Repairing the Immune System:

Transcription

1 Repairing the Immune System: Autologous Stem Cell Transplantation for the Treatment of Multiple Sclerosis and Other Autoimmune Diseases of the Nervous System. Christopher Bredeson 22-April-2017

2 Learning Objectives Understand the basis for using HSCT to treat autoimmune diseases Understand the consequences of immune ablation with HSCT rescue Be aware of the spectrum of immunological disorders that can or might improve with HSCT.

3 Autoimmune Diseases (AID)

4 Case Study Part 1 32 year old woman 6 yr. prior: episodic bladder and bowel incontinence, decreased mobility 20 mo. prior: optic neuritis 17 mo. prior: difficulty running 10 mo. prior: began using a cane for mobility, started dimethyl fumarate. Presentation: Neuropathic discomfort in feet, slow deterioration in symptoms, EDSS 5.5

5 Case Study Part 2 2 mo. later: Cyclophosphamide 2.5 gm/m2, Neupogen Autologous stem cell collection CD34 graft selection 1 day admission for febrile neutropenia 4 mo. later: Autologous stem cell transplant. Chemo induced nausea, Gr 2 mucositis LOS 26 days. 7 mo. later: return home. Ongoing infection prophylaxis Improved bowel & bladder function, normal gait, not using cane.

6 What is Multiple Sclerosis? A Hematologist s Primer

7 Multiple sclerosis can cause: 1. Mobility and Gait dysfunction 2. Bowel and Bladder dysfunction 3. Impairment of Cognition, memory and speech 4. Tremor and muscle spasms 5. Vision, hearing and swallowing difficulties 6. Loss of coordination 7. Neuropathic pain, numbness or loss of sensation

8 Multiple Sclerosis results from an autoimmune attack on myelin

9 Pathological Processes in MS Time (Years) Disease Parameter INFLAMMATORY ACTIVITY RELAPSES NEW & ENHANCING LESIONS NEURODEGENERATION PROGRESSION BRAIN ATROPHY Inflammation and Degeneration are linked processes

10 Measuring Disability in MS Subscores: Pyramidal Cerebellar Brainstem Bowel and Bladder Mental (and emotional) Sensory Vision

11 HSCT really? Why should autologous HSCT be used to treat MS?

12 Current Treatments for MS & Unmet Clinical Need Relapsing Glatiramer Acetate(Copaxone) IFNβ (βseron, Avonex, Rebif) Dimethyl fumarate (Tecifedera) Teriflunomide (Aubagio) Natalizumab (Tysabri) Fingolimod (Gilenya) Daclizumab (Zinbryta) Alemtuzumab (Lemtrada) Ocrelizumab (Ocrevus) Cladribine Cyclophosphamide Progressive Primary: Ocrelizumab (Ocrevus) Secondary: Mitoxantrone Kalincik T, et al. Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study. Lancet Neurol Feb 10.

13 HSCT really? What foundational information exists to justify the use of autologous HSCT to treat MS?

14 Autoimmune Disease A Paradigm Patients are born with the genetic predisposition to develop AID but require an exposure to trigger the immune system. Concordant Discordant Immune Response Genes 30-55% 45-70% The immune system learns the WRONG lesson and attacks the patient s body

15 Allogeneic HSCT Immunology Unmanipulated HSC Grafts Chemotherapy T cell replete Graft No GvHD GvHD Tolerance T cell Homeostatic Expansion HSC De Novo Lymphopoiesis

16 Allogeneic HSCT Immunology Ex vivo Immune cell depletion Chemotherapy T cell deplete Graft GvHD Tolerance HSC De Novo Lymphopoiesis

17 Autologous HSCT for Autoimmunity Chemotherapy T cell deplete Graft Tolerance? HSC De Novo Lymphopoiesis

18 Depletion of immune cells from the stem cell graft Pre-Selection # cells x 10 6 /kg recipient weight Post-selection MNC 940 ( ) 8 (2-16) HSPC 20 (4-38) 8 (2-16) T Cells 43 (11-108) 0.01 (0-0.14) B Cells 2 (0-17) 0.00 (0-0.05) NK Cells 1 (0-4) 0.01 (0-0.08)

