment responseDistinct patternsSociety for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with chemotherapy
Rizvi N, Ademuyiwa F, Cao Z, Chen H, Ferris R, Goldberg S, Hellmann M, Mehra R, Rhee I, Park J, Kluger H, Tawbi H, Sullivan R. Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with chemotherapy. Journal For ImmunoTherapy Of Cancer 2023, 11: e005920. PMID: 36918220, PMCID: PMC10016262, DOI: 10.1136/jitc-2022-005920.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsConsensus definitionCheckpoint inhibitorsAddition of ICIsAnti-programmed cell death protein 1Combination of ICIsCell death protein 1Consensus clinical definitionProfound clinical benefitDeath protein 1Immunotherapy of cancerSolid tumor indicationsClinical trial designICI combinationsImmunotherapy combinationsRecurrent diseaseUpfront treatmentClinical benefitLung cancerMechanisms of resistanceTargeted therapyClinical definitionTumor indicationsTrial designUS FoodSociety for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with targeted therapies
Atkins M, Ascierto P, Feltquate D, Gulley J, Johnson D, Khushalani N, Sosman J, Yap T, Kluger H, Sullivan R, Tawbi H. Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with targeted therapies. Journal For ImmunoTherapy Of Cancer 2023, 11: e005923. PMID: 36918225, PMCID: PMC10016252, DOI: 10.1136/jitc-2022-005923.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsConsensus definitionCheckpoint inhibitorsAntiangiogenic therapySingle-agent immune checkpoint inhibitorsConsensus clinical definitionSolid tumor settingTumor immune microenvironmentImmunotherapy of cancerDurable disease controlClinical trial designSignal transduction inhibitorsICI combinationsEndometrial cancerImproved survivalRandomized trialsImmune microenvironmentMechanisms of resistanceHepatocellular carcinomaClinical definitionKidney cancerImmunotherapyTumor settingsCombination treatmentTrial designSociety for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors
Kluger H, Barrett J, Gainor J, Hamid O, Hurwitz M, LaVallee T, Moss R, Zappasodi R, Sullivan R, Tawbi H, Sharon E. Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors. Journal For ImmunoTherapy Of Cancer 2023, 11: e005921. PMID: 36918224, PMCID: PMC10016305, DOI: 10.1136/jitc-2022-005921.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsCheckpoint inhibitorsAnti-PD-1 immune checkpoint inhibitorTrial designConsensus definitionConsensus clinical definitionExtended disease controlNew combination regimensImmunotherapy of cancerStandard of careLong-term survivalClinical trial designICI combinationsInitial immunotherapyMetastatic settingTreatment discontinuationDurable responsesTreatment landscapeCombination regimensMechanisms of resistancePerioperative settingPrimary resistanceClinical definitionDefinition of resistanceImmunotherapyGermline genetic variants are associated with development of insulin-dependent diabetes in cancer patients treated with immune checkpoint inhibitors
Caulfield J, Aizenbud L, Perdigoto A, Meffre E, Jilaveanu L, Michalek D, Rich S, Aizenbud Y, Adeniran A, Herold K, Austin M, Kluger H. Germline genetic variants are associated with development of insulin-dependent diabetes in cancer patients treated with immune checkpoint inhibitors. Journal For ImmunoTherapy Of Cancer 2023, 11: e006570. PMID: 36898736, PMCID: PMC10008335, DOI: 10.1136/jitc-2022-006570.Peer-Reviewed Original ResearchConceptsImmune-related adverse eventsInsulin-dependent diabetesImmune checkpoint inhibitorsType 1 diabetesCheckpoint inhibitorsControl patientsSevere immune-related adverse eventsImmunotherapy-treated patientsCheckpoint inhibitor therapyIslet cell destructionPotential predictive biomarkersIslet cell functionWhole-exome sequencingICI exposureAdverse eventsGermline genetic variantsInhibitor therapyPatient selectionTreatment regimensCancer patientsPredictive biomarkersGeneral populationPatientsDiabetesSame drug
