Cell therapy besides HCT Mesenchymal stem cells

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1 Cell therapy besides HCT Mesenchymal stem cells Katarina Le Blanc Division of Clinical Immunology and Transfusion Medicine, Hematology Center, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden,

2 Cell Therapy Registry The CTR, managed through ProMISe, aims to collect data on the cell preparations outcome of patients treated with stem cells or progenitor cells, hematopoietic and nonhematopoietic, for indications other than HSCT after high dose chemoirradiation or donor lymphocyte infusions (DLI). Katarina Le Blanc 22 mars

3 Cell Therapy is treating damaged organs/tissues with stem or progenitor cells Katarina Le Blanc 22 mars

4 The human body contains many different kinds of stem cells Katarina Le Blanc 22 mars

5 Mesenchymal Stem Cells (MSC) Sources of cells: bone marrow fetal liver, lung, blood adipose synovial membrane Katarina Le Blanc 22 mars

6 Common properties of MSC Stromal precursors in adult bone marrow and fetal liver CD34-, CD45-, CD14- CD166+, CD105+, CD44+, CD29+, CD73+, CD90+ Single clones retain pluripotentiality Rare in vivo Expandable in vitro Stable genotype Friedenstein et al. Transplant 1968; 6, 230 Bruder et al. J Cell Biol 1997; 64, 278 Prockop et al. Science 1997; 276, 71 Haynesworth et al. Bone 1992; 13, 69 Pittenger et al. Science 1999; 284, 143 Haynesworth et al. Bone 1992; 13, 81 Katarina Le Blanc 22 mars

7 10-15ml Marrow aspirate Preparation of MSC for clinical use Density separation Remove non-adherent cells Change media every 3 days Adhere overnight x 10 6 /cm 2 Day Passage 1 Healthy donor (related or unrelated) Passage 2 Infuse IV: 2 x 10 6 /kg x 3 thaw Passage 3 Cell density 1-3 x 10 3 /cm 2 Post-transplant patient Up tp 10 9 MSC Cryopreserve 1-2 x 10 8 MSC aliquots

8 Properties of MSCs: Stimulate the formation of blood cells by: The secretion of growth factors Constitutive cytokine production (G-CSF, GM-CSF, LIF, IL-6, IL-11, Flt-3 etc). Thousand fold increase in cytokine production in the presence of IL-1 The expression of adhesion molecules Are immunosuppressive /anti-inflammatory % specific lysis * * A+Px 10% MSC 10% MSC TW :1 25:1 12.5:1 6.25:1 Effector:Target Ratio Katarina Le Blanc 22/03/2010 8

9 Disease Clinical experience of mesenchymal stem cells in hematopoietic stem cell transplantation No. patients Source of MSCs/SCT Setting Outcome Study Hematologic malignancies 15 Autologous No adverse events Lazarus et al Breast cancer 28 Autologous in autologous SCT IV infusion safe; autologous SCT recovery rapid Koç et al Inborn errors of metabolism 11 HLA-identical from SCT donor No immune response; improved nerve-conduction velocity Koç et al Osteogenesis imperfecta 5 HLA-identical from SCT donor Gene-marked MSCs engrafted; new dense bone formation; few fractures Horwitz et al Severe plastic anemia 1 Haploidentical MSC Engraftment; improved stroma Fouillard et al Severe acute GvHD 1 Haploidentical MSC; matched unrelated SCT Resolution of grade IV acute GvHD Le Blanc et al Leukemia 46 HLA-identical sibling Safe, stable HSC engraftment Lazarus et al Severe acute GvHD 8 Matched or mismatched allogeneic Complete response 6/8 Ringdén et al Graft failure 1 Haploidentical MSC, autologous SCT Stable HSC reconstitution Fouillard et al Leukemia 7 Matched allogeneic SCT, HLAidentical or haploidentical MSC Safe, stable HSC engraftment Le Blanc et al Malignant and nonmalignant disorders 14 Haploidentical SCT and MSC Stable HSC engraftment, reduced engraft failure Ball et al Tissue toxicity, hemorrhagic cystitis 10 Matched or msmatched MSC; allogeneic SCT Safe Ringdén et al. 2007