19 SCT results in ablation of pre-existing immune responses and reconstitution of a functional immune system. T-Lymphocyte proliferation to Tetanus Toxoid Pooled responses of 6 patients (mean +/- SEM) Amit Bar-Or

20 HSCT for Multiple Sclerosis Does it work?

21 HSCT for MS Treatment Intervention 4 - Conditioning Regimen Autoimmune attack of the CNS Destroy the autoreactive immune system with chemotherapy Patient with poor prognosis MS Immune Reconstitution 1 - Stem cell mobilization 2 - Stem cell harvest 5 - HSCT 3 - Graft Processing by CD34 Selection Stem cell graft containing immune cells Purified hematopoietic stem cells

22 HSCT Treatment Protocol Mobilization/Collection d1: Cyclophosphamide 2.5 gm/m 2 iv + supportive care d2 to 11: Filgrastim 10 µg/kg/d (rounded to vial) d11: Peripheral vein apheresis CD34 Selection (Miltenyi CliniMacs) Cryopreserved. HSCT Conditioning d-10 to d-7: Busulphan mg/kg/dose once po iv daily q6h x x doses doses d-6 to d-3: Cyclophosphamide 50 mg/kg/day d-4 to d-1: Thymoglobulin (ratg) 1.25 mg/kg/day d0: Autologous CD34 Selected Graft re-infusion Pre- and Post- Transplant Supportive Care.

23 MS BMT Conditioining Regimen Thymoglobulin Busulfex

24 Supportive Care Measures Active relapses suppressed prior to mobilization With CTX: Hydration, foley catheter, MESNA With Bu: 1st dose AUC, ursodiol x 100 days Infectious prophylaxis: Valacyclovir 2 gm tid x 100 days the Acyclovir 800 mg bid x 1 yr Acyclovir 800 mg bid x 1 yr with CMV monitoring Septra 2 DS bid twice weekly x 1 year Fluconazole 400 mg bid x 100 days IVIG 0.5 mg/kg monthly x 1 year Reimmunize at months after HSCT

25 Patient characteristics

26 MSBMT: Elimination of CNS Inflammation Clinical ClinicalRelapses Relapses Before HSCT New or Enhancing After HSCTLesions 24 patients 146 patient-years at risk 23 patients 160 patient-years at risk 167 relapses 1.2 relapses/patient/year 0 relapses 0 relapses/patient/year

27 Elimination of CNS Inflammation reduces the risk of progression A Time to sustained EDSS prior to ahsct EDSS EDSS # at risk time to EDSS % of patients with sustained progression 100 % of patients reaching EDSS B Time to EDSS progression after ahsct Time from Diagnosis (years) Time after ahsct (years) #risk

28 MSBMT: Changes in Rate of Brain Atrophy

29 MSBMT: Recovery of Disabilities %of patients with sustained improvement A EDSS improvement Time after ahsct (years) # at risk

30 MSBMT: Impact of Halting Progression PreHSCT PostHSCT Work or School 4 (25%) 9 (58%) Not on LTD 9 (56%) 13 (81%) In a relationship 9 (56%) 13 (81%) Driving 7 (44%) 11 (69%)

31 MS-BMT: Immunology Clinical: No MS disease activity No opportunistic infections Appropriate responses to vaccination TREC: Thymic output returns to baseline by mo. Spectratyping: Polyclonal TCR usage Flow: Profound and persistent reduction in circulating naïve CD4 cells Time dependent increase in circulating T & B memory cells Time dependent increase in circulating anti-mbp cells Increase in antigen specific T cells to re-immunization CSF: Decrease in oligoclonal bands in some patients at 2 years.

32 What are the risks of HSCT? Is the MS population unusually susceptible to toxicity

33 HSC Mobilization and Collection 16 pts (67%) developed febrile neutropenia, 3 pts (13%) with UTI. 22 pts (92%) required 1 apheresis. 2 pts ( 8%) required 2 apheresis.

