2024
Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix
Bellone S, Jeong K, Halle M, Krakstad C, McNamara B, Greenman M, Mutlu L, Demirkiran C, Hartwich T, Yang-Hartwich Y, Zipponi M, Buza N, Hui P, Raspagliesi F, Lopez S, Paolini B, Milione M, Perrone E, Scambia G, Altwerger G, Ravaggi A, Bignotti E, Huang G, Andikyan V, Clark M, Ratner E, Azodi M, Schwartz P, Quick C, Angioli R, Terranova C, Zaidi S, Nandi S, Alexandrov L, Siegel E, Choi J, Schlessinger J, Santin A. Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2321898121. PMID: 38625939, PMCID: PMC11046577, DOI: 10.1073/pnas.2321898121.Peer-Reviewed Original ResearchConceptsWhole-exome sequencingPatient-derived-xenograftsBase excision repairCopy number lossMultiregion whole-exome sequencingCopy number gainHigh-grade neuroendocrine carcinomaCNV analysisPhylogenetic analysisEvolutionary historyNeuroendocrine cervical cancerHuman papillomavirus DNAMutator phenotypeSensitivity to afatinibGenetic landscapeRecurrent mutationsRNA sequencingGene fusionsMutational landscape analysisExcision repairGenesMutationsPan-HERConsistent with deficiencyNeuroendocrine carcinomaRandomized Phase II Trial of Imiquimod with or without 9-Valent HPV Vaccine versus Observation in Patients with High-grade Pre-neoplastic Cervical Lesions (NCT02864147)
Sheth S, Oh J, Bellone S, Siegel E, Greenman M, Mutlu L, McNamara B, Pathy S, Clark M, Azodi M, Altwerger G, Andikyan V, Huang G, Ratner E, Kim D, Iwasaki A, Levi A, Buza N, Hui P, Flaherty S, Schwartz P, Santin A. Randomized Phase II Trial of Imiquimod with or without 9-Valent HPV Vaccine versus Observation in Patients with High-grade Pre-neoplastic Cervical Lesions (NCT02864147). Clinical Cancer Research 2024, 30: of1-of10. PMID: 38592381, DOI: 10.1158/1078-0432.ccr-23-3639.Peer-Reviewed Original ResearchConceptsRandomized phase II trialCD4/CD8 T cellsT cellsHPV clearanceArm BNo significant differenceClinical surveillanceRate of HPV clearanceSecondary outcomesPre-neoplastic cervical lesionsCervical intraepithelial neoplasiaT cell infiltrationT cell responsesSignificant differenceCIN3 patientsIntraepithelial neoplasiaArm ACervical lesionsImiquimod groupSurveillance armVaginal suppositoriesProspective trialsArm CHPV vaccinationImiquimod
2009
Human Papillomavirus Type 16 (HPV-16) Virus-Like Particle L1-Specific CD8+ Cytotoxic T Lymphocytes (CTLs) Are Equally Effective as E7-Specific CD8+ CTLs in Killing Autologous HPV-16-Positive Tumor Cells in Cervical Cancer Patients: Implications for L1 Dendritic Cell-Based Therapeutic Vaccines
Bellone S, El-Sahwi K, Cocco E, Casagrande F, Cargnelutti M, Palmieri M, Bignotti E, Romani C, Silasi DA, Azodi M, Schwartz PE, Rutherford TJ, Pecorelli S, Santin AD. Human Papillomavirus Type 16 (HPV-16) Virus-Like Particle L1-Specific CD8+ Cytotoxic T Lymphocytes (CTLs) Are Equally Effective as E7-Specific CD8+ CTLs in Killing Autologous HPV-16-Positive Tumor Cells in Cervical Cancer Patients: Implications for L1 Dendritic Cell-Based Therapeutic Vaccines. Journal Of Virology 2009, 83: 6779-6789. PMID: 19386711, PMCID: PMC2698533, DOI: 10.1128/jvi.02443-08.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedCancer VaccinesCapsid ProteinsCell Line, TumorDendritic CellsFemaleGene Expression ProfilingHuman papillomavirus 16HumansMiddle AgedOncogene Proteins, ViralPapillomavirus E7 ProteinsPapillomavirus InfectionsRepressor ProteinsRNA, ViralT-Lymphocytes, CytotoxicUterine Cervical NeoplasmsYoung AdultConceptsCervical cancer patientsCytotoxic T lymphocytesAutologous tumor cellsCancer patientsDendritic cellsT lymphocytesL1 VLPsCervical cancerTumor cellsE7 RNADendritic cell-based therapeutic vaccineE7-specific cytotoxic T lymphocytesHPV-16 positive cervical cancerCell-mediated immune responsesExpression levelsAutologous dendritic cellsHPV-16 VLPPromising prophylactic vaccineE7-specific CD8Human papillomavirus infectionT lymphocyte responsesStrong cytolytic activityTreatment of patientsPeripheral blood lymphocytesPrimary cervical tumors
