2024
Immune Cell Dynamics in EGFR-Mutated NSCLC Treated With Afatinib and Pembrolizumab: Results From a Phase IB Study
Riess J, Lara M, de Rodas M, Luxardi G, Herbert S, Shimoda M, Kelly K, Meerlev A, Moore E, Beckett L, Monjazeb A, Schalper K, Maverakis E, Gandara D. Immune Cell Dynamics in EGFR-Mutated NSCLC Treated With Afatinib and Pembrolizumab: Results From a Phase IB Study. JTO Clinical And Research Reports 2024, 5: 100706. PMID: 39318388, PMCID: PMC11420451, DOI: 10.1016/j.jtocrr.2024.100706.Peer-Reviewed Original ResearchImmune related adverse eventsNon-small cell lung cancerEGFR-mutant non-small cell lung cancerMaximum tolerated doseEpidermal growth factor receptorImmune cell subsetsT cellsEGFR-TKIsCell subsetsPD-1 antibody pembrolizumabRecommended phase 2 doseCentral memory T cellsAssociated with anti-tumor activityCD8+ T cellsCD3+ T cellsEGFR-TKI afatinibPD-(L)1 blockadePhase 2 doseTreated with afatinibPhase Ib studyMemory T cellsImmune cell dynamicsControlling brain metastasesCell lung cancerCD4/CD8 T cellsUp-regulated PLA2G10 in cancer impairs T cell infiltration to dampen immunity
Zhang T, Yu W, Cheng X, Yeung J, Ahumada V, Norris P, Pearson M, Yang X, van Deursen W, Halcovich C, Nassar A, Vesely M, Zhang Y, Zhang J, Ji L, Flies D, Liu L, Langermann S, LaRochelle W, Humphrey R, Zhao D, Zhang Q, Zhang J, Gu R, Schalper K, Sanmamed M, Chen L. Up-regulated PLA2G10 in cancer impairs T cell infiltration to dampen immunity. Science Immunology 2024, 9: eadh2334. PMID: 38669316, DOI: 10.1126/sciimmunol.adh2334.Peer-Reviewed Original ResearchConceptsT cell infiltrationT cell exclusionT cellsResistance to anti-PD-1 immunotherapyPoor T-cell infiltrationAnti-PD-1 immunotherapyImmunogenic mouse tumorsT cell mobilizationHuman cancer tissuesTherapeutic immunotherapyCancer immunotherapyMouse tumorsChemokine systemImmunotherapyTumor tissuesImpaired infiltrationTumorLipid metabolitesHuman cancersCancer tissuesInfiltrationA2 groupCancerPLA2G10Up-regulated
2023
Atezolizumab plus stereotactic ablative radiotherapy for medically inoperable patients with early-stage non-small cell lung cancer: a multi-institutional phase I trial
Monjazeb A, Daly M, Luxardi G, Maverakis E, Merleev A, Marusina A, Borowsky A, Mirhadi A, Shiao S, Beckett L, Chen S, Eastham D, Li T, Vick L, McGee H, Lara F, Garcia L, Morris L, Canter R, Riess J, Schalper K, Murphy W, Kelly K. Atezolizumab plus stereotactic ablative radiotherapy for medically inoperable patients with early-stage non-small cell lung cancer: a multi-institutional phase I trial. Nature Communications 2023, 14: 5332. PMID: 37658083, PMCID: PMC10474145, DOI: 10.1038/s41467-023-40813-w.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerStereotactic ablative radiotherapyEarly-stage non-small cell lung cancerCell lung cancerAblative radiotherapyLung cancerMulti-institutional phase I trialSingle-arm phase IThird of patientsPhase I trialEx vivo stimulationT cell activationInoperable patientsPrimary endpointSecondary endpointsEfficacy signalsI trialT cellsAdaptive immunityCell activationPatientsPhase IPhase IIIEarly responseAtezolizumabQuantitative DNA Repair Biomarkers and Immune Profiling for Temozolomide and Olaparib in Metastatic Colorectal Cancer