34 MSBMT: Early Toxicity Drug Cyclophosphamide BCNU Etoposide AraC (Cytarabine) CSF:Plasma ratio 0.2 to 0.8 n/a to to 0.22 Melphalan Undetectable to Busulphan Thymoglobulin n/a Alemtuzumab n/a

35 Late Issues Herpes Virus Infection Shingles CMV viremia no disease HHV6 pneumonia BK hematuria Secondary Secondary Cancers Gonadal Function Autoimmune Disease ITP (2 cases) Hypo and Hyperthyroid AML in a Mitoxantrone treated patient : All menopausal 1 child of mother that underwent HSCT (donated egg) : 2 children of fathers that have undergone HSCT

36 MSBMT: Overall Survival

37 Can the risks modified? Perhaps the risks to the patients be reduced by using less intense conditioning?

38 Can the risks and toxicity be reduced? Number of Patients % Patients with serious infections Median Day of Hospital discharge Regimen Related Mortality CTX + ATG % bacterial Day 10 0 deaths BEAM + ATG % bacterial n/a 0 deaths BEAM + ATG % bacterial n/a 3 deaths (4%) BU CTX + ATG 24 58% bacterial Day 18 1 death (4%) 1Burt et al JAMA Nash et al JAMA Neurology Mancardi et al Multiple Sclerosis 2012

39 HSCT for MS: CTX + ATG conditioning Burt R et al. Association of Non-myeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting Multiple Sclerosis. JAMA 2015;313(3):275-84

40 HSCT for MS: BEAM + ATG Richard A. Nash, et al. Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALTMS) A 3-Year Interim Report JAMA Neurology 2015; 72(2):

41 Can the risks and toxicity be reduced? Number of Patients % Patients with serious infections Median Day of Hospital discharge Regimen Related Mortality CTX + ATG % bacterial Day 10 0 deaths BEAM + ATG % bacterial n/a 0 deaths BEAM + ATG % bacterial n/a 3 deaths (4%) BU CTX + ATG 24 58% bacterial Day 18 1 death (4%) 1Burt et al JAMA Nash et al JAMA Neurology Mancardi et al Multiple Sclerosis 2012

42 Which are the best patients? How much disability? How much prior treatment? How active relapses?

43 Inclusion/Exclusion Criteria Age meeting clinical and MRI definition of MS High probability of significant disease progression over 10 years based on natural history data set from London Ont. Multiple early relapses &/or early sustained disability EDSS 3.0 & 6.0 Ongoing active disease despite of 1 year of treatment No significant medical comorbidities.

44 MSBMT: Who will benefit? C Baseline MSSS predicts change in EDSS Change in EDSS MSSS prior to ahsct 10

45 Current Recommendations Upfront HSCT Malignant Multiple Sclerosis Initial presentation with several relapses in a short time that result in severe disabilities and extensive MRI lesions. Salvage HSCT Highly Active Multiple Sclerosis Multiple early relapses that are not controlled by one or more DMD with or without early sustained disability. Early Progressive Multiple Sclerosis while on highly active DMD with evidence of active inflammatory lesions on MRI scanning. Primary Progressive MS with evidence of active inflammatory lesions on MRI scanning.

46 MS-BMT summary High dose chemotherapy can ablate the immune system Loss of reactivity against vaccines Loss of reactivity against the CNS Following ablation there is no further damage to the CNS. No new MRI lesions No clinical relapse, halt progression in the majority Patients develop protective immunity No opportunistic infections, respond to revaccination Functional Immune System + No Organ Damage = Tolerance re-established. Improvement in disabilities CNS repair induced, mechanism unclear.

47 What about? If this works for MS could it work for other autoimmune diseases of the nervous system?

48 Indications for HSCT at TOH. MS (n=42) Myasthenia (N=8) CIDP (n=6) NMO (n=4) SPS (n=3) December 2015

49 Myasthenia Gravis Foundation of America Clinical Classification 8 patients between Class I: Ocular weakness Class II: Mild weakness Class III: Moderate weakness (N=3, 2 x IIIB, 1 x IIIA) Class IV: Severe weakness (N=3, 2 x IVB, 1 x IVA) Class V: Intubation (N=2) A: predominantly limb & axial muscles B: predominantly oropharyngeal & respiratory IVB if feeding tube required.