2007
Human Papillomavirus Type 16 and 18 E7-Pulsed Dendritic Cell Vaccination of Stage IB or IIA Cervical Cancer Patients: a Phase I Escalating-Dose Trial
Santin AD, Bellone S, Palmieri M, Zanolini A, Ravaggi A, Siegel ER, Roman JJ, Pecorelli S, Cannon MJ. Human Papillomavirus Type 16 and 18 E7-Pulsed Dendritic Cell Vaccination of Stage IB or IIA Cervical Cancer Patients: a Phase I Escalating-Dose Trial. Journal Of Virology 2007, 82: 1968-1979. PMID: 18057249, PMCID: PMC2258728, DOI: 10.1128/jvi.02343-07.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntibodies, ViralAntibody FormationCancer VaccinesCarcinomaCD4-Positive T-LymphocytesDendritic CellsDNA-Binding ProteinsEnzyme-Linked Immunosorbent AssayFemaleHemocyaninsHumansImmunity, CellularNeoplasm StagingOncogene Proteins, ViralPapillomavirus E7 ProteinsPapillomavirus VaccinesRecombinant ProteinsUterine Cervical NeoplasmsVaccinationConceptsCervical cancer patientsIIA cervical cancer patientsDendritic cell vaccinationHuman papillomavirus type 16Cancer patientsDC vaccinationStage IBPapillomavirus type 16Cell vaccinationE7 antigenType 16Delayed-type hypersensitivity reactionEnzyme-linked immunosorbent spotHPV E7 antigenLimited tumor burdenT-cell countsEvidence of diseaseIIA cervical cancerT cell responsesKeyhole limpet hemocyaninEnzyme-linked immunosorbentHPV16/18 E7Vaccine doseAutologous DCsDTH response
2006
Recognition of a cervical cancer derived tumor cell line by a human papillomavirus type 16 E6 52-61-specific CD8 T cell clone.
Kim KH, Dishongh R, Santin AD, Cannon MJ, Bellone S, Nakagawa M. Recognition of a cervical cancer derived tumor cell line by a human papillomavirus type 16 E6 52-61-specific CD8 T cell clone. Cancer Immunology Research 2006, 6: 9. PMID: 16808432.Peer-Reviewed Original ResearchConceptsT cell clonesEnzyme-linked immunospotCervical cancerTumor cell linesCell clonesHomologous epitopesCell linesHigh-risk human papillomavirus (HPV) typesIFN-gamma enzyme-linked immunospotCD8 T cell clonesHigh-risk HPV typesCervical cancer patientsIFN-gamma secretionHuman papillomavirus typesChromium release assaysHLA class IHigh risk HPV sequencesPrimary tumor cell linesAddition of antigenLevel of killingHLA-B57HPV 35Specific CD8HPV typesELISPOT assay
2003
Influence of Allogeneic Blood Transfusion on Clinical Outcome during Radiotherapy for Cancer of the Uterine Cervix
Santin AD, Bellone S, Parrish RS, Coke C, Dunn D, Roman J, Theus JW, Cannon MJ, Parham GP, Pecorelli S. Influence of Allogeneic Blood Transfusion on Clinical Outcome during Radiotherapy for Cancer of the Uterine Cervix. Gynecologic And Obstetric Investigation 2003, 56: 28-34. PMID: 12867765, DOI: 10.1159/000072328.Peer-Reviewed Original ResearchConceptsAllogeneic blood transfusionStage IIB patientsStage III patientsBlood transfusionRadiation treatmentCervical cancerRisk ratioIndependent variable predictivePrimary radiation treatmentRoutine blood transfusionProspective Randomized StudyCervical cancer patientsOnset of treatmentDuration of treatmentTotal radiation doseUntransfused groupException of hemoglobinRandomized studyClinical outcomesUterine cervixImmune suppressionCervical carcinomaCancer patientsDistribution of ageDiminished survival
