2023
Digital spatial profiling of melanoma shows CD95 expression in immune cells is associated with resistance to immunotherapy
Martinez-Morilla S, Moutafi M, Fernandez A, Jessel S, Divakar P, Wong P, Garcia-Milian R, Schalper K, Kluger H, Rimm D. Digital spatial profiling of melanoma shows CD95 expression in immune cells is associated with resistance to immunotherapy. OncoImmunology 2023, 12: 2260618. PMID: 37781235, PMCID: PMC10540659, DOI: 10.1080/2162402x.2023.2260618.Peer-Reviewed Original ResearchConceptsDigital spatial profilingImmune checkpoint inhibitor therapyShorter progression-free survivalQuantitative immunofluorescenceCheckpoint inhibitor therapyProgression-free survivalMetastatic melanoma patientsPre-treatment specimensIndependent validation cohortMetastatic melanoma casesAdjuvant settingNanoString GeoMxMultivariable adjustmentAdverse eventsImmunotherapy cohortInhibitor therapyPD-L1Immune markersMelanoma patientsUnivariable analysisValidation cohortImmune cellsMelanoma casesMultiplex immunofluorescenceCD95 expressionSociety for Immunotherapy of Cancer (SITC) checkpoint inhibitor resistance definitions: efforts to harmonize terminology and accelerate immuno-oncology drug development
Tawbi H, Sullivan R, Feltquate D, LaVallee T, Rizvi N, Sharon E, Sosman J, Kluger H. Society for Immunotherapy of Cancer (SITC) checkpoint inhibitor resistance definitions: efforts to harmonize terminology and accelerate immuno-oncology drug development. Journal For ImmunoTherapy Of Cancer 2023, 11: e007309. PMID: 37487665, PMCID: PMC10373737, DOI: 10.1136/jitc-2023-007309.Peer-Reviewed Original ResearchCombinatorial 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 challengeSociety 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 ResearchMeSH KeywordsConsensusDrug Therapy, CombinationHumansImmune Checkpoint InhibitorsImmunotherapyLung NeoplasmsConceptsImmune 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 ResearchMeSH KeywordsConsensusHumansImmune Checkpoint InhibitorsImmunotherapyKidney NeoplasmsMelanomaTumor MicroenvironmentConceptsImmune 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 resistanceImmunotherapy
2022
FRACTION-RCC: nivolumab plus ipilimumab for advanced renal cell carcinoma after progression on immuno-oncology therapy
Choueiri T, Kluger H, George S, Tykodi S, Kuzel T, Perets R, Nair S, Procopio G, Carducci M, Castonguay V, Folefac E, Lee C, Hotte S, Miller W, Saggi S, Lee C, Desilva H, Bhagavatheeswaran P, Motzer R, Escudier B. FRACTION-RCC: nivolumab plus ipilimumab for advanced renal cell carcinoma after progression on immuno-oncology therapy. Journal For ImmunoTherapy Of Cancer 2022, 10: e005780. PMID: 36328377, PMCID: PMC9639138, DOI: 10.1136/jitc-2022-005780.Peer-Reviewed Original ResearchConceptsAdvanced renal cell carcinomaObjective response rateDuration of responseIO therapyImmuno-oncology therapiesRenal cell carcinomaOverall survivalCell carcinomaAnti-PD-1/PD-L1 therapyImmune-mediated adverse eventsMedian DORProgression-free survival ratesTreatment-related deathsManageable safety profileMedian overall survivalPD-L1 therapyDurable clinical benefitKarnofsky performance statusPrimary outcome measureHigh unmet needExploratory endpointsIpilimumab armPFS ratesStable diseaseAdverse eventsMelanoma central nervous system metastases: An update to approaches, challenges, and opportunities
