2024
The Teplizumab Saga: The Challenge of Not Getting Lost in Clinical Translation.
Chatenoud L, Herold K, Bach J, Bluestone J. The Teplizumab Saga: The Challenge of Not Getting Lost in Clinical Translation. Cold Spring Harbor Perspectives In Medicine 2024, a041600. PMID: 39284671, DOI: 10.1101/cshperspect.a041600.Peer-Reviewed Original ResearchNanoparticles loaded with IL-2 and TGF-β promote transplantation tolerance to alloantigen
Horwitz D, Wang J, Kim D, Kang C, Brion K, Bickerton S, La Cava A. Nanoparticles loaded with IL-2 and TGF-β promote transplantation tolerance to alloantigen. Frontiers In Immunology 2024, 15: 1429335. PMID: 39131162, PMCID: PMC11310063, DOI: 10.3389/fimmu.2024.1429335.Peer-Reviewed Original ResearchNP-treated miceT regulatory cellsMixed lymphocyte reactionDendritic cellsTolerogenic nanoparticlesAllogeneic cellsIL-2CD8+ T regulatory cellsGraft-versus-host diseaseAlloantigen-specific TregInhibition of mixed lymphocyte reactionTGF-bRecipient dendritic cellsGraft-versus-hostTolerogenic dendritic cellsResponse to alloantigensTolerance to alloantigensStrains of miceAlloantigen immunizationDecreased alloreactivityTolerogenic phenotypeCD4+Allogeneic splenocytesAllograft rejectionImmune suppressionTBCRC 039: a phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative inflammatory breast cancer
Lynce F, Stevens L, Li Z, Brock J, Gulvady A, Huang Y, Nakhlis F, Patel A, Force J, Haddad T, Ueno N, Stearns V, Wolff A, Clark A, Bellon J, Richardson E, Balko J, Krop I, Winer E, Lange P, Hwang E, King T, Tolaney S, Thompson A, Gupta G, Mittendorf E, Regan M, Overmoyer B, Polyak K. TBCRC 039: a phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative inflammatory breast cancer. Breast Cancer Research 2024, 26: 20. PMID: 38297352, PMCID: PMC10829369, DOI: 10.1186/s13058-024-01774-0.Peer-Reviewed Original ResearchConceptsInflammatory breast cancerPathological complete responseTriple-negative IBCPhase II studyTN-IBCIL-6/JAK/STAT3 signalingBreast cancerRandomized phase II studyRun-inInvestigation of novel therapiesDoxorubicin plus cyclophosphamideTreatment naive patientsImmune suppressive effectsGrowth inhibitory effectNeoadjuvant therapyPreoperative therapyComplete responsePhosphorylated STAT3Tumor biopsiesWorse survivalII studyPrimary endpointSecondary endpointsImmune suppressionT cells
2023
Abatacept-Prophylaxis Based Haploidentical Transplantation May Allow Sustained Engraftment and Offset Gvhd in Non-Malignant Disorders
Ngwube A, Shah N, Schulz G, Krishnamurti L, Shenoy S. Abatacept-Prophylaxis Based Haploidentical Transplantation May Allow Sustained Engraftment and Offset Gvhd in Non-Malignant Disorders. Blood 2023, 142: 4901. DOI: 10.1182/blood-2023-191145.Peer-Reviewed Original ResearchNon-malignant disordersPost-transplant cyclophosphamideSickle cell diseaseGVHD prophylaxisHematopoietic transplantationEvaluable patientsHaploidentical transplantationImmune suppressionBone marrowFirst year post-HCTGrade 1 acute GVHDChronic GVHD riskChronic skin GVHDGVHD-free survivalPost-transplant lymphoproliferationsRadiation-containing regimensYear post-HCTPhase 2 trialReduced intensity conditioningSerious infectious complicationsSystemic immune suppressionT-cell chimerismAllogeneic hematopoietic transplantationPrimary outcome measureStem cell boostThe local microenvironment drives activation of neutrophils in human brain tumors
Maas R, Soukup K, Fournier N, Massara M, Galland S, Kornete M, Wischnewski V, Lourenco J, Croci D, Álvarez-Prado Á, Marie D, Lilja J, Marcone R, Calvo G, Santalla Mendez R, Aubel P, Bejarano L, Wirapati P, Ballesteros I, Hidalgo A, Hottinger A, Brouland J, Daniel R, Hegi M, Joyce J. The local microenvironment drives activation of neutrophils in human brain tumors. Cell 2023, 186: 4546-4566.e27. PMID: 37769657, DOI: 10.1016/j.cell.2023.08.043.Peer-Reviewed Original ResearchTumor-associated neutrophilsHuman brain tumorsBrain tumorsTumor necrosis factor alphaDistinct inflammatory signatureOverall immune suppressionBrain metastasis patientsPro-inflammatory mediatorsSoluble inflammatory mediatorsAbundant immune cellsNecrosis factor alphaActivation of neutrophilsTumor-associated macrophagesPro-angiogenic capacityBrain metastasesInflammatory signatureMetastasis patientsInflammatory mediatorsNeutrophil phenotypeImmune suppressionPeripheral bloodBlood neutrophilsDifferent cancer typesImmune cellsBrain microenvironmentScRNA-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 samplesTissue Engineering Scaffolds Remotely Surveil Presymptomatic Allograft Rejection
