Role of Stem Cell in Chronic Liver Disease

Transcription

1 KASL 2014 Role of Stem Cell in Chronic Liver Disease Ja Kyung Kim, MD, PhD Dept. of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea Liver Cirrhosis Clinical Research Center, Korea

2 Contents 1. Introduction 2. Stem cell trials in chronic liver disease 3. Issues to be solved in the Stem cell therapy clinical trials 4. Conclusion

3 INTRODUCTION

4 Stem Cell Chronic Liver Disease Liver disease Acute Chronic Hepatitis Fibrosis/Cirrhosis Fulminant liver failure Chronic liver failure

5 First suggestion for epithelial precursor Oval cells were generated by bone marrow cells in 2-AAF treated rats after partial hepatectomy. Female rats were lethally irradiated and rescued with a BM transplant from a male animal. Peterson et al. Science 1999

6 Hepatocytes from non-hepatic adult stem cells # Y-chromosome A: hepatocytes in male control B: bile ducts in male control C: y-positive inflamm. Cell in female liver D: female patient received male BM E-G: transplanted female liver into male recipient G: cytokeratin-8 hepatocyte Alison et al. Nature July 2000

7 Adult stem cells Stemcells.nih.gov, 2001 Terese Winslow, Lydia Kibiuk

8 Clinical Course of Liver Disease Pellicoro et al. Nat Rev Immunol 2014

9 Treatment of Liver Cirrhosis Liver Transplantation!!! Limitations Lack of donors Surgical complications and morbidity Immunosuppressant after Tx. Rejection High cost Need Bridge therapy Cell based therapy

10 The liver transplantation in Korea Waiting Living donor Cadaver donor

11 The rationalization for stem cell therapies in liver failure and cirrhosis massive inflammation and necrosis the accumulation of scar tissue Zhang et al J Hepatol

12 Adult stem cell sources Bone marrow Umbilical cord blood Adipocyte Skin fibroblasts Placenta Amniotic fluid Dental pup Menstrual blood (endometrium) Breast milk Dailey et al. J Clin Med 2013

13 Cells in clinical trials Hepatocyte Physiologic source of restoration Limitation of donor hepatocytes Functionally complete Xenograft Artificial device Whole BM cell Concentrated mononuclear cell Heterogenous cell component Directly aspirated or mobilized by G-CSF Therapeutic cells Hematopoietic stem cell Main stem cell population in the BM Selected by CD34+ or CD133+ markers Endothelial progenitor cell? Mesenchymal stem cell Immune modulation and antifibrotic Cell sorting needed but no marker Cell culture

14 REPORTED TRIALS WITH STEM CELLS IN CHRONIC LIVER DISEASES

15 Clinical Trials (I) Autologous BM infusion Terai, Sakaida et al. (Japan) Whole BM MNC concentration Cytomate used Cells injected into the peripheral vein Advanced LC Goal: improvement of hepatic function 9 patients 5.62 ± 0.63 x 10 9 MNCs Albumin and total protein elevated at 24 weeks Child-Pugh score improved at 24 weeks Decreased ascites Stem cells (10):2292-8

16 Portal application of autologous CD133+ Bone Marrow Cells Am Esch, Knoefel et al. (Germany) CD 133+ cells selection CliniMACS used Clinical Trials (II) Cells injected to the portal vein after PV embolization before surgery Goal: to support liver regeneration after PVE before extended surgery 3 patients with cell injection vs. 3 control patients More rapid gain of left lateral liver

17 Clinical Trials (III) Application of CD34+ cells mobilized by G-CSF Gordon, Habib et al. (UK) 5 patients G-CSF mobilization CD34+ cells were selected using the CliniMACS 10 6 or 2 x 10 8 cells Cells were injected via the hepatic artery (2) or portal vein (3) Liver cirrhosis: HBV/HCV/Alcohol=1/2/2 Goal: safety and tolerability of injecting autologous CD34+ cells Improvement of serum bilirubin (3) and albumin (4) Stem Cells 2006

18 Clinical Trials (IV) Application of CD34+ cells after expansion in alcoholic LC Pai, Habib et al. (UK) 9 patients G-CSF mobilization & CD34+ cells selection In vitro expansion upto 2.3 x 10 8 cells Injected via the hepatic artery Goal: safety and tolerability of injecting autologous CD34+ cells Improvement of serum bilirubin significantly Improvement of CTP score (7) and ascites (5) Am J Gastroenterol (8):1952