Cecchini M, Zhang J, Wei W, Sklar J, Lacy J, Zhong M, Kong Y, Zhao H, DiPalermo J, Devine L, Stein S, Kortmansky J, Johung K, Bindra R, LoRusso P, Schalper K. Quantitative DNA Repair Biomarkers and Immune Profiling for Temozolomide and Olaparib in Metastatic Colorectal Cancer. Cancer Research Communications 2023, 3: 1132-1139. PMID: 37387791, PMCID: PMC10305782, DOI: 10.1158/2767-9764.crc-23-0045.Peer-Reviewed Original ResearchConceptsWhole-exome sequencingMGMT protein expressionColorectal cancerStable diseaseQuantitative immunofluorescenceT cellsProtein expressionPromoter hypermethylationLow MGMT protein expressionPARP inhibitorsRadiographic tumor regressionMetastatic colorectal cancerAdvanced colorectal cancerPretreatment tumor biopsiesEffector T cellsTumor-infiltrating lymphocytesMGMT proteinDNA repair biomarkersBaseline CD8Eligible patientsIncreased CD8Methylguanine-DNA methyltransferaseObjective responseProgressive diseaseImmune markersDeveloping a definition of immune exclusion in cancer: results of a modified Delphi workshop
Clifton G, Rothenberg M, Ascierto P, Begley G, Cecchini M, Eder J, Ghiringhelli F, Italiano A, Kochetkova M, Li R, Mechta-Grigoriou F, Pai S, Provenzano P, Puré E, Ribas A, Schalper K, Fridman W. Developing a definition of immune exclusion in cancer: results of a modified Delphi workshop. Journal For ImmunoTherapy Of Cancer 2023, 11: e006773. PMID: 37290925, PMCID: PMC10254706, DOI: 10.1136/jitc-2023-006773.Peer-Reviewed Original ResearchConceptsImmune exclusionTumor microenvironmentCheckpoint inhibitorsImmune checkpoint inhibitorsMinority of patientsT cell infiltrationPoor clinical outcomeImmune regulatory pathwaysEffective treatment approachDevelopment of treatmentsVariety of cancersLack of responseCheckpoint therapyImmune profileClinical outcomesClinical benefitPatient outcomesCancer expertsCancer histologyT cellsConsensus definitionTreatment approachesCancer typesRound questionnaireDelphi process
2019
Functional profile and clinical significance of major tumor infiltrating lymphocyte subsets in lung cancer-associated brain metastases.
Lu B, Gupta R, Stewart T, Kluger H, Jilaveanu L, Schalper K, Goldberg S. Functional profile and clinical significance of major tumor infiltrating lymphocyte subsets in lung cancer-associated brain metastases. Journal Of Clinical Oncology 2019, 37: 2066-2066. DOI: 10.1200/jco.2019.37.15_suppl.2066.Peer-Reviewed Original ResearchPrimary lung tumorsMajor T cell subsetsMultiplexed quantitative immunofluorescenceT cell subsetsExtracranial metastasesT cellsLung tumorsBrain metastasesQuantitative immunofluorescenceAdaptive anti-tumor responsesLow T cell infiltrationMajor clinicopathologic variablesYale Cancer CenterAdaptive immune cellsRegulatory T cellsT cell infiltrationAnti-tumor responseLonger overall survivalOptimal treatment strategyLung cancer patientsKi-67 levelsLung cancer histologyLymphocyte subsetsOverall survivalPrimary malignancy
2018
PD-1/PD-L1 interaction and CD25/FOXP3+ t cells to predict survival benefit from adjuvant chemotherapy in early stage non–small-cell lung cancer (ES-NSCLC).