50 MGFA Post-Intervention Status Complete Stable Remission: No signs of MG for > 1 year without therapy Pharmacologic Remission: No signs of MG for >1 year but needs some therapy other than cholinesterase inhibitors Minimal Manifestations

51 Stem Cell Transplantation for Myasthenia Bryant A et al. Myasthenia Gravis Treated with Autologous Hematpoietic Stem Cell Transplantation. DOI /jamaneurol Online 4-April-2016

52 CIDP/MADSAM 6 patients treated between TOH 2 with MADSAM variant 1 CSR, 1 PharmR One rapid response, one developed over 2.5 yrs. 4 with distal motor neuropathy 1 CSR, 1 unchanged, 2 too early to evaluate About 20 other cases reported in Pubmed. Vogl U, et al. Wien Klin Wochenschr Feb 26. Scheibe F, et al. Eur J Neurol Mar;23(3):e12-4. Press R, et al. J Neurol NeurosurgPsychiatry Jun;85(6): Bregante S, et al. Bone Marrow Transplant Aug;48(8): Vermeulen M, Van Oers MH. J Neurol Neurosurg Psychiatry Jan;72(1): Reményi P, et al. Eur J Neurol Aug;14(8):e1-2. Vermeulen M, van Oers MH. J Neurol Neurosurg Psychiatry Oct;78(10):1154. Oyama Y, et al. Neurology Oct 30;69(18): Axelson HW, et al. J Neurol Neurosurg Psychiatry May;79(5): Mahdi-Rogers M, et al. J Peripher Nerv Syst Jun;14(2):

53 Neuromyelitis Optica TOH N=4 ( ) 24 to 64 yr old. 1 death EBMT:. N=16 ( ) 3 yr OS 94% +/- 6% 3 yr PFS 48% +/- 13% mobilized with CTX/Rituximab 3 yr RFS 31% +/- 12% Bu/CTX/ATG/HSCT No further relapses No further progression 12, 21, 49 mo. follow-up 2 have improvement in function 1 returned to work Greco et al. MSJ 2015, v21(2), p189

54 Stem Cell Transplantation for SPS

55 Myeloablative Autologous Stem Cell Transplant vs Cyclophosphamide for Severe Scleroderma with Internal Organ Involvement: Outcomes of a Randomized North American Clinical Trial Keith M Sullivan MD, Duke University for the SCOT (Scleroderma: Cyclophosphamide or Transplantation) Trial Investigators

56 Background Systemic Sclerosis (SSc) with internal involvement is devastating with no mortality change in 40 years of reporting. Survival in SSc with internal organ complications. Royal Free Hospital Arthritis Rheum 2014; 66:1625 Preclinical* and clinical** studies suggest high-dose immunosuppressive therapy and autologous hematopoietic stem cell transplant (HSCT) can modify SSc. Our hypothesis is that myeloablative HSCT will lead to improved outcome at 54 months compared to 12 monthly pulses of IV cyclophosphamide (CY). * PNAS 1985; 82:7743: PNAS 1989; 86:10090 **Blood 2002; 100:1602; Blood 2007; 110:1388; Lancet 2011; 378:498; JAMA 2014; 311:2490.

57 SCOT Trial Study Design Select Subjects by Screening Randomize Hematopoietic Stem Cell Transplant (HSCT) Arm Cyclophosphamide (CY) Arm Stem cell mobilization with G-CSF alone & cell selection ( 2.5x106 CD34 cells/kg) Initial Pulse CY of 500 mg/m2 Myeloablative Autologous Transplant: TBI 800 cgy (with renal and lung shields) + IV CY 120 mg/kg* + equine ATG 90 mg/kg followed by CD34+ cell autologous HSCT *Total CY dose: 9.0 gm given over 2 days (for a 75 kg recipient) 11 additional treatments of IV CY 750 mg/m2 ** at day intervals. ** Total CY dose: 15.7 gm given over 12 months (for a 1.74 meter, 75 kg recipient)

58 The GRCS Primary Endpoint (at 54 months in the intent to treat population) Global Rank Composite Score (GRCS) is a hierarchical ordering of: 1. Mortality 2. Event-free survival (EFS, survival without organ failure*) 3. Lung function (FVC, >10% from baseline) 4. SHAQ** (> 0.4 point change from baseline) 5. mrss (>25% change from baseline) *EFS: death or respiratory failure ( in DLCO >30% or FVC >20% from baseline) or renal failure (dialysis or renal transplant) or cardiac failure (LVEF <30% or NY class III) **scored as HAQ-DI