19 Clinical Trials (V) Autologous BM mesenchymal stem cell transplantation: phase I Mohamadnejad, Malekzadeh et al. (Iran) 4 patients with decompensated LC BM culture x 10 6 (mean) mesenchymal stem cells Infused to peripheral vein MELD score improve in 2 patients Quality of life improved in all the patients Autologous BM hematopoietic stem cell transplantation: phase I 4 patients with decompensated LC (Child >7, 6 pts planned) B,PBC, AIH, cryptogenic x 10 6 CD34+ cells from 200ml BM by clinimacs Infused to hepatic artery One patient died of liver failure and type 1 hepatorenal syndrome from radiocontrast nephropathy Early stopped Arch Iran Med 2007: 10:459 JGH 2007: 13:3359

20 Clinical Trials (VI) Autologous bone marrow mononuclear cell transplantation Lyra et al. (Brazil) 50 ml aspiration Centrifugation in a ficoll-hypaque gradient 100 million of mononuclear cells Injection into hepatic artery 10 patients HCV/Alcohol/HCV+Alcohol/NBNC = 3/3/2/2 1.6 x 10 8 ~ 13.1 x 10 8 Decreased bilirubin and INR Increased albumin World J Gastoenterol 2006

21 Clinical Trials (VII) PBMT vs. G-CSF mobilization in B-viral LC Han et al. (China, Xijing hospital, Xian) Child 7, B or B+C viral without antiviral Tx Group 1: G-CSF (5-10 ug/kg/day) for 4 days following PBMC collection by COBE spectra and Injection into hepatic artery (n=20) Group 2: G-CSF for 4 days (n=20) 10 7 ~ 10 8 /kg Improvement in albumin and PT in both group Group I gained better results (albumin and CTP) Decreased ascites at 2 weeks in 60% of group I patients No change of HBV DNA level in both groups Cytotherapy (4):390-6

22 Clinical Trials (VIII) Autologous Bone Marrow Cell Infusion in Decompensated Liver Cirrhosis Kim et al. (Korea) 18 HBV, 1 alcohol Decompensated LC Concentrated mononuclear cells from whole bone marrow cells Mean cell number 1.00 x 10 8 Via peripheral vein Elevated albumin, increased liver volume, hepatic progenitor cell compartment activation after cell infusion Cell Transpl 2010

23 Clinical Trials (IX) Autologous BM mesenchymal stem cell transplantation Amin et al. (Egypt) Single arm 20 C-viral patients with Child C - LC BM culture for 24 days 10 x 10 6 (mean) mesenchymal stem cells Injected in the spleen with US guidance Bilirubin decrease, albumin increase, edema improved in a half Cell Transpl 2013

24 Clinical Trials (X) Autologous Bone Marrow Mononuclear Cell Transplantation in Patients with Decompensated Alcoholic Liver Disease: A Randomized Controlled Trial Switzerland, Geneva Primary Outcome : MELD score of at least 3 points at 90 days Secondary Outcome : safety and parameters associated with liver regeneration and inflammation (cytokines and liver tissues studies) Bone marrow mononuclear cell mobilization and infusion into the hepatic artery (n=28) vs. standard medical therapy (n=30) 103±18 ml of bone marrow was collected The mean MNC infused : 0.47± /kg (0.24± CD34+ cells/kg and 3.39± MSC/kg) This did not result in an expanded HPC compartment or improved liver function Spahr et al. PLoS One. 2013

25 Clinical Trials (XI) A pilot study of autologous CD34-depleted bone marrow mononuclear cell transplantation via the hepatic artery in five patients with liver failure HBV, HCV, propylthiouracil-induced toxic hepatitis and Wilson disease CD34-depleted BM-MNCs by CliniMACS CD34 Reagent System Via hepatic artery Serum albumin levels, liver stiffness, liver volume, subjective healthiness and quality of life improved Park et al. Cytotherapy 2013

26 Clinical Trials (XII) Histological improvement following administration of autologous bone marrowderived mesenchymal stem cells for alcoholic cirrhosis: a pilot study Bone marrow-derived mesenchymal stem cells (BM-MSCs) after 1 month culture 5 10^7 cells injected twice, at weeks 4 and 8, Through the hepatic artery Child-Pugh score improved in 90.9% Decreased TGF-β1, type 1 collagen and α-sma Histological improvement was observed in 6 of 11 patients (54.5%) according to the Laennec fibrosis system, 12 weeks after 2 nd infusion Jang et al Liver Int

27 Bone marrow mononuclear cells Authors Number of patients Improvement after cell infusion Terai S, et al., HCV, 3 HBV, 1 unknown Improved ALB and CP Lyra AC, et al., HCV, 3 alcoholic, 4 others cryptogenic Lyra AC, et al., treatment, 15 control Decreased TBIL and INR and improved ALB Improved ALB and CP score Saito T, et al., treatment, 5 control Improved ALB, PT and CP score Amer, et al., intrasplenic, 10 intrahepatic, 20 control Improved ascites and MELD Kim JK, et al., HBV Increased liver volume and CP score

