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 modelDevelopment of anex vivo patient-derived tumor model (PDTM) to assess the tumor microenvironment in renal cell carcinoma (RCC)
Kashima S, Gupta R, Moritz V, Sadak K, Adeniran A, Humphrey P, Dinulescu D, Palmer D, Hammond S, Bosenberg M, Hurwitz M, Kenney P, Braun D. Development of anex vivo patient-derived tumor model (PDTM) to assess the tumor microenvironment in renal cell carcinoma (RCC). The Oncologist 2024, 29: s5-s6. PMCID: PMC11301923, DOI: 10.1093/oncolo/oyae181.008.Peer-Reviewed Original ResearchRCC tumor microenvironmentPatient-derived tumor modelsRenal cell carcinomaImmune checkpoint inhibitorsT cell functionPeripheral blood mononuclear cellsEnzyme-linked immunosorbent assayTumor microenvironmentT cellsFlow cytometryTumor fragmentsIFN-gTumor modelTumor samplesCytokine productionHealthy donor peripheral blood mononuclear cellsImpact of immune checkpoint inhibitorsAnti-PD-1 monoclonal antibodyDonor peripheral blood mononuclear cellsCD4+CD25+ regulatory T cellsCD8+ T cell populationsResection of renal cell carcinomaSurgical resection of renal cell carcinomaAnti-PD-1 antibodyMetastatic renal cell carcinoma
2023
Immune 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 samples
2019
Baseline tumor-immune signatures associated with response to bempegaldesleukin (NKTR-214) and nivolumab.
Hurwitz M, Cho D, Balar A, Curti B, Siefker-Radtke A, Sznol M, Kluger H, Bernatchez C, Fanton C, Iacucci E, Liu Y, Nguyen T, Overwijk W, Zalevsky J, Tagliaferri M, Hoch U, Diab A. Baseline tumor-immune signatures associated with response to bempegaldesleukin (NKTR-214) and nivolumab. Journal Of Clinical Oncology 2019, 37: 2623-2623. DOI: 10.1200/jco.2019.37.15_suppl.2623.Peer-Reviewed Original ResearchPD-L1CD8 TILsResponse rateAnti-PD-1 therapyOngoing phase 1/2 studyPre-treatment tumor biopsiesTumor microenvironmentBaseline immune signaturesSurface PD-1Tumor immune signaturePhase 1/2 studyAdvanced solid tumorsUrothelial carcinoma patientsFavorable tumor microenvironmentBaseline immune phenotypeLow groupMedian valueRECIST 1.1Baseline demographicsImmune signaturesPrognostic factorsCarcinoma patientsPD-1Biomarker subgroupsImmune cells
2017
A phase 1/2 study of a novel IL-2 cytokine, NKTR-214, and nivolumab in patients with select locally advanced or metastatic solid tumors.
Diab A, Tannir N, Bernatchez C, Haymaker C, Bentebibel S, Curti B, Wong M, Gergel I, Tagliaferri M, Zalevsky J, Hoch U, Aung S, Imperiale M, Cho D, Tykodi S, Puzanov I, Kluger H, Hurwitz M, Hwu P, Sznol M. A phase 1/2 study of a novel IL-2 cytokine, NKTR-214, and nivolumab in patients with select locally advanced or metastatic solid tumors. Journal Of Clinical Oncology 2017, 35: e14040-e14040. DOI: 10.1200/jco.2017.35.15_suppl.e14040.Peer-Reviewed Original ResearchNKTR-214Phase 1/2 studyT cellsIL-2 receptor pathwayTumor immune cell infiltratesTumor microenvironmentNivolumab combination therapyDose limiting toxicitiesImmune cell infiltratesUnconfirmed complete responseMetastatic solid tumorsWeeks of treatmentFavorable safety profileIL-2 pathwayIL-2 cytokineT-cell clonalityBiomarker dataTumor response dataImmunotherapy-naïveMonotherapy trialsQ3w scheduleRECIST 1.1Checkpoint inhibitorsEffector CD8Adverse eventsEffect of a novel IL-2 cytokine immune agonist (NKTR-214) on proliferating CD8+T cells and PD-1 expression on immune cells in the tumor microenvironment in patients with prior checkpoint therapy.
Bernatchez C, Haymaker C, Hurwitz M, Kluger H, Tetzlaff M, Jackson N, Gergel I, Tagliaferri M, Zalevsky J, Hoch U, Fanton C, Iacucci E, Aung S, Imperiale M, Liao E, Bentebibel S, Tannir N, Hwu P, Sznol M, Diab A. Effect of a novel IL-2 cytokine immune agonist (NKTR-214) on proliferating CD8+T cells and PD-1 expression on immune cells in the tumor microenvironment in patients with prior checkpoint therapy. Journal Of Clinical Oncology 2017, 35: 2545-2545. DOI: 10.1200/jco.2017.35.15_suppl.2545.Peer-Reviewed Original ResearchNKTR-214PD-1 expressionT-cell clonalityTumor microenvironmentNK cellsCell clonalityIL-2 receptor pathwayDays post doseDrug-related AEsImmune-related AEAnti-PD1 therapyCapillary leak syndromePhase 1/2 trialMetastatic solid tumorsFavorable safety profileImmune checkpoint genesSignificant tumor regressionTumor tissue samplesGene expression analysisCytotoxic markersEffector CD8Leak syndromeCheckpoint therapyPrior immunotherapyRegulatory cellsEffect of NKTR-214 on the number and activity of CD8+ tumor infiltrating lymphocytes in patients with advanced renal cell carcinoma.
Hurwitz M, Diab A, Bernatchez C, Haymaker C, Kluger H, Tetzlaff M, Gergel I, Tagliaferri M, Imperiale M, Aung S, Hoch U, Zalevsky J, Hwu P, Sznol M, Tannir N. Effect of NKTR-214 on the number and activity of CD8+ tumor infiltrating lymphocytes in patients with advanced renal cell carcinoma. Journal Of Clinical Oncology 2017, 35: 454-454. DOI: 10.1200/jco.2017.35.6_suppl.454.Peer-Reviewed Original ResearchNKTR-214T cellsTumor microenvironmentIL-2 receptor pathwayAnti-PD-1 blockadeAdvanced renal cell carcinomaImmune-related AEPatient experienced DLTPrior TKI treatmentImmune checkpoint inhibitorsT-cell receptor diversityAdvanced solid tumorsPD-1 expressionT-cell infiltratesActivity of CD8Effector T cellsFavorable safety profileRenal cell carcinomaAnti-tumor activityBaseline CD8Experienced DLTsLow TILsRECIST 1.1Checkpoint inhibitorsEffector CD8