10 Clinical experience of mesenchymal stem cells in hematopoietic stem cell transplantation Disease No. patients Source of MSCs/SCT Setting Outcome Study Leukemia 25 HLA-identical from SCT donor Increased relapse in MSC recipients Ning et al Severe acute GvH 55 Matched or mismatched MSC, allogeneic SCT Improved survival in responder patients Le Blanc e t al Leukemia 7 HLA-identical or haplo MSC, allogeneic SCT Safe Müller et al Aplastic anaemia, graft failure 2 Haploidentical MSC, HLA identical sibling SCT Stable engraftment Fang et al Leukemia, graft failure 6 HLA identical or haploidentical from SCT donor Hematopoietic recovery 2/6 Meuleman et al Pure Red Cell Aplasia after allogeneic SCT 2 Haplo or matched sibling MSC, matched allogeneic SCT Recovery from aplasia Fang et al Leukemia 8 Haploidentical MSC, umbilical cord SCT Safe, stable engraftment Macmillan et al Leukemia, acute GvHD 9 Haploidentical MSC, cord blood + haplo CD34 SCT Safe, stable engraftment Gonzalo-Daganzo et al Severe acute GvHD 13 Allogeneic mismatched MSC, allogeneic matched SCT Overall response day 28, 54% Von Bonin et al Denovo acute GvHD 31 Allogeneic mismatched MSC, matched allogeneic SCT 94% response to MSC + steroids Kebriaei et al Leukemia 20 Related or unrelated MSC; matched reduced intensity SCT Safe, stable HSC engraftment Baron F et al Hematologic disease 13 Haplo MSC, umbilical cord blood SCT Safe, low incidence severe acute GvH Bernardo et al 2010

11 Clinical use of MSC in hematopoietic stem cell transplantation 1. To enhance engraftment 2. For tissue repair 3. For prevention and treatment of acute GvHD Olle Ringdén 11

12 MSC may enhance HSC engraftment when the risk of rejection is high Transplantation of mesenchymal stem cells to enhance engraftment of hematopoietic stem cells Le Blanc K et al. Leukemia 2007, 8, Cotransplantation of ex vivo expanded mesenchymal stem clls accelerates recovery and may reduce the ris of graft failure in haploidentical hematopoietic stem cell transplantation Ball LM et al. Blood. 2007, 110:2764. Infusion of mesenchymal stem cells can aid hematopoietic recovery following allogeneic hematopoietic stem cell myeloablative transplant: a pilot study Meuleman N et al. Stem Cells Dev. 2009, 18: Results of a pilot study on the use of third-party donor mesenchymal stem cells in cord blood transplantation in adults Gonzalo-Daganzo R et al. Cytotherapy Mar 23:1-11 Katarina Le Blanc 22 mars

13 MSC co-transplantation in haploidentical SCT Ball LM et al. Blood, 2007 Patients (n = 20) Controls (n = 52) Transplant years (range) Dec July 2007 March Nov. 2 Graft characteristics Number of CD34+ cells infused x 10 6 /kg (median, range) 21.3 ( ) 23.0 ( ) Number of CD3+ cells infused x 10 5 /kg 0.3 (0.3) 0.5 (0.7) MSC Dose 1.6x10 6 MSCs/kg (range 1-3.3). 0 Haematopoietic recovery Days to Leukocyte count> 1,000/mL 11.5 (9-16) p= ( ) Days to PMN recovery 12 (10-17) 14 (9-28) Days to PLT recovery 11 (9-24) 13 (9-100) Days to reticulocyte recovery 12 (10-31) 23 (9-41) Post- HSCT complications Graft failure 0 (0%) p= (20%) Primary 7 Secondary 4 Acute GvHD Grade I- II 2 (10%) 12 (23%) Grade III- IV 0 (0%) 2 ( 3%) Chronic GvHD 1 (5%) 6 (12%) Katarina Le Blanc 22 mars

14 Prevention of GvHD in MUD transplants MSC CTR report HSCT D30 D60 D100 6 months Registration form D - 40 Randomization Form D-5-2 Acute GVHD

15 The European Group for Blood and Marrow Transplantation

16 The European Group for Blood and Marrow Transplantation

17 Katarina Le Blanc 22/03/ The European Group for Blood and Marrow Transplantation

18 MSC to treat steroid-resistant GvHD Cyclosporin Cyclosporin Prednisolone Bilirubin 400 MSC 6 2x10 /kg MSC 6 1x10 /kg 25 No of stools/day Days after ASCT Le Blanc et al, Lancet 2004;363,1439 Ringdén et al, Transplantation 2006 Katarina Le Blanc 22 mars

19 GvHD treatment study HSC T D-7 Occurence of GvHD MSC Treatment resistant D+8 D+30 D+60 D+100 CTR report 6 months 7 days Cyclosporine Prednisolone Randomise MSC/Placebo 2 x 42 patients with steroid resistant GvHD grades II-IV Randomised to receive MSC or placebo Katarina Le Blanc 22 mars

20 The European Group for Blood and Marrow Transplantation

21 The European Group for Blood and Marrow Transplantation

22 Katarina Le Blanc 22/03/ The European Group for Blood and Marrow Transplantation

23 1 2 Katarina Le Blanc 22/03/ The European Group for Blood and Marrow Transplantation

24 Katarina Le Blanc 22/03/ The European Group for Blood and Marrow Transplantation

25 Severe GvHD Katarina Le Blanc 22/03/ The European Group for Blood and Marrow Transplantation

26 Severe GvHD Katarina Le Blanc 22/03/ The European Group for Blood and Marrow Transplantation

27 Tha nk you for your a ttention!