2001
Tumor-Infiltrating Lymphocytes Contain Higher Numbers of Type 1 Cytokine Expressors and DR+ T Cells Compared with Lymphocytes from Tumor Draining Lymph Nodes and Peripheral Blood in Patients with Cancer of the Uterine Cervix
Santin A, Ravaggi A, Bellone S, Pecorelli S, Cannon M, Parham G, Hermonat P. Tumor-Infiltrating Lymphocytes Contain Higher Numbers of Type 1 Cytokine Expressors and DR+ T Cells Compared with Lymphocytes from Tumor Draining Lymph Nodes and Peripheral Blood in Patients with Cancer of the Uterine Cervix. Gynecologic Oncology 2001, 81: 424-432. PMID: 11371133, DOI: 10.1006/gyno.2001.6200.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAdultAgedCarcinoma, Squamous CellCD4-CD8 RatioCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCytokinesFemaleHLA-DR AntigensHumansImmunophenotypingInterferon-gammaInterleukin-2Interleukin-4Lymph NodesLymphocytesLymphocytes, Tumor-InfiltratingMiddle AgedNeoplasm StagingReceptors, Interleukin-2Th1 CellsTh2 CellsUterine Cervical NeoplasmsConceptsType 1 cytokinesLymph nodesPeripheral bloodT cellsTumor tissueLymphocyte subsetsStage IB-IIA cervical cancerAntigen-experienced T lymphocytesIB-IIA cervical cancerTumor draining lymph nodeActivation markers HLA-DREarly activation markers CD25Draining Lymph NodesMarkers HLA-DRType 2 cytokinesCervical cancer patientsRegional lymph nodesActivation markers CD25Tumor-Infiltrating LymphocytesMajor leukocyte populationsFunction of lymphocytesCervical tumor tissuesDifferent anatomical sitesHLA-DRUterine cervixExpression of CD56 by human papillomavirus E7-specific CD8+ cytotoxic T lymphocytes correlates with increased intracellular perforin expression and enhanced cytotoxicity against HLA-A2-matched cervical tumor cells.
Santin AD, Hermonat PL, Ravaggi A, Bellone S, Roman JJ, Jayaprabhu S, Pecorelli S, Parham GP, Cannon MJ. Expression of CD56 by human papillomavirus E7-specific CD8+ cytotoxic T lymphocytes correlates with increased intracellular perforin expression and enhanced cytotoxicity against HLA-A2-matched cervical tumor cells. Clinical Cancer Research 2001, 7: 804s-810s. PMID: 11300476.Peer-Reviewed Original ResearchMeSH KeywordsCD56 AntigenCD8-Positive T-LymphocytesCell LineDendritic CellsDNA-Binding ProteinsFemaleFlow CytometryHLA-A2 AntigenHumansImmunotherapyInterferon-gammaMembrane GlycoproteinsOncogene Proteins, ViralPapillomavirus E7 ProteinsPerforinPhenotypePore Forming Cytotoxic ProteinsT-Lymphocytes, CytotoxicTime FactorsTumor Cells, CulturedUterine Cervical NeoplasmsConceptsAntigen-specific CTL responsesE7-specific CD8Dendritic cellsTumor target cellsHPV 16CTL responsesHLA-A2Lymphoblastoid cell linesCD56 expressionTumor cellsHealthy individualsType 1 cytokine profileAnti-HLA class IHLA-A2 monoclonal antibodyAutologous dendritic cellsE7-specific CTLExpression of CD56Subset of CD8Human papillomavirus infectionTarget cellsImportant risk factorHigh cytolytic activityCervical cancer cell linesIntracellular perforin expressionCell lines
2000
Effects of concurrent cisplatinum administration during radiotherapy vs. radiotherapy alone on the immune function of patients with cancer of the uterine cervix