Karz A, Dimitrova M, Kleffman K, Alvarez‐Breckenridge C, Atkins MB, Boire A, Bosenberg M, Brastianos P, Cahill DP, Chen Q, Ferguson S, Forsyth P, Oliva I, Goldberg SB, Holmen SL, Knisely JPS, Merlino G, Nguyen DX, Pacold ME, Perez‐Guijarro E, Smalley KSM, Tawbi HA, Wen PY, Davies MA, Kluger HM, Mehnert JM, Hernando E. Melanoma central nervous system metastases: An update to approaches, challenges, and opportunities. Pigment Cell & Melanoma Research 2022, 35: 554-572. PMID: 35912544, PMCID: PMC10171356, DOI: 10.1111/pcmr.13059.Peer-Reviewed Original ResearchMeSH KeywordsBrainBrain NeoplasmsEcosystemHumansImmunotherapyMelanomaNeoplasms, Second PrimaryTumor MicroenvironmentConceptsMelanoma brain metastasesMBM patientsBrain metastasesCheckpoint inhibitor trialsCommon brain malignancyMelanoma Research FoundationDedicated clinical trialsRole of astrocytesNovel treatment approachesImmunotherapy trialsInhibitor trialsBrain malignanciesClinical trialsPatient outcomesBrain microenvironmentTreatment approachesPatient advocatesPatientsTrialsTherapeutic purposesMetabolic adaptationMetastasisCurrent standardTherapyRecent reportsSociety for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of nonmelanoma skin cancer
Silk AW, Barker CA, Bhatia S, Bollin KB, Chandra S, Eroglu Z, Gastman BR, Kendra KL, Kluger H, Lipson EJ, Madden K, Miller DM, Nghiem P, Pavlick AC, Puzanov I, Rabinowits G, Ruiz ES, Sondak VK, Tavss EA, Tetzlaff MT, Brownell I. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of nonmelanoma skin cancer. Journal For ImmunoTherapy Of Cancer 2022, 10: e004434. PMID: 35902131, PMCID: PMC9341183, DOI: 10.1136/jitc-2021-004434.Peer-Reviewed Original ResearchConceptsNonmelanoma skin cancerClinical practice guidelinesImmune checkpoint inhibitorsCutaneous squamous cell carcinomaMerkel cell carcinomaBasal cell carcinomaCell carcinomaPractice guidelinesSkin cancerCancer clinical practice guidelinesCancer care professionalsManagement of toxicitiesSpecial patient populationsSquamous cell carcinomaImmunotherapy of cancerConsensus-based recommendationsOwn clinical experienceRoutine clinical useCheckpoint inhibitorsMetastatic diseasePatient selectionPatients' qualityImmunotherapeutic treatmentPatient populationAggressive subtypeAssociation Between Food and Drug Administration Approval and Disparities in Immunotherapy Use Among Patients With Cancer in the US
Ermer T, Canavan ME, Maduka RC, Li AX, Salazar MC, Kaminski MF, Pichert MD, Zhan PL, Mase V, Kluger H, Boffa DJ. Association Between Food and Drug Administration Approval and Disparities in Immunotherapy Use Among Patients With Cancer in the US. JAMA Network Open 2022, 5: e2219535. PMID: 35771575, PMCID: PMC9247736, DOI: 10.1001/jamanetworkopen.2022.19535.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerRenal cell carcinomaUse of immunotherapyFDA approvalImmunotherapy useCohort studyClinical trialsNovel therapiesStage IV non-small cell lung cancerMultivariable logistic regression modelingFirst checkpoint inhibitorCheckpoint inhibitor therapyNational Cancer DatabasePatients 20 yearsCell lung cancerSocioeconomic strataTreatment of patientsDrug Administration approvalLife-saving treatmentReceipt of immunotherapyLogistic regression modelingSocioeconomic characteristicsImmunotherapy administrationCheckpoint inhibitorsPatient characteristicsEmerging Studies of Melanoma Brain Metastasis
