Clinical Applications of Mesenchymal Stromal Cells

Transcription

1 Clinical Applications of Mesenchymal Stromal Cells John Girdlestone PhD Head of Laboratory Cellular and Molecular Therapies NHSBT Oxford

2 Cellular and Molecular Therapies 7 HTA-licensed Cell Therapy Laboratories - 70 Customer Accounts for routine BMT - Support 1,400 BM Transplants per annum 1 Clinical Biotechnology Centre - GMP grade plasmids for direct vaccination, ips cells or viral vector production 4 MHRA-licensed laboratories for ATMP preparation with internal QA/QP support

3 Cellular and Molecular Therapies 7 HTA-licensed Cell Therapy Laboratories - 70 Customer Accounts for routine BMT - Support 1,400 BM Transplants per annum 1 Clinical Biotechnology Centre - GMP grade plasmids for direct vaccination, ips cells or viral vector production 4 MHRA-licensed laboratories for ATMP preparation with internal QA/QP support

4 Cellular and Molecular Therapies 7 HTA-licensed Cell Therapy Laboratories - 70 Customer Accounts for routine BMT - Support 1,400 BM Transplants per annum 1 Clinical Biotechnology Centre - GMP grade plasmids for direct vaccination, ips cells or viral vector production 4 MHRA-licensed laboratories for ATMP preparation with internal QA/QP support

5 NHSBT Supply Chain & Core Competencies Innovate UK: Standard Approach to atmp tissue collection (SAMPLE) Recruit & retain Select Process Store & Distribute SCDT H&I laboratories CMT CMT Blood collection teams Logistics Donor Patient SCDT H&I Colindale SCDT Tissue Services* Therapeutic Apheresis CMT H&I laboratories NTMRL Type & register Consent & procure Assess CMT Cellular and Molecular Therapies TAS Therapeutic Apheresis Service H&I Histocompatibility & Immunogenetics SCDT Stem Cell Donation and Transplantation * decellularised scaffolds

6 Mesenchymal Stromal Cells (MSC) Bone Fat Cartilage Images: edc2, sciweb, MMG

7 MSC are Immunosuppressive T Lymphocytes B Lymphocytes Dendritic Cells Monocytes NK Cells

8 MSC Projects in NHSBT-CMT PROJECT PRODUCT / INDICATION PARTNERS AZELLON BM-MSC for cartilage repair Azellon Cell Therapeutics University of Liverpool Cell Therapy Catapult MERLIN MSC for primary sclerosing cholangitis University of Birmingham Orbsen Therapeutics NEPHSTROM MSC for diabetic kidney disease University of Leiden Ludwig Maximilians Univ. Orbsen Therapeutics REALIST 2 MSC for Acute Respiratory Distress Syn Queens University Belfast Guys, Birm. Heartlands/QEH Orbsen Therapeutics Renal IRI Cord MSC for Kidney Transplantation Oxford University Hospitals Trial Support ips MSC for Graft vs Host Disease Cynata Multistem for ARDS Athersys

9 PROJECT PRODUCT / INDICATION PARTNERS AZELLON BM-MSC for cartilage repair Azellon Cell Therapeutics University of Liverpool Cell Therapy Catapult MERLIN MSC for primary sclerosing cholangitis University of Birmingham Orbsen Therapeutics NEPHSTROM MSC for diabetic kidney disease European Union Horizon 2020 REALIST 2 MSC for Acute Respiratory Distress Syn Orbsen Th Renal IRI Cord MSC for Kidney Transplantation Oxford University Hospitals Trial Support ips MSC for Graft vs Host Disease Cynata Multistem for ARDS Athersys

10 Production of MSC for the Nephstrom Trial Bone marrow aspirates from young donors CD362 selection Leiden P0/P1 expansion Expansion in Quantum Bioreactor Transported to Trial Centres Belfast, Bergamo, Birmingham & Galway Cells harvested, & frozen in clinical cell doses Expansion in Quantum Bioreactors Transported to 3 GMP production facilities Bergamo, Galway & Liverpool Cells harvested and frozen in 20 million cell doses