Santin A, Hermonat P, Ravaggi A, Bellone S, Roman J, Pecorelli S, Cannon M, Parham G. Effects of concurrent cisplatinum administration during radiotherapy vs. radiotherapy alone on the immune function of patients with cancer of the uterine cervix. International Journal Of Radiation Oncology • Biology • Physics 2000, 48: 997-1006. PMID: 11072156, DOI: 10.1016/s0360-3016(00)00769-0.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntineoplastic AgentsCisplatinCombined Modality TherapyFemaleHumansImmunity, CellularInterferon-gammaInterleukin-2Killer Cells, NaturalLymphocyte ActivationLymphocyte SubsetsMembrane GlycoproteinsMiddle AgedPerforinPore Forming Cytotoxic ProteinsProspective StudiesReceptors, Interleukin-2Uterine Cervical NeoplasmsConceptsT cellsIL-2Lymphoblast transformationRadiation therapyImmune functionNatural killer cytotoxic activityCD25-positive lymphocytesRadiation-induced immunosuppressionPercentage of CD8Advanced cervical cancerT cell numbersNatural killer cellsT cell subsetsActivation markers CD25C-RTMean absolute numberB cell numbersK562 cellsCisplatinum administrationConcurrent cisplatinumLymphocyte subsetsNK cellsConcurrent administrationKiller cellsUterine cervixInterleukin-10 Increases Th1 Cytokine Production and Cytotoxic Potential in Human Papillomavirus-Specific CD8+ Cytotoxic T Lymphocytes
Santin A, Hermonat P, Ravaggi A, Bellone S, Pecorelli S, Roman J, Parham G, Cannon M. Interleukin-10 Increases Th1 Cytokine Production and Cytotoxic Potential in Human Papillomavirus-Specific CD8+ Cytotoxic T Lymphocytes. Journal Of Virology 2000, 74: 4729-4737. PMID: 10775611, PMCID: PMC111995, DOI: 10.1128/jvi.74.10.4729-4737.2000.Peer-Reviewed Original ResearchMeSH KeywordsCells, CulturedCytokinesCytotoxicity, ImmunologicFemaleFlow CytometryHistocompatibility Antigens Class IHumansInterleukin-10Interleukin-2Lymphocyte ActivationMembrane GlycoproteinsPapillomaviridaePapillomavirus InfectionsPerforinPore Forming Cytotoxic ProteinsT-Lymphocytes, CytotoxicTh1 CellsTumor Cells, CulturedTumor Virus InfectionsUterine Cervical NeoplasmsConceptsIL-10IL-2Immunosuppressive cytokinesT lymphocytesSolid-phase anti-CD3 antibodyTumor necrosis factor alphaIntracellular perforin levelsTh1 cytokine secretionAutologous tumor cellsTime pointsTumor-specific CTLsTh1 cytokine productionCervical cancer patientsCytotoxic activityCytotoxic T lymphocytesNecrosis factor alphaT cell proliferationAnti-CD3 antibodyIFN-gamma expressionFluorescence-activated cell sorterGrowth factor betaIL-2 expressionLater time pointsAdoptive transfusionCD56 moleculesDevelopment, characterization and distribution of adoptively transferred peripheral blood lymphocytes primed by human papillomavirus 18 E7--pulsed autologous dendritic cells in a patient with metastatic adenocarcinoma of the uterine cervix.
Santin AD, Hermonat PL, Ravaggi A, Bellone S, Cowan C, Korourian S, Pecorelli S, Cannon MJ, Parham GP. Development, characterization and distribution of adoptively transferred peripheral blood lymphocytes primed by human papillomavirus 18 E7--pulsed autologous dendritic cells in a patient with metastatic adenocarcinoma of the uterine cervix. European Journal Of Gynaecological Oncology 2000, 21: 17-23. PMID: 10726612.Peer-Reviewed Original ResearchConceptsPeripheral blood mononuclear cellsAutologous dendritic cellsDendritic cellsT cellsMetastatic diseaseUterine cervixAutologous Epstein-Barr virus-transformed lymphoblastoid cellsNK-sensitive K562 cellsSerial gamma camera imagingTumor-specific T cellsTwo-color flow cytometric analysisPeripheral blood T cellsTumor cellsIntracellular cytokine productionAutologous tumor cellsExtensive metastatic diseaseInvasive cervical cancerTumor-specific CTLsIntracellular cytokine expressionEpstein-Barr virus-transformed lymphoblastoid cellsBlood mononuclear cellsTreatment of patientsBlood T cellsCytotoxic T cellsPeripheral blood lymphocytes