Bordeaux J, Dakappagari N, Pennell N, Stevenson J, Khunger M, Vaupel C, Schalper K, Rimm D, Velcheti V. PD-1/PD-L1 interaction and CD25/FOXP3+ t cells to predict survival benefit from adjuvant chemotherapy in early stage non–small-cell lung cancer (ES-NSCLC). Journal Of Clinical Oncology 2018, 36: 12059-12059. DOI: 10.1200/jco.2018.36.15_suppl.12059.Peer-Reviewed Original ResearchSpatially Resolved and Quantitative Analysis of VISTA/PD-1H as a Novel Immunotherapy Target in Human Non–Small Cell Lung Cancer
Villarroel-Espindola F, Yu X, Datar I, Mani N, Sanmamed M, Velcheti V, Syrigos K, Toki M, Zhao H, Chen L, Herbst RS, Schalper KA. Spatially Resolved and Quantitative Analysis of VISTA/PD-1H as a Novel Immunotherapy Target in Human Non–Small Cell Lung Cancer. Clinical Cancer Research 2018, 24: 1562-1573. PMID: 29203588, PMCID: PMC5884702, DOI: 10.1158/1078-0432.ccr-17-2542.Peer-Reviewed Original ResearchMeSH KeywordsAgedAntigens, CDAntigens, Differentiation, MyelomonocyticB7 AntigensB7-H1 AntigenBiomarkers, TumorCarcinoma, Non-Small-Cell LungCD8-Positive T-LymphocytesEvaluation Studies as TopicFemaleGene Expression Regulation, NeoplasticHumansImmunologic FactorsImmunotherapyLung NeoplasmsMaleMembrane ProteinsMutationProgrammed Cell Death 1 ReceptorRetrospective StudiesConceptsNon-small cell lung cancerHuman non-small cell lung cancerT helper cellsCytotoxic T cellsT cellsPD-1Localized expression patternQuantitative immunofluorescenceTumor-infiltrating lymphocytesCell lung cancerLung cancer casesGenomic analysisTissue microarray formatTumor-associated macrophagesPD-L1 proteinCytoplasmic staining patternClin Cancer ResExpression patternsLow mutational burdenTumor epithelial cellsSpecific genomic alterationsVISTA expressionVISTA proteinPD-L1Immunomodulatory role
2017
Tetrahydrouridine-decitabine for non-cytotoxic epigenetic therapy of NSCLC to enhance immunotherapeutic effect of anti-PD1 in vivo.
Kang K, Schrump D, Thomas A, Schalper K, Saunthararajah Y, Velcheti V. Tetrahydrouridine-decitabine for non-cytotoxic epigenetic therapy of NSCLC to enhance immunotherapeutic effect of anti-PD1 in vivo. Journal Of Clinical Oncology 2017, 35: 11552-11552. DOI: 10.1200/jco.2017.35.15_suppl.11552.Peer-Reviewed Original ResearchT cellsC57/BL6 miceAbsolute lymphocyte countAnti-PD1 therapyRegulatory T cellsTumor-Infiltrating LymphocytesImmune memory effectTumor-bearing miceDNMT1 depletionMost NSCLCNSCLC responsePharmacologic rationaleG-MDSCSolid cancer tissuesImmunotherapeutic effectsLymphocyte countMedian survivalIFNγ expressionInfiltrating lymphocytesSurvival improvementMAGE-A3BL6 miceLung invasionAntigen presentationMAGE-A1Measurement of PD-1, TIM-3 and LAG-3 protein in non-small cell lung carcinomas (NSCLCs) with acquired resistance to PD-1 axis blockers.