Urie R, Xiao C, Hughes E, Lombard E, Chen J, Morris A, Farris D, Goldstein D, Shea L. Tissue Engineering Scaffolds Remotely Surveil Presymptomatic Allograft Rejection. The Journal Of Immunology 2023, 210: 173.40-173.40. DOI: 10.4049/jimmunol.210.supp.173.40.Peer-Reviewed Original ResearchAcute cellular allograft rejectionEndomyocardial biopsyRisk of rejectionAllograft rejectionT cell-mediated rejectionRoutine endomyocardial biopsyCellular allograft rejectionHeterotopic heart transplantationMinimally-invasive samplingHealthy allograftsPersonalized immunosuppressionGraft biopsyPredictive biomarkersImmune suppressionHeart transplantationImmune cellsInvasive biopsyImmunological nicheHistological evidenceSkin transplantationBiopsyHistological evaluationGene profilesMolecular biomarkersPorous biomaterials
2022
Pneumonitis in immunotherapy alone vs. chemoimmunotherapy: A systematic review and meta-analysis.
Barbaro A, Siskin M, Grello C, Hernandez A, Dublin J, Breslin S, Punekar S, Velcheti V. Pneumonitis in immunotherapy alone vs. chemoimmunotherapy: A systematic review and meta-analysis. Journal Of Clinical Oncology 2022, 40: e21120-e21120. DOI: 10.1200/jco.2022.40.16_suppl.e21120.Peer-Reviewed Original ResearchNon-small cell lung cancerImmune related adverse eventsImmune checkpoint inhibitorsAdvanced non-small cell lung cancerSevere pneumonitisPD-L1Combination therapyCTLA-4Use of ICIsCombination immune checkpoint inhibitorsLife-threatening complicationsRelated adverse eventsCell lung cancerLung cancer patientsT cell populationsInverse variance weightingGrade pneumonitisCheckpoint inhibitorsInterventional armAdverse eventsCytotoxic chemotherapyImmune suppressionCancer patientsLung cancerClinical trialsSTING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer
Wang Q, Bergholz JS, Ding L, Lin Z, Kabraji SK, Hughes ME, He X, Xie S, Jiang T, Wang W, Zoeller JJ, Kim HJ, Roberts TM, Konstantinopoulos PA, Matulonis UA, Dillon DA, Winer EP, Lin NU, Zhao JJ. STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer. Nature Communications 2022, 13: 3022. PMID: 35641483, PMCID: PMC9156717, DOI: 10.1038/s41467-022-30568-1.Peer-Reviewed Original ResearchConceptsAnti-tumor immunityBreast cancerPARP inhibitorsSTING agonistsBRCA-mutant breast cancerTumor cellsAnti-tumor stateAdvanced ovarian tumorsCell-mediated suppressionType I IFN responseTumor-associated macrophagesInnate immune suppressionI IFN responseBreast tumor cellsTreatment landscapePro-tumor macrophagesImmune suppressionOvarian tumorsImmune cellsBRCA mutationsSystemic administrationT cellsMouse modelTherapeutic benefitBreast tumorsCECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression
Zhang M, Liu ZZ, Aoshima K, Cai WL, Sun H, Xu T, Zhang Y, An Y, Chen JF, Chan LH, Aoshima A, Lang SM, Tang Z, Che X, Li Y, Rutter SJ, Bossuyt V, Chen X, Morrow JS, Pusztai L, Rimm DL, Yin M, Yan Q. CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression. Science Translational Medicine 2022, 14: eabf5473. PMID: 35108062, PMCID: PMC9003667, DOI: 10.1126/scitranslmed.abf5473.Peer-Reviewed Original ResearchConceptsBreast cancer metastasisReticuloendotheliosis viral oncogene homolog ACancer metastasisImmune suppressionM2 macrophagesWorse metastasis-free survivalMetastatic breast cancerMetastasis-free survivalV-rel avian reticuloendotheliosis viral oncogene homolog ACancer-related deathPrimary breast tumorsMultiple mouse modelsNF-κB signalingImmunocompetent settingNuclear factor-κB family membersMetastasis-promoting genesDistant metastasisMetastatic sitesPrimary tumorEffective therapyBreast cancerMetastasis treatmentMouse modelBreast tumorsMetastasis
2021
Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A
