Cell-based Therapy in RA: Proof of Concept
Cell-based Therapy in RA: Proof of Concept
批准号:
9173719
负责人:
HILLARD M LAZARUS
金额:
$18.23万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-01 至 2019-08-31
关键词:
Adrenal Cortex HormonesAdultAdverse effectsAffectAgeAllogenicAnti-Inflammatory AgentsAnti-inflammatoryAntibodiesAntirheumatic AgentsArthritisAutoimmunityAutologousAutomobile DrivingB-LymphocytesBiological MarkersBiologyBlindedBone MarrowBone Marrow AblationBone Marrow Stem CellCaringCell CountCell TherapyCell physiologyCellsClinicalClinical TrialsCytokine SignalingCytometryDefectDendritic CellsDiagnosisDiseaseDisease ProgressionDoseDouble-Blind MethodEarly treatmentEnrollmentExploratory/Developmental GrantFamily memberFlareFocus GroupsGenetic PolymorphismGoalsHeavy MetalsHematopoieticHome environmentImmuneImmune ToleranceImmune responseImmune systemImmunityImmunologic SurveillanceImmunologicsImmunophenotypingImmunosuppressive AgentsIndividualInfectionInflammationInflammatoryInfusion proceduresInjuryInstitutionInstitutional Review BoardsInvestigationIsotopesLabelLaboratoriesLifeLife StyleMHC Class II GenesMalignant NeoplasmsMeasurementMeasuresMedical centerMesenchymal Stem CellsMethotrexateOnset of illnessOutcomePTPN22 genePathway interactionsPatient Outcomes AssessmentsPatientsPeptidesPericytesPhasePhase I Clinical TrialsPhenotypePhysiciansPlacebo ControlPlacebosPopulationPredispositionPropertyProtocols documentationRandomizedRecrudescencesRegenerative MedicineRegimenRegulatory T-LymphocyteResearch PersonnelRheumatoid ArthritisRheumatoid FactorRiskSafetyScheduleServicesSignal PathwaySignaling MoleculeSiteSocietiesSymptomsTechnologyTestingTherapeuticTherapy Clinical TrialsThinkingTimeTranslational ResearchUndifferentiatedUniversitiesUniversity HospitalsWithdrawalWomanWorkactive methodarthritis therapycareerchronic autoimmune diseasecyclic citrullinated peptidecytokinedosagehealth disparityhuman diseaseimprovedimproved outcomeinnovationjoint injurymenmiddle agenovelphase I trialphase II trialpreventprogramsrandomized placebo controlled trialrepairedresponsesafety studysmoking cessationsuccesstime use
中文摘要
本申请提出了一项双盲安慰剂对照I期细胞治疗临床试验,
英文摘要
This application proposes a double blind placebo-controlled Phase I cell therapy clinical trial in sero-positive,
new-onset RA patients (within 2 years of diagnosis) who have high disease activity despite an adequate trial of
a methotrexate, a Disease Modifying Anti-Rheumatic Drug (DMARD). The trial will take place at CWRU with
two clinical performanace sites [MetroHealth Medical Center (MHMC) and University Hospitals Case Medical
Center]. Cell based therapy using mesenchymal stem cells (MSCs) holds great promise. MSCs appear to be
pericytes, poised to sense and repair damage arising from exogenous or endogenous threats, i.e. the
“guardians of inflammation”. These cells home to sites of inflammation and/or injury and facilitate repair while
selectively reducing inflammation.
The driving hypothesis for this clinical trial is that MSCs will have therapeutic value in restoring immune
tolerance. MSCs have potential to delay or abort onset of full blown RA by resetting the immune system,
inducing immune tolerance and dampening the observed amplification of adaptive immune mechanisms that
perpetuate joint inflammation. Multiple RA therapies are available but none specifically repair autoimmunity;
rather most interfere with both autoimmunity and protective host immunity. Most affected require lifelong
therapy, rendering RA patients susceptible to infection and malignancy beyond that which RA itself confers.
This study will focus on the safety of IV delivery of adult, bone marrow-derived allogeneic MSCs collected from
a normal donor and expanded ex vivo. Patients will be randomized to MSCs or placeo and treated with a single
infusion of MSCs while remaining on concomitant methotrexate except in the interval immediately after MSC
infusion (so as not to damage the infused MSCs). Three MSC dose-escalation levels and studies will be
performed. The enrollment schedule of one subject per month is acceptable to regulatory agencies. Dose
escalation rules and early stopping rules have been developed. Patient reported outcomes (legacy and
PROMIS) will be collected. In addition, we have engaged the Center for Health Disparities at MHMC in
conducting focus groups to understand what RA patients think about the potential and appropriate timing for
MSCs as RA therapy. An IRB application has been submitted and an IND submission will be completed prior to
review of this application.