Caulfield JI, Kluger HM. Emerging Studies of Melanoma Brain Metastasis. Current Oncology Reports 2022, 24: 585-594. PMID: 35212922, DOI: 10.1007/s11912-022-01237-9.Peer-Reviewed Original ResearchMeSH KeywordsBrain NeoplasmsHumansImmunotherapyIncidenceMelanomaPrognosisRadiosurgeryRetrospective StudiesTumor MicroenvironmentConceptsMelanoma brain metastasesBrain metastasesClinical studiesTreatment approachesRecent FindingsClinical trialsImmune checkpoint inhibitorsAdditional treatment approachesRecent preclinical studiesNew treatment approachesCentral nervous systemBrain disseminationCheckpoint inhibitorsSignificant morbidityPerilesional edemaRadiation necrosisPatient populationClinical challengePreclinical studiesNervous systemSolid tumorsEmerging studiesMetastasisTumor microenvironmentDisease controlTumor homingInhibition of renalase drives tumour rejection by promoting T cell activation
Guo X, Jessel S, Qu R, Kluger Y, Chen TM, Hollander L, Safirstein R, Nelson B, Cha C, Bosenberg M, Jilaveanu LB, Rimm D, Rothlin CV, Kluger HM, Desir GV. Inhibition of renalase drives tumour rejection by promoting T cell activation. European Journal Of Cancer 2022, 165: 81-96. PMID: 35219026, PMCID: PMC8940682, DOI: 10.1016/j.ejca.2022.01.002.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsHumansImmune Checkpoint InhibitorsImmunotherapyMelanomaMiceMonoamine OxidaseTumor MicroenvironmentConceptsPD-1 inhibitorsMurine melanoma modelMelanoma-bearing miceMelanoma modelTumor microenvironmentTumor rejectionCell death protein 1 (PD-1) inhibitorsAnti-PD-1 activityEnhanced T cell infiltrationT cell-dependent fashionMelanoma cellsMelanoma tumor regressionPreclinical melanoma modelsT cell infiltrationNatural killer cellsForkhead box P3Expression of IFNγWild-type miceProtein 1 inhibitorT cell activationTumor cell contentWild-type melanoma cellsCD4 cellsAdvanced melanomaAntibody treatmentAutoimmune retinopathy with associated anti-retinal antibodies as a potential immune-related adverse event associated with immunotherapy in patients with advanced cutaneous melanoma: case series and systematic review
Heng JS, Kim JM, Jones DK, Stoessel KM, Weiss SA, Sznol M, Kluger HM, Walter SD, Silverstein NA, Pointdujour-Lim R. Autoimmune retinopathy with associated anti-retinal antibodies as a potential immune-related adverse event associated with immunotherapy in patients with advanced cutaneous melanoma: case series and systematic review. BMJ Open Ophthalmology 2022, 7: e000889. PMID: 35047671, PMCID: PMC8724805, DOI: 10.1136/bmjophth-2021-000889.Peer-Reviewed Original ResearchConceptsAdvanced cutaneous melanomaAnti-retinal antibodiesImmune-related adverse eventsAutoimmune retinopathyCutaneous melanomaNivolumab immunotherapySystematic reviewAdverse eventsMucosal melanomaAcute exudative polymorphous vitelliform maculopathyPotential immune-related adverse eventsBilateral visual field lossNew visual symptomsImmune checkpoint inhibitionRetrospective chart reviewCutaneous melanoma patientsVaried clinical manifestationsVisual field lossComplete ophthalmic examinationScreening of patientsMeta-Analyses (PRISMA) guidelinesPreferred Reporting ItemsVitelliform maculopathyChart reviewFunduscopic changes
2021
Merkel Cell Carcinoma: Changing Practice Patterns and Impact on Recurrence-Free and Overall Survival at a Single Institution and Nationally