59 Baseline Characteristics of 75 Participants (Intent to treat population) Transplant N=36 Cyclophosphamide N=39 45 (11) 47 (10) 19 (53%) 29 (74%) 29 (81%) 31 (80%) Black or African American 2 (6%) 4 (10%) Asian 2 (6%) 1 (3%) Other 3 (8%) 3 (8%) Ever 14 (39%) 10 (26) Never 22 (61%) 29 (74%) Duration Scleroderma, mean (SD) mo 25 (13) 29 (16) Lung Involvement, n 36 (100%) Age, mean (SD) year Female Race, n White Smoking Status, n 37 (95%) Modified Rodnan Skin Score, mean (SD) 29 (9) 31 (11) DLCO (% Predicted), mean (SD) 54 (8) 53 (8) Abbreviations: DLCO, diffusion capacity lung for carbon monoxide; FVC, forced vital capacity; ITT, intent to treat (all randomized participants); SD, standard deviation

60 Efficacy Endpoints in the Randomized (ITT) Population Transplant (N=36) Cyclophosphamide (N=39) p-value Median (min, max) 17 (-58, 52) - 6 (-58, 52) Median (min, max) 20 (-58, 55) - 8 (-58, 55) Primary Endpoint: GRCS at Month 54 Secondary Endpoints: GRCS at Month 48 EFS at Months 48 & 54 n (%) failure 10 (28%) 20 (51%) Mortality (all causes) at Months 48 & 54 n (%) deaths 6 (17%) 11 (28%) 0.28 Abbreviations: EFS, event free survival; GRCS, global ranks composite score; ITT, intent to treat

61 Secondary Disease Progression Events (month 54 in the treated population*) HSCT (N=33) CY (N=34) P - value 3 (9%) 15 (44%) Pulmonary artery hypertension, n 0 5 (15%) Congestive heart failure**, n 0 4 (12%) Initiated DMARDs, n Abbreviations: CY, cyclophosphamide; DMARDS, Disease Modifying Anti-Rheumatic Drugs; HSCT, Hematopoietic Stem Cell Transplant * Those transplanted or given 9 doses of cyclophosphamide (per protocol population) ** Requiring Treatment

62 Kaplan-Meier Survival Estimates: (Treated Population) Per Protocol (Treated) Population

63 ASTIS* compared to SCOT (Transplant Recipients) ASTIS SCOT Transplant Mortality at 54 mo. 10 % 3% Post Transplant DMARDs use 22 % at 24 mo. 9 % at 54 mo. Abbreviations: ASTIS, Autologous Stem Cell Transplantation International Scleroderma; DMARD, Disease-Modifying Anti-Rheumatic Drug. *van Laar et al. JAMA 2014; 311:2490

64 Now for something completely different! ASCOTT: AutoSCT for Allogeneic Organ Tolerance Trial Post liver transplants to induce tolerance Chronic immune suppression is toxic To treat underlying relapse of liver disease primary biliary sclerosis, sclerosing cholangitis, autoimmune hepatitis, ETOH, Wilson s, hemochromatosis Same regimen as our MS protocol 4 patients so far 1 late TRM (had normal liver and off immune suppression) 2 off immune suppression and back to normal life 1 in the midst of their transplant 2 consented and moving ahead

65 Acknowledgements Neurology Mark Freedman Marjorie Bowman Guylaine Theoret Catherine Hilliker Jack Antel Pierre Bourque Pierre Duquette Yves Lapierre Roland Martin Luanne Metz Paul O Connor Elizabeth Pringle George Rice NeuroImmunology Amit Bar-Or Remi Cheynier Peter Darlington Rafick Sekaly NeuroImaging Doug Arnold Robb Brown Jacqueline Chen Hyunwoo Lee Donald Paty Neuropsychology Jason Berard Lisa Walker Stem Cell Transplant The whole team Michael Barnett Hans Messner Ann Smith Sheilagh Sanders Adam Bryant Statistics Dean Fergusson Tim Ramsey ASCOTT Gary Levy Andrzej Chruscinski Meaghan MacArthur Anne Marie Clement Melissa Ruttan Harry Atkins The dedicated patients with MS and their families. Staff of the Ottawa Hospital Transplant Unit. Staff of the Stem Cell Laboratory Canadian Blood Services. MS Society of Canada Department of Medicine Stem Cell Network