深入探討造血干細胞移植治療多發性硬化癥的潛力.pdf

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1、Deep dive into the potential of Hematopoietic Stem Cell Transplant in treating Multiple SclerosisAmanda L.Piquet,MDAssociate Professor of NeurologyDirector,Autoimmune Neurology ProgramNeuroimmunology,Neuroinfectious Disease and Neurohospitalist SectionsUniversity of Colorado School of MedicineObject

2、ivesDescribe hematopoietic stem cell transplant what is it?Background and history of transplant in MSCurrent data in stem cell transplant for MS where are we now?Future research where are we going?What is hematopoietic stem cell transplant?What it is NOT?Medical Tourism(especially in foreign countri

3、es)“Infusion”of stem cells into spinal fluid or through and IV through“stem cell clinics”Swart JF,Delemarre EM,van Wijk F,Boelens JJ,Kuball J,van Laar JM,Wulffraat NM.Haematopoietic stem cell transplantation for autoimmune diseases.Nat Rev Rheumatol.2017.Hematopoietic stem cell transplant(HSCT)invol

4、ves administering healthy hematopoietic stem cells(either self or donor)to patients with dysfunctional immune system with the positional to induce long-term,drug-free and symptom-free remission in several refractory autoimmune rheumatic disease.Systemic sclerosis is the first autoimmune disease for

5、which HSCT has been shown in a randomized,controlled trial,to be associated with transplant-related mortality in the first year,but a significant long-term,event-free survival benefit afterwards.Stem Cell Therapies:Medical TourismUnapproved stem cell therapies can be harmful and may be illegal and u

6、nprovenhttps:/www.fda.gov/consumers/consumer-updates/fda-warns-about-stem-cell-therapiesStem Cell Therapies:Medical TourismUnapproved stem cell therapies can be harmful and may be illegal and unprovenhttps:/www.fda.gov/consumers/consumer-updates/fda-warns-about-stem-cell-therapiesStem Cell Therapies

7、:Medical Tourismhttps:/www.fda.gov/consumers/consumer-updates/fda-warns-about-stem-cell-therapiesKnow the FDA plays a role in stem cell treatment oversight1.Ask if the FDA has reviewed the treatment2.Request the facts and ask questions if you dont understandIf you are considering treatment in anothe

8、r country:1.Learn about regulations that cover products in that country2.Know the FDA does not have oversight of treatments done in other countries3.Be cautious it may be hard to know if treatment is safe!Stem Cell Therapies:Medical TourismWhat is hematopoietic stem cell transplant(HSCT)?High-dose I

9、mmunosuppressive Therapy(HDIT)and Autologous HSCT Rapid reduction of autoimmune effector cells Sustained immunomodulatory effect:Reset of the immune systemAllogeneic HSCT Uses donor-derived cells:Replace host autoreactive immune system with donor-derived immune system Promote regulatory mechanisms t

10、hat control autoimmune disease(e.g.mixed donor-host chimerism)What is hematopoietic stem cell transplant(HSCT)?HDIT and Autologous HSCTReset of the immune systemFigure from:Consensus Guidelines and Recommendations for Best Clinical Practice on Behalf of the Autoimmune Diseases Working Party,Nurses G

11、roup,and Patient Advocacy Committee of the European Society for Blood and Marrow Transplantation(EBMT).Front Neurol.2020.Allogeneic HSCTReplace host autoreactive immune systemWhat is hematopoietic stem cell transplant(HSCT)?Immune MechanismEarly:High dose chemotherapy ablates autoimmune cellsLater:R

12、esetting of the immune system T-cell receptor diversificationElimination of memory cells Thymic gen of nave T cells&TregTreg:TconMuraro et al.J.Exp.Med.2005Autologous HSCT for Severe Autoimmune DiseaseNeurology1.Multiple sclerosis2.Stiff Person Syndrome3.Chronic Inflammatory Demyelinating Polyneurop

13、athy(CIDP)4.Myasthenia Gravis5.Rasmussen EncephalitisRheumatology1.Systemic sclerosis2.Systemic Lupus Erythematosus3.Rheumatoid ArthritisGastroenterology1.Crohns diseaseHistorical Data:Autologous HSCT for MSRetrospective analysis of 281 MS patients undergoing high-dose chemotherapy and autologous HS

14、CT between 1995 and 2006.Median follow-up-6.6 years.Median EDSS before transplant-6.578%had progressive forms of MSMuraro PA,et al.Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis.JAMA Neurol.74:459-469,2017Autologous HSCT for Multiple SclerosisMurar

15、o PA,et al.Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis.JAMA Neurol.74:459-469,2017Continued loss of neurological function in many patients with advanced MS in the early studies of high-dose chemotherapy and autologous HSCT.Outcomes poor in patie