Esposito A, Jacobs D, Ariyan S, Galan A, Kluger H, Clune J, Weiss S, Tran T, Olino K. Merkel Cell Carcinoma: Changing Practice Patterns and Impact on Recurrence-Free and Overall Survival at a Single Institution and Nationally. Annals Of Surgical Oncology 2021, 29: 415-424. PMID: 34494169, PMCID: PMC8677689, DOI: 10.1245/s10434-021-10727-2.Peer-Reviewed Original ResearchMeSH KeywordsAgedCarcinoma, Merkel CellFemaleHumansImmunotherapyMaleRadiation OncologyRetrospective StudiesSkin NeoplasmsConceptsDisease-specific survivalOverall survivalCT2 diseasePractice patternsSingle-institution retrospective reviewShorter disease-specific survivalActive cigarette smokersAdoption of immunotherapyMultivariable Cox regressionUse of immunotherapyUse of radiotherapyResultsOne hundred fiftyShorter overall survivalAggressive neuroendocrine carcinomaRisk of mortalitySurrogate outcome measureBackgroundMerkel cell carcinomaTreatment of MCCMCC managementImmunocompromised stateMCC patientsMedian ageUnknown primaryRetrospective reviewCigarette smokersOutcomes of Stereotactic Radiosurgery and Immunotherapy in Renal Cell Carcinoma Patients With Brain Metastases
Uezono H, Nam D, Kluger HM, Sznol M, Hurwitz M, Yu JB, Chiang VL. Outcomes of Stereotactic Radiosurgery and Immunotherapy in Renal Cell Carcinoma Patients With Brain Metastases. American Journal Of Clinical Oncology 2021, 44: 495-501. PMID: 34432667, DOI: 10.1097/coc.0000000000000849.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsRCC brain metastasesBrain metastasesRenal cell carcinomaStereotactic radiosurgeryOverall survivalUse of ICIsCentral nervous system toxicityRenal cell carcinoma patientsImpact of immunotherapyLocal control outcomesMedian overall survivalCell carcinoma patientsKaplan-Meier curvesNervous system toxicityBetter median OSLog-rank testMann-Whitney U testMargin doseMedian OSNonimmunotherapy groupSRS doseCheckpoint inhibitorsImmunotherapy groupCarcinoma patientsCirculating clonally expanded T cells reflect functions of tumor-infiltrating T cells
Lucca LE, Axisa PP, Lu B, Harnett B, Jessel S, Zhang L, Raddassi K, Zhang L, Olino K, Clune J, Singer M, Kluger HM, Hafler DA. Circulating clonally expanded T cells reflect functions of tumor-infiltrating T cells. Journal Of Experimental Medicine 2021, 218: e20200921. PMID: 33651881, PMCID: PMC7933991, DOI: 10.1084/jem.20200921.Peer-Reviewed Original ResearchConceptsTumor-infiltrating T cellsT cellsUnique transcriptional patternsFeatures of exhaustionLongitudinal immune monitoringPeripheral immune environmentsT cell responsesT cell functionSingle-cell levelTranscriptional patternsTCR sharingTerminal exhaustionImmune environmentImmune monitoringCancer immunotherapyMetastatic melanomaEffector functionsCell responsesTumor tissueGene signatureTumorsCell functionImmunotherapyTCRαβBloodAdverse events induced by immune checkpoint inhibitors
Perdigoto AL, Kluger H, Herold KC. Adverse events induced by immune checkpoint inhibitors. Current Opinion In Immunology 2021, 69: 29-38. PMID: 33640598, PMCID: PMC8122053, DOI: 10.1016/j.coi.2021.02.002.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAutoantibodiesAutoantigensAutoimmune DiseasesAutoimmunityCytotoxicity, ImmunologicDrug-Related Side Effects and Adverse ReactionsGene-Environment InteractionGenetic Predisposition to DiseaseHumansImmune Checkpoint InhibitorsImmunotherapyLymphocyte ActivationNeoplasmsT-LymphocytesConceptsImmune checkpoint inhibitorsCheckpoint inhibitorsAdverse eventsT cellsImmune related adverse eventsEmergence of autoantibodiesRelated adverse eventsAnti-tumor responseAutoreactive T cellsActivated T cellsAutoimmune mechanismsTreatment of cancerAutoimmune diseasesInflammatory responsePredictive valueHost factorsToxic effectsInhibitorsDirect effectOngoing investigationAutoantibodiesCellsAutoimmunityPathogenesisCancer
2020
Quantitative analysis of CMTM6 expression in tumor microenvironment in metastatic melanoma and association with outcome on immunotherapy