2022
Baseline gene expression profiling determines long-term benefit to programmed cell death protein 1 axis blockade
Vathiotis I, Salichos L, Martinez-Morilla S, Gavrielatou N, Aung T, Shafi S, Wong P, Jessel S, Kluger H, Syrigos K, Warren S, Gerstein M, Rimm D. Baseline gene expression profiling determines long-term benefit to programmed cell death protein 1 axis blockade. Npj Precision Oncology 2022, 6: 92. PMID: 36522538, PMCID: PMC9755314, DOI: 10.1038/s41698-022-00330-3.Peer-Reviewed Original ResearchProgression-free survivalLong-term benefitsPredictive valueAnti-PD-1 therapyCell death protein 1Baseline tumor samplesImmune checkpoint inhibitorsAntitumor immune responseCohort of patientsDeath protein 1Gene expression profilesAdvanced diseaseCheckpoint inhibitorsAdvanced melanomaAxis blockadeImmunotherapy outcomesTreatment initiationEarly outcomesDisease progressionMalignant melanomaBaseline gene expressionImmune responseBaseline gene expression profilesExpression profilesTumor samplesAssociation between immune-mediated adverse events and efficacy in metastatic non-small-cell lung cancer patients treated with durvalumab and tremelimumab
Dey A, Austin M, Kluger H, Trunova N, Mann H, Shire N, Morgan C, Zhou D, Mugundu G. Association between immune-mediated adverse events and efficacy in metastatic non-small-cell lung cancer patients treated with durvalumab and tremelimumab. Frontiers In Immunology 2022, 13: 1026964. PMID: 36405729, PMCID: PMC9670978, DOI: 10.3389/fimmu.2022.1026964.Peer-Reviewed Original ResearchConceptsCell lung cancer patientsLung cancer patientsAdverse eventsBaseline characteristicsOverall survivalCancer patientsMultivariate Cox proportional hazards modelImmune-mediated adverse eventsCox proportional hazards modelIndividual patient-level dataImmune checkpoint inhibitorsImproved overall survivalEfficacy of immunotherapyPatient demographic featuresOptimal clinical benefitPatient-level dataProportional hazards modelCheckpoint inhibitorsCombination armLaboratory featuresSteroid treatmentClinical benefitPatient survivalPatient populationHigher odds789 Lifileucel TIL cell monotherapy in patients with advanced melanoma after progression on immune checkpoint inhibitors (ICI) and targeted therapy: pooled analysis of consecutive cohorts (C-144–01 study)
Sarnaik A, Lewis K, Kluger H, Hamid O, Whitman E, Thomas S, Wermke M, Cusnir M, Domingo-Musibay E, Phan G, Kirkwood J, Hassel J, Orloff M, Larkin J, Weber J, Furness A, Khushalani N, Medina T, Finckenstein F, Jagasia M, Hari P, Sulur G, Shi W, Wu X, Chesney J. 789 Lifileucel TIL cell monotherapy in patients with advanced melanoma after progression on immune checkpoint inhibitors (ICI) and targeted therapy: pooled analysis of consecutive cohorts (C-144–01 study). 2022, a821-a822. DOI: 10.1136/jitc-2022-sitc2022.0789.Peer-Reviewed Original ResearchLocation 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 therapyImmune cells and their inflammatory mediators modify beta cells and cause checkpoint inhibitor-induced diabetes
Perdigoto AL, Deng S, Du KC, Kuchroo M, Burkhardt DB, Tong A, Israel G, Robert ME, Weisberg SP, Kirkiles-Smith N, Stamatouli AM, Kluger HM, Quandt Z, Young A, Yang ML, Mamula MJ, Pober JS, Anderson MS, Krishnaswamy S, Herold KC. Immune cells and their inflammatory mediators modify beta cells and cause checkpoint inhibitor-induced diabetes. JCI Insight 2022, 7: e156330. PMID: 35925682, PMCID: PMC9536276, DOI: 10.1172/jci.insight.156330.Peer-Reviewed Original ResearchConceptsCheckpoint inhibitorsΒ-cellsPD-1/PD-L1 pathwayT-lymphocyte antigen-4PD-1 blockadePD-L1 pathwayDeath ligand 1NOD mouse modelDevelopment of diabetesHuman β-cellsAutoimmune complicationsNOD miceΒ-cell populationDeath-1Diabetes mellitusImmune infiltratesInflammatory mediatorsPancreatic inflammationPD-L1Induced diabetesLymphocytic infiltrationInflammatory cytokinesAntigen-4Immune cellsT cells