Presuming safety, this study will be followed by a Phase II randomized placebo-controlled trial adequately
powered to detect primary clinical and translational endpoints validated in the Phase I investigation. While the
primary endpoint for the Phase I proof of concept program is safety, this study will use sensitive approaches to
detect MSC immunologic effects in new onset RA patients in whom 12 weeks of methotrexate therapy has
resulted in incomplete response (DAS28-CRP ≥ 4.4 ). Immunologic measures to detect tolerance will include
measuement of number and function of Tregs using a novel functional biomarker developed in the PI's
laboratory. At study end, we should be able to demonstrate safety of infusing MSCs in RA, pick two dosages
for a successor Phase II trial, and identify which biomarkers should be used that trial.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
ZOSUQUIDAR TRIHYDROCHLORIDE FOR ACUTE MYELOID LEUKEMIA AMP; REFRACTORY ANEMIA
-
批准号:7202782
-
项目类别:
-
资助金额:$0.11万
-
财政年份:2005
-
负责人:HILLARD M LAZARUS
-
依托单位:
Zosuquidar trihydrochloride for acute myeloid leukemia & refractory anemia
-
批准号:6974999
-
项目类别:
-
资助金额:$0.01万
-
财政年份:2004
-
负责人:HILLARD M LAZARUS
-
依托单位:
NHLBI Blood /Marrow Transplant Clinical Research Network
-
批准号:7671210
-
项目类别:
-
资助金额:$11.52万
-
财政年份:2001
-
负责人:HILLARD M LAZARUS
-
依托单位:
Phase III Trial of UCB +/- MSCs in Hematologic Cancers
-
批准号:6439407
-
项目类别:
-
资助金额:$40.5万
-
财政年份:2001
-
负责人:HILLARD M LAZARUS
-
依托单位:
NHLBI Blood /Marrow Transplant Clinical Research Network
-
批准号:7479251
-
项目类别:
-
资助金额:$11.52万
-
财政年份:2001
-
负责人:HILLARD M LAZARUS
-
依托单位:
NHLBI Blood /Marrow Transplant Clinical Research Network
-
批准号:7897784
-
项目类别:
-
资助金额:$11.52万
-
财政年份:2001
-
负责人:HILLARD M LAZARUS
-
依托单位:
Case BMT CTN: Antibacterial Prophylaxis in Post-Engraftment Allogeneic HCT
-
批准号:8485633
-
项目类别:
-
资助金额:$14.72万
-
财政年份:2001
-
负责人:HILLARD M LAZARUS
-
依托单位:
Case BMT CTN: Antibacterial Prophylaxis in Post-Engraftment Allogeneic HCT
-
批准号:8316238
-
项目类别:
-
资助金额:$14.76万
-
财政年份:2001
-
负责人:HILLARD M LAZARUS
-
依托单位:
Phase III Trial of UCB +/- MSCs in Hematologic Cancers
-
批准号:6528144
-
项目类别:
-
资助金额:$14.83万
-
财政年份:2001
-
负责人:HILLARD M LAZARUS
-
依托单位:
Phase III Trial of UCB +/- MSCs in Hematologic Cancers
-
批准号:6799962
-
项目类别:
-
资助金额:$39.03万
-
财政年份:2001
-
负责人:HILLARD M LAZARUS
-
依托单位:
Phase III Trial of UCB +/- MSCs in Hematologic Cancers
-
批准号:6946351
-
项目类别:
-
资助金额:$28.25万
-
财政年份:2001
-
负责人:HILLARD M LAZARUS
-
依托单位:
NHLBI Blood /Marrow Transplant Clinical Research Network
-
批准号:7124963
-
项目类别:
-
资助金额:$15.5万
-
财政年份:2001
-
负责人:HILLARD M LAZARUS
-
依托单位:
Case BMT CTN: Antibacterial Prophylaxis in Post-Engraftment Allogeneic HCT
-
批准号:8678984
-
项目类别:
-
资助金额:$14.68万
-
财政年份:2001
-
负责人:HILLARD M LAZARUS
-
依托单位:
NHLBI Blood /Marrow Transplant Clinical Research Network
-
批准号:7290438
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2001
-
负责人:HILLARD M LAZARUS
-
依托单位:
Phase III Trial of UCB +/- MSCs in Hematologic Cancers
-
批准号:6667137
-
项目类别:
-
资助金额:$38.93万
-
财政年份:2001
-
负责人:HILLARD M LAZARUS
-
依托单位:
Case BMT CTN: Antibacterial Prophylaxis in Post-Engraftment Allogeneic HCT
-
批准号:8174350
-
项目类别:
-
资助金额:$16.67万
-
财政年份:2001
-
负责人:HILLARD M LAZARUS
-
依托单位:
LEUKAPHERESIS IN PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) PATIENTS
-
批准号:3763409
-
项目类别:
-
资助金额:$0.0万
-
财政年份:--
-
负责人:HILLARD M LAZARUS
-
依托单位:
PERIPHERAL BLOOD LEUKAPHERESIS FOR USE DURING INTENSIVE THERAPY FOR MALIGNANCY
-
批准号:3785463
-
项目类别:
-
资助金额:$0.0万
-
财政年份:--
-
负责人:HILLARD M LAZARUS
-
依托单位:
INFUSION OF BONE MARROW MESENCHYMAL STEM CELL
-
批准号:3763380
-
项目类别:
-
资助金额:$0.0万
-
财政年份:--
-
负责人:HILLARD M LAZARUS
-
依托单位:
INFUSION OF BONE MARROW MESENCHYMAL STEM CELL
-
批准号:3741137
-
项目类别:
-
资助金额:$0.0万
-
财政年份:--
-
负责人:HILLARD M LAZARUS
-
依托单位:
海外基金