Martinez-Morilla S, Zugazagoitia J, Wong PF, Kluger HM, Rimm DL. Quantitative analysis of CMTM6 expression in tumor microenvironment in metastatic melanoma and association with outcome on immunotherapy. OncoImmunology 2020, 10: 1864909. PMID: 33457084, PMCID: PMC7781756, DOI: 10.1080/2162402x.2020.1864909.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsPD-L1CMTM6 expressionControl patientsLonger survivalTissue microarrayQuantitative immunofluorescenceEffectiveness of immunotherapyMetastatic melanoma patientsDeath ligand 1Like MARVEL transmembrane domainCancer Genome Atlas (TCGA) databaseExpression of CMTM6MARVEL transmembrane domainExpression of mRNAChemokine-like factorICI treatmentCheckpoint inhibitorsPretreatment biopsiesCD68 markersImmune compartmentMultivariable analysisMelanoma patientsImmune-related proteinsPredictive factorsBempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02)
Diab A, Tannir NM, Bentebibel SE, Hwu P, Papadimitrakopoulou V, Haymaker C, Kluger HM, Gettinger SN, Sznol M, Tykodi SS, Curti BD, Tagliaferri MA, Zalevsky J, Hannah AL, Hoch U, Aung S, Fanton C, Rizwan A, Iacucci E, Liao Y, Bernatchez C, Hurwitz ME, Cho DC. Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02). Cancer Discovery 2020, 10: 1158-1173. PMID: 32439653, DOI: 10.1158/2159-8290.cd-19-1510.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntineoplastic Agents, ImmunologicalAntineoplastic Combined Chemotherapy ProtocolsCarcinoma, Non-Small-Cell LungCarcinoma, Renal CellFemaleGene Expression Regulation, NeoplasticHumansImmune Checkpoint InhibitorsImmunotherapyInterleukin-2Kidney NeoplasmsLung NeoplasmsLymphocyte CountLymphocytes, Tumor-InfiltratingMaleMelanomaMiddle AgedNivolumabPolyethylene GlycolsProgrammed Cell Death 1 ReceptorTreatment OutcomeYoung AdultConceptsTreatment-related adverse eventsAdvanced solid tumorsPD-L1 statusSolid tumorsGrade 3/4 treatment-related adverse eventsPD-1/PD-L1 blockadeCommon treatment-related adverse eventsPhase I dose-escalation trialPoor prognostic risk factorsTotal objective response rateI dose-escalation studyI dose-escalation trialLongitudinal tumor biopsiesPD-L1 blockadeT-cell enhancementTreatment-related deathsObjective response ratePhase II doseDose-escalation studyDose-escalation trialDose-limiting toxicityFlu-like symptomsPrognostic risk factorsTumor-infiltrating lymphocytesCytotoxicity of CD8Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce
Kluger HM, Tawbi HA, Ascierto ML, Bowden M, Callahan MK, Cha E, Chen HX, Drake CG, Feltquate DM, Ferris RL, Gulley JL, Gupta S, Humphrey RW, LaVallee TM, Le DT, Hubbard-Lucey VM, Papadimitrakopoulou VA, Postow MA, Rubin EH, Sharon E, Taube JM, Topalian SL, Zappasodi R, Sznol M, Sullivan RJ. Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce. Journal For ImmunoTherapy Of Cancer 2020, 8: e000398. PMID: 32238470, PMCID: PMC7174063, DOI: 10.1136/jitc-2019-000398.Peer-Reviewed Original ResearchMeSH KeywordsBiomarkers, TumorFemaleHumansImmunotherapyMaleNeoplasmsProgrammed Cell Death 1 ReceptorConceptsCancer immunotherapyClinical definitionNew agentsPD-1/PD-L1 blockadePD-1 pathway blockadeConsensus clinical definitionPD-L1 blockadeDeath receptor-1Immunotherapy of cancerStandard of careClinical trial designTreatment discontinuationMechanisms of resistancePathway blockadeClinical trialsConfirmatory scanPrimary resistancePatient benefitSecondary resistanceTrial designTreatment approachesUnmet needReceptor 1Tumor resistancePattern of response