28 Hematopoietic stem cells Authors Types of cell Number of patients Am Esch JS, et al., 2005 Gordon MY, et al., 2006 MoHamadnejad M, et al., 2007 Pai M, et al., 2008 Han Y, et al., 2008 Garg V, et al., 2012 CD133+ cells 3 treatment, 3 control Improvement after cell infusion Improved liver volume after liver resection CD34+ cells 5 treatment Improved ALB CD34+ cells Cultured CD34+ cells PBMCs from G- CSF mobilized PB G-CSF mobilized CD34+ cells 1 HBV, 1 AIH, 1 PBC, 1 cryptogenic 5 treatment, 5 control 20 treatment, 20 control 23 treatment, 24 placebo Improved MELD Improved ALB, PT and CP score Improved ALB and CP score Increased survival, reduced MELD scores

29 Mesenchymal stem cells Authors Cell source Number of patients MoHamadnejad M, et al., 2007 Kharaziha P, et al., 2009 Bone marrow Bone marrow 3 cryptogenic, 1 AIH 4 HBV, 1 HCV, 1 alcoholic, 2 cryptogenic Peng, et al., 2011 Bone marrow 53 treatment, 105 control Improvement after cell infusion Improved MELD Improved MELD and liver function Improved ALB, TBIL and MELD Jang, et al Bone marrow 11 alcoholic Improved CP score, histology Zhang Z, et al., 2012 Umbilical cord 30 treatment, 15 control Improved liver function, MELD and reduced ascites

30 The rationalization for stem cell therapies in liver failure and cirrhosis Zhang et al J Hepatol

31 In real Human Animal

32 ISSUES TO BE SOLVED IN THE STEM CELL THERAPY CLINICAL TRIALS

33 Issues to be solved Indication Outcome measure Durability Safety Stem cell for CLD Cell source Cell population Cell delivery Cell tracing Translational researches to reveal the mechanism and to potentiate beneficial effect should be parallel.

34 Debating points Injected cell Which cell population do the key role? Whole marrow cells vs. subpopulation MSC Bone marrow derived/adipocyte derived/umbilical cord blood derived How many cells are sufficient? Cell culture: Effective? Safe? Bone marrow derived Direct aspiration vs. G-CSF mobilization How can injected cells be traced?

35 Debating points Infusion route Peripheral vein: How to prove that injected cells home onto liver Portal vein Hepatic artery Direct injection to the liver Direct injection to the spleen Mechanism of regeneration/fibrolysis No more direct transdifferentiation or fusion Paracrine salvage effect from BM Anti-inflammation, Fibrolysis by cytokines

36 Debating points Patients selection Difference from etiology? More advanced or more early Effect of antiviral treatment in viral disease Who will be beneficial? Response evaluation Liver function test: Child class QOL check and standardization Biopsy, liver volume How long will the effect go on? Effect of repetitive treatment

37 Stem cell therapy development Cell Therapy for Liver Cirrhosis First in human Terai & Sakaida et al. Whole bone marrow Effectiveness Improvement of clinical Advancement findings Standardization Mechanism not fully Global trials revealed Comparative study Expansion of indication Combination with conventional therapy Safety Issue No SUSAR various cell sources injection routes Auto vs. Allo Cancer?

38 Investigator Initiative Trial (IIT) vs. Sponsor Initiative Trial (SIT) Investigator (IND) Proposal IRB Review by 5 experts Q & A Revision Proposal Revision KFDA Bioethics Evidence-based Safety Q/C EMP Q & A Biologics HQ GMP Facility Approval Decision Approval or Disapproval EMP: Emergency management plan IND: Investigational New Drug application IRB: Institutional Internal Review Board < 3 Month Biologics Safety policy team Biologics Management team Cell & Tissue engineering product team

39 Future application with

40 It s time to expand trials COOPERATION WITH RESEARCHERS IS MANDATORY! Now, randomized trial Early phase trial Multicenter Single center Globalized or standardized trial is warranted to save resources. TRI of Japan supports cooperative studies in East Asia.

41 Stem Cell Therapy as a new medical option and hope Patient Care Sharing Clinical Achievement Physician Cell Processing Clinical Trial Translational Research

42 Conclusion Clinical trials with stem cells in chronic liver disease have been undergone resulting in improved hepatic function and fibrosis, although controversies still exist. The role of stem cells in chronic liver disease is still limited to replace liver transplantation.

43 THANK YOU

44 Overview of different antifibrotic strategies Tampe, D. & Zeisberg, M. (2014) Potential approaches to reverse or repair renal fibrosis Nat. Rev. Nephrol. doi: /nrneph

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