16、nts with primary progressive MS.Studies were started in patients with relapsing-remitting disease and earlier in the course of the diseaseEarly Studies of High-Dose Therapy and Autologous HSCT for Advanced MSAcute Inflammation NeurodegenerationDemyelination Axonal TransectionEnhancing&New Lesions At

17、rophyRelapses Accumulation of DisabilityEarly MSLate MSOutcomes poor in patient with primary progressive MSStudies focus on relapsing-remitting MS,early in the disease courseHALT MS Clinical TrialHALT MS Clinical TrialStudy design:Prospective,open-label,single-arm,multicenter Phase II clinical trial

18、(n=25).Primary Objective:To determine the 5-year durability of disease stabilization in MS subjects after HDIT and autologous HSCT.Event-free survival(EFS)during the 5 years after high-dose therapy.Event-free survival was defined as a composite endpoint and included:a)Relapse New neurological S/S pe

19、rsisting 48 hrsb)MRI abnormalities(12 months post-tx)2 or more independent MS lesionsc)Progression in disability(6 months post-tx)1.0 EDSS confirmed 3 months laterd)MortalityHALT MS Clinical Trial5-year EFS:69.2%(90%CI:50.2%,82.1%)Number of Primary Endpoint Events7EDSS increase 0.52Clinical relapse3

20、MRI criteria2Death0HDIT/HSCT without maintenance therapy was effective for inducing long-term sustained remissions of active RRMS at 5 yearsHALT MS Clinical Trial:MRIMS International Stem Cell Transplant(MIST)Randomized Clinical TrialMedian follow up 3.5 yearsMinimal toxicityNo Evidence of Disease A

21、ctivity:Transplant arm 80%;BAT 0-5%at 4 years(p=1.0 and sustained for 6 months):Transplant BAT p=0.0001.Autologous Hematopoietic Stem Cell Transplant in MSBest candidates are likely people younger than 50 years with shorter durations of disease(10 years).The procedure should only be performed at cen

22、ters with substantial experience and expertise.Further research is needed to establish ideal cell mobilization and immune-conditioning regimens.May be a useful treatment option for people with relapsing multiple sclerosis who demonstrate substantial breakthrough disease activity despite treatment wi

23、th high-efficacy disease-modifying therapy or have contraindications to high-efficacy disease-modifying therapies.Where are we now?BEAT MS Clinical Trial(NIAID/NIH)Randomized,Multicenter clinical trial:best available therapy vs autologous HSCTOpened in 2019 Participating:Rocky Mountain MS Center,Uni

24、versity of Colorado and Colorado Blood Cancer Institute(CBCI)Major questions being addressed are:Assessment of high-dose immunosuppression conditioningMore up-to-date high efficacy treatments vs transplant compared to the MIST clinical trialBeat MS:Study Locationshttps:/www.beat-ms.org/Future Studie

25、s What about Primary Progressive MS?Allogeneic HSCT in PPMS with CBCI and ORCA Bio:Protocol is under development(Improved,less toxic approach to allogeneic transplant)Beyond transplant CAR-T(Chimeric Antigen Receptor T cells)Targeted therapy that alters the function of your own T cells and engineers

26、 them to target a specific antigen to destroy them(cancer)or use this to bring tolerance to antigen(cure an underlying autoimmune disease)CAR-T as a Treatment Option for MSHow CAR-T therapy works in HumansBy Reyasingh56-Own work,CC BY-SA 4.0,https:/commons.wikimedia.org/w/index.php?curid=69702021CAR

27、-T as a Treatment Option for MSHow CAR-T therapy works in HumansBy Reyasingh56-Own work,CC BY-SA 4.0,https:/commons.wikimedia.org/w/index.php?curid=69702021Clinical scores and lymphocyte infiltration were reduced in mice treated with CAR-T cellsCAR-T as a Treatment Option for MSHypothesis:CAR-T cell

28、s may be more effective at targeting CNS-resident B cells relative to anti-CD20 monoclonal antibodiesPhase 1,multicenter,single-arm,dose-escalation study of CC-97540(BMS-986353),CD19-targeted NEX-T chimeric antigen receptor(CAR)T cells,evaluating safety and tolerability in participants with relapsin

29、g forms of multiple sclerosis(RMS)or progressive forms of multiple sclerosis(PMS)https:/classic.clinicaltrials.gov/ct2/show/NCT06220201Take Home Points There are good,regulated studies ongoing in hematopoietic stem cell transplant in MS Medical tourism and boutique clinics advertising stem cell treatments are NOT these studies-Ask if the FDA has reviewed the treatment!Future research with less toxic side effects and new target methods are on the horizonThank you!