George L, Monahan P, Eyster M, Sullivan S, Ragni M, Croteau S, Rasko J, Recht M, Samelson-Jones B, MacDougall A, Jaworski K, Noble R, Curran M, Kuranda K, Mingozzi F, Chang T, Reape K, Anguela X, High K. Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A. New England Journal Of Medicine 2021, 385: 1961-1973. PMID: 34788507, PMCID: PMC8672712, DOI: 10.1056/nejmoa2104205.Peer-Reviewed Original ResearchConceptsFactor VIII expressionAdeno-associatedHemophilia AAdverse eventsFactor VIIIGoal of gene therapyTreatment-related adverse eventsImmune responseAAV gene transferDiscontinuation of prophylaxisHighest-dose cohortLowest-dose cohortSafety observation periodAnnualized bleeding rateExpression of factor VIIICellular immune responsesFactor VIII activityFactor VIII assayGlucocorticoid-relatedVector doseDose cohortsVector administrationBleeding episodesVector genomesImmune suppressionAdmission Lymphopenia is Associated With Discharge Disposition in Blunt Chest Wall Trauma Patients
Koch K, Troester A, Chevuru P, Campbell B, Galet C, McGonagill P. Admission Lymphopenia is Associated With Discharge Disposition in Blunt Chest Wall Trauma Patients. Journal Of Surgical Research 2021, 270: 293-299. PMID: 34717263, PMCID: PMC8712416, DOI: 10.1016/j.jss.2021.09.013.Peer-Reviewed Original ResearchConceptsBlunt chest wall traumaAbsolute lymphocyte countChest Abbreviated Injury ScoreAdmission lymphopeniaBlunt chest wall trauma patientsLevel I trauma centerInstitution's trauma registryAbbreviated Injury ScoreI trauma centerInjury Severity ScoreChest wall traumaImportant prognostic informationBowel perforationHospital deathHospital stayAdult patientsCritical illnessDischarge dispositionLymphocyte countTrauma patientsClinical outcomesInjury characteristicsTrauma centerTrauma registryImmune suppressionImaging brain cortisol regulation in PTSD with a target for 11β-hydroxysteroid dehydrogenase type 1
Bhatt S, Hillmer AT, Rusowicz A, Nabulsi N, Matuskey D, Angarita GA, Najafzadeh S, Kapinos M, Southwick SM, Krystal JH, Carson RE, Huang Y, Cosgrove KP. Imaging brain cortisol regulation in PTSD with a target for 11β-hydroxysteroid dehydrogenase type 1. Journal Of Clinical Investigation 2021, 131: e150452. PMID: 34651587, PMCID: PMC8516462, DOI: 10.1172/jci150452.Peer-Reviewed Original ResearchConceptsPosttraumatic stress disorderPositron emission tomographyVolume of distributionDehydrogenase type 1Trauma-exposed controlsPTSD groupTranslocator proteinType 1Veterans Affairs (VA) National CenterOverall PTSD severityBrain glucocorticoidBrain immuneMethodsSixteen individualsPeripheral cortisolMicroglial markersImmune suppressionTranslational Science AwardsCortisol levelsNIH National CenterTC groupCortisol regulationEmission tomographyStress disorderLower PTSD symptomsPTSD symptoms
2020
Targeted glycan degradation potentiates the anticancer immune response in vivo
Gray MA, Stanczak MA, Mantuano NR, Xiao H, Pijnenborg JFA, Malaker SA, Miller CL, Weidenbacher PA, Tanzo JT, Ahn G, Woods EC, Läubli H, Bertozzi CR. Targeted glycan degradation potentiates the anticancer immune response in vivo. Nature Chemical Biology 2020, 16: 1376-1384. PMID: 32807964, PMCID: PMC7727925, DOI: 10.1038/s41589-020-0622-x.Peer-Reviewed Original ResearchMeSH KeywordsAllograftsAnimalsAntibodies, MonoclonalB7-H1 AntigenCell Line, TumorHumansHydrolysisImmunoconjugatesImmunotherapyKiller Cells, NaturalMelanoma, ExperimentalMiceMice, Inbred C57BLMice, KnockoutModels, MolecularMolecular Targeted TherapyNeuraminidasePolysaccharidesProgrammed Cell Death 1 ReceptorProtein BindingProtein Interaction Domains and MotifsProtein Structure, SecondaryReceptor, ErbB-2Sialic Acid Binding Immunoglobulin-like LectinsSurvival AnalysisT-LymphocytesConceptsImmune checkpoint inhibitor therapyTumor-infiltrating myeloid cellsCheckpoint inhibitor therapyImmune cell infiltrationPowerful treatment optionAnticancer immune responseSurvival of miceSyngeneic breast cancer modelImmune cell activationBreast cancer modelBreast cancer cellsCheckpoint therapyMost patientsInhibitor therapyPD-1Checkpoint receptorsImmune suppressionTreatment optionsCell infiltrationImmune responseMyeloid cellsCancer modelCell activationCertain cancersCancer typesTrial in progress: A phase I/II, open-label, dose-escalation, safety and tolerability study of NC318 in subjects with advanced or metastatic solid tumors.