Datar I, Mani N, Henick B, Wurtz A, Kaftan E, Herbst R, Rimm D, Gettinger S, Politi K, Schalper K. Measurement of PD-1, TIM-3 and LAG-3 protein in non-small cell lung carcinomas (NSCLCs) with acquired resistance to PD-1 axis blockers. Journal Of Clinical Oncology 2017, 35: e14611-e14611. DOI: 10.1200/jco.2017.35.15_suppl.e14611.Peer-Reviewed Original ResearchNon-small cell lung carcinomaTim-3PD-1LAG-3T cellsInhibitory receptorsAdvanced non-small cell lung carcinomaPD-1 axis blockadeHigh TIM-3Immune suppressive pathwaysImmune inhibitory receptorsCell lung carcinomaMembranous staining patternPre-treatment samplesWhole tissue sectionsWhole tumor areaClinical responseMost patientsAxis blockadeLow levelsLung carcinomaT lymphocytesMultiplex immunofluorescenceHigh levelsSuppressive pathways
2016
Abscopal Effects of Radiotherapy Are Enhanced by Combined Immunostimulatory mAbs and Are Dependent on CD8 T Cells and Crosspriming
Rodriguez-Ruiz ME, Rodriguez I, Garasa S, Barbes B, Solorzano JL, Perez-Gracia JL, Labiano S, Sanmamed MF, Azpilikueta A, Bolaños E, Sanchez-Paulete AR, Aznar MA, Rouzaut A, Schalper KA, Jure-Kunkel M, Melero I. Abscopal Effects of Radiotherapy Are Enhanced by Combined Immunostimulatory mAbs and Are Dependent on CD8 T Cells and Crosspriming. Cancer Research 2016, 76: 5994-6005. PMID: 27550452, DOI: 10.1158/0008-5472.can-16-0549.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalBasic-Leucine Zipper Transcription FactorsCD8-Positive T-LymphocytesCell Line, TumorFemaleHumansLymphocytes, Tumor-InfiltratingMiceMice, Inbred BALB CMice, Inbred C57BLNeoplasms, ExperimentalProgrammed Cell Death 1 ReceptorReceptor, Interferon alpha-betaRepressor ProteinsTumor MicroenvironmentTumor Necrosis Factor Receptor Superfamily, Member 9ConceptsAnti-CD137 mAbsCD8 T cellsEffector T cellsT cellsTumor lesionsMyeloid-derived suppressor cellsSelective depletion experimentsType I IFN systemTumor-infiltrating lymphocytesCombination of radiotherapyField of irradiationImmunostimulatory mAbsImmunotherapy combinationsIntracellular IFNγProimmune effectsContralateral tumorsSuppressor cellsDendritic cellsClinical evidenceRadiotherapy strategiesIrradiation regimenAntitumor effectsClinical developmentTumor siteEx vivo
2014
Programmed death-1/programmed death-1 ligand axis as a therapeutic target in oncology: current insights
Velcheti V, Schalper K, Venur V. Programmed death-1/programmed death-1 ligand axis as a therapeutic target in oncology: current insights. Journal Of Receptor Ligand And Channel Research 2014, Volume 8: 1-7. DOI: 10.2147/jrlcr.s39986.Peer-Reviewed Original ResearchPD-1Tumor typesImmune checkpoint inhibitorsDeath-1 (PD-1) pathwayPD-1 ligandsDeath-1/Death 1 ligandDurable antitumor activityImmune checkpoint pathwaysAntigen-presenting cellsPromising anticancer therapeutic strategyPD-L1Immune toleranceInvestigational agentsImmune microenvironmentClinical activityT cellsAnticancer therapeutic strategiesTherapeutic strategiesTherapeutic targetClinical developmentTumor cellsMonoclonal antibodiesAntitumor activityTherapeutic antibodies
2013
Sarcomatoid Lung Carcinomas Show High Levels of Programmed Death Ligand-1 (PD-L1)
Velcheti V, Rimm DL, Schalper KA. Sarcomatoid Lung Carcinomas Show High Levels of Programmed Death Ligand-1 (PD-L1). Journal Of Thoracic Oncology 2013, 8: 803-805. PMID: 23676558, PMCID: PMC3703468, DOI: 10.1097/jto.0b013e318292be18.Peer-Reviewed Original ResearchConceptsDeath ligand 1Sarcomatoid carcinomaCell lung carcinomaLung carcinomaPD-L1PD-1/PD-L1 axisPD-1/PD-L1 pathwayProgrammed Death Ligand 1PD-L1 protein expressionEffector immune responsesPD-L1 axisPD-L1 pathwayLung sarcomatoid carcinomaLung cancer cohortSarcomatoid lung carcinomasLigand 1Mouse monoclonal antibodyDeath-1Lymphocytic infiltrationRare subtypeSuch therapyCancer cohortT cellsCarcinomaTumor types