11 > 10 8 / year kilometers H&I Colindale H&I Research, Colindale

12 > 10 8 / year H&I Colindale H&I Research, Colindale

13 > 10 8 / year H&I Colindale H&I Research, Colindale

14 In-House production of cord derived MSCs for GvHD and other diseases Cord collected into Hypothermosol Disinfect with 70% ethanol Dissect into 2-3mm pieces Final expansion in Quantum Bioreactor Harvest cells and expand in TC flask Incubate in DMEMalpha with HPL and bfgf - 7 days DH funding to develop GMP products from Cord derived tissue

15 Mesenchymal Stromal Cells We can produce them in large numbers They can be infused safely Do they work?

16 The COCHRANE Library: Systematic Review Mesenchymal stromal cells (MSC) for treating immune-mediated inflammation post-transplantation and in autoimmunity Fisher S, Cutler A, Brunskill S, Stanworth S, Navarrete C, Girdlestone J Intervention Protocol 16 May 2012 DOI: / CD Randomised, controlled trials

17 MSC Database Hits Google PubMed Cochrane search clinicaltrials.gov

18 MSC Database Hits x 10 6 Google PubMed Cochrane search clinicaltrials.gov

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20 No adverse events on mortality, relapse, or infections More trials needed, particularly for agvhd therapeutic use

21 Prophylaxis for Chronic GvHD 62 / arm Gao et al. J Clin Oncol :

22 Cynata CYP-001 Stem Cell Therapy Meets All Safety and Efficacy Endpoints in Phase 1 Trial in GvHD August 30, 2018 Athersys Announces Positive Results From Its Exploratory Clinical Study of MultiStem Cell Therapy for Treatment of Acute Respiratory Distress Syndrome (ARDS) January 23, 2019 TiGenix and Takeda announce Alofisel (darvadstrocel) receives approval to treat complex perianal fistulas in Crohn s disease in Europe March 23, 2018

23 Mesenchymal Stromal Cells Can we make them better?

24 MSC as Drug Delivery Systems Rapamycin (Sirolimus) RBC 95% MSC ~25%. Everolimus FK506 (Tacrolimus) CsA X MMF, Aza

25 MSC as Drug Delivery Systems Rapamycin (Sirolimus) RBC 95% MSC ~25%. Everolimus. Anti-Cancer FK506 (Tacrolimus) Antibiotics CsA

26 Enhancement of the immunoregulatory potency of MSC by treatment with immunosuppressive drugs In a xenogeneic model of agvhd, Rapamycin-treated MSC are superior at suppressing disease at 4x lower numbers than untreated cord MSC Survival 0.5x10^6 treated 2x10^6 untreated 0.5x10^6 untreated No MSC MSC added The ability to use low levels of standard drugs with lower numbers of MSC has the potential to reduce costs and provide greater therapeutic efficacy. Girdlestone et al. Cytotherapy 17: 1188 REVIEW - Girdlestone Immunotherapy 8: 1405

27 Summary - MSC have immunosuppressive properties in addition to their ability to differentiate into connective tissue derivatives - Clinical trial evidence is accumulating to support their clinical use - A simple incubation with immunosuppressive (& anti-cancer and anti-bacterial) drugs can enhance their potency in vitro and in vivo - Using standard drugs should hopefully lower the barriers to developing an enhanced therapeutic cell product

28 Acknowledgments H&I Colindale Dr Cristina Navarrete Saket Srivastava Jeff Pido King s College Giovanna Lombardi Cellular and Molecular Therapies Eric Austin Vivien Hanson Jacqui Thompson Jon Smythe Harefield Hospital Neil Leaver NIHR Programme Grant NHSBT Project Grant Bloodwise (Leukaemia and Lymphoma Research) Department of Health And Social Care

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