Gutierrez M, Hamid O, Shum E, Wise D, Balar A, Weber J, LoRusso P, Shafi S, Rimm D, Tolcher A, Basudhar D, Dujka M, Heller K. Trial in progress: A phase I/II, open-label, dose-escalation, safety and tolerability study of NC318 in subjects with advanced or metastatic solid tumors. Journal Of Clinical Oncology 2020, 38: tps3166-tps3166. DOI: 10.1200/jco.2020.38.15_suppl.tps3166.Peer-Reviewed Original ResearchMetastatic solid tumorsT cell functionSolid tumorsPD-L1 tumor proportion scoreAnti-tumor immune responseNon-small cell lungPhase I/IIPhase 2 doseTumor proportion scoreAnti-tumor immunityKey eligibility criteriaCell functionDose-escalation designBreast cancer subjectsNon-randomized studiesT cell proliferationPrevents tumor growthClass monoclonal antibodyCollection of biopsiesMeasurable diseaseRECIST v1.1Phase 1/2Escalation designTolerability studyImmune suppressionRegulatory T-cell Depletion Alters the Tumor Microenvironment and Accelerates Pancreatic Carcinogenesis
Zhang Y, Lazarus J, Steele NG, Yan W, Lee HJ, Nwosu ZC, Halbrook CJ, Menjivar RE, Kemp SB, Sirihorachai VR, Velez-Delgado A, Donahue K, Carpenter ES, Brown KL, Irizarry-Negron V, Nevison AC, Vinta A, Anderson MA, Crawford HC, Lyssiotis CA, Frankel TL, Bednar F, di Magliano M. Regulatory T-cell Depletion Alters the Tumor Microenvironment and Accelerates Pancreatic Carcinogenesis. Cancer Discovery 2020, 10: 422-439. PMID: 31911451, PMCID: PMC7224338, DOI: 10.1158/2159-8290.cd-19-0958.Peer-Reviewed Original ResearchConceptsPancreatic cancerTreg depletionPancreatic carcinogenesisRegulatory T cellsT cell responsesMyeloid cell recruitmentMouse pancreatic cancerNew therapeutic approachesSmooth muscle actinPromotion of carcinogenesisImmune suppressionImmunosuppressive microenvironmentReceptors CCR1T cellsTherapeutic approachesCell recruitmentMouse modelMyeloid cellsMuscle actinRelated commentaryTumor progressionTregsTumor microenvironmentCancerFibroblast subsets
2019
IMMU-28. TARGETING IMMUNOSUPPRESSIVE MYELOID DERIVED SUPPRESSOR CELLS VIA MIF/CD74 SIGNALING AXIS TO ATTENUATE GBM GROWTH
Alban T, Bayik D, Otvos B, Grabowski M, Ahluwalia M, Bucala R, Vogelbaum M, Lathia J. IMMU-28. TARGETING IMMUNOSUPPRESSIVE MYELOID DERIVED SUPPRESSOR CELLS VIA MIF/CD74 SIGNALING AXIS TO ATTENUATE GBM GROWTH. Neuro-Oncology 2019, 21: vi125-vi125. PMCID: PMC6847354, DOI: 10.1093/neuonc/noz175.521.Peer-Reviewed Original ResearchMacrophage migration inhibitory factorTumor growthTumor microenvironmentMIF receptorM-MDSCsCytokine macrophage migration inhibitory factorGeneration of MDSCsTumor-infiltrating MDSCsMigration inhibitory factorMCP-1 secretionPersistent tumor growthImmune cell recognitionFuture clinical assessmentImmunosuppressive myeloidMDSC generationMDSC inhibitionMonocytic MDSCsPotent immunosuppressionMDSC functionSuppressor cellsImmunosuppressive microenvironmentImmune suppressionPoor prognosisImmune cellsCo-culture systemPhase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors
Jung KH, LoRusso P, Burris H, Gordon M, Bang YJ, Hellmann MD, Cervantes A, de Olza M, Marabelle A, Hodi FS, Ahn MJ, Emens LA, Barlesi F, Hamid O, Calvo E, McDermott D, Soliman H, Rhee I, Lin R, Pourmohamad T, Suchomel J, Tsuhako A, Morrissey K, Mahrus S, Morley R, Pirzkall A, Davis SL. Phase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors. Clinical Cancer Research 2019, 25: 3220-3228. PMID: 30770348, PMCID: PMC7980952, DOI: 10.1158/1078-0432.ccr-18-2740.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntibodies, Monoclonal, HumanizedAntineoplastic Combined Chemotherapy ProtocolsB7-H1 AntigenBiomarkers, TumorHumansImidazolesIndoleamine-Pyrrole 2,3,-DioxygenaseIndolesMagnetic Resonance ImagingMiddle AgedNeoplasm MetastasisNeoplasm StagingNeoplasmsTomography, X-Ray ComputedTreatment OutcomeConceptsPD-L1 inhibitorsT cellsPartial responseAdvanced cancerDay 1Dose levelsCommon treatment-related AEsDose-escalation stageTreatment-related AEsAdvanced solid tumorsEffector T cellsRegulatory T cellsLinear pharmacokinetic profileLocal tumor microenvironmentInvestigational small-molecule inhibitorExpansion patientsKynurenine accumulationComplete responseImmune suppressionIntravenous infusionAcceptable safetyTryptophan depletionNavoximodAtezolizumabPlasma KynPhase II multi-institutional study of nivolumab (Nivo), cabiralizumab (Cabira), and stereotactic body radiotherapy (SBRT) for locally advanced unresectable pancreatic cancer (LAUPC).
Cohen D, Medina B, Du K, Coveler A, Manji G, Oberstein P, Perna S, Miller G. Phase II multi-institutional study of nivolumab (Nivo), cabiralizumab (Cabira), and stereotactic body radiotherapy (SBRT) for locally advanced unresectable pancreatic cancer (LAUPC). Journal Of Clinical Oncology 2019, 37: tps4163-tps4163. DOI: 10.1200/jco.2019.37.15_suppl.tps4163.Peer-Reviewed Original ResearchStereotactic body radiotherapyImmune suppressionResection rateUnacceptable toxicityEfficacy of SBRTPhase II multi-institutional studySingle-arm phase II studyAdvanced unresectable pancreatic cancerArm phase II studyHigher R0 resection rateAdaptive immune suppressionImmune suppressive phenotypeM-CSFPD-1 blockadePhase II studyR0 resection rateStandard induction chemotherapyUnresectable pancreatic cancerSurgical resection rateAnti-tumor responseT cell populationsEfficacy of RTPlacement of fiducialsPre-clinical modelsMulti-institutional study
2018
Reduced Cancer Survival Among Adults With HIV and AIDS-Defining Illnesses Despite No Difference in Cancer Stage at Diagnosis
Grover S, Desir F, Jing Y, Bhatia RK, Trifiletti DM, Swisher-McClure S, Kobie J, Moore RD, Rabkin CS, Silverberg MJ, Salters K, Mathews WC, Gill MJ, Thorne JE, Castilho J, Kitahata MM, Justice A, Horberg MA, Achenbach CJ, Mayor AM, Althoff KN. Reduced Cancer Survival Among Adults With HIV and AIDS-Defining Illnesses Despite No Difference in Cancer Stage at Diagnosis. JAIDS Journal Of Acquired Immune Deficiency Syndromes 2018, 79: 421-429. PMID: 30211722, PMCID: PMC6203623, DOI: 10.1097/qai.0000000000001842.Peer-Reviewed Original ResearchConceptsLung cancer diagnosisCancer diagnosisLung cancerCancer stageNorth American AIDS Cohort CollaborationAdjusted mortality rate ratioHodgkin lymphoma diagnosisOnly lung cancerRole of HIVRisk of deathMortality rate ratiosCohort CollaborationImmune dysfunctionCervical cancerImmune suppressionCancer outcomesSignificant immunosuppressionCancer survivalPoor survivalLymphoma diagnosisMortality rateProbability of survivalPWHHigh mortalityCancer
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