An Innovative Approach to Cell Manufacturing Protocol
Product: Human Mesenchymal Stromal Cells, Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells
“One of the first clinical grade stromal cell therapies which have received approval for use in a clinical trial.”
The production of clinical-grade stromal cells is an important part of the VISICORT project. In order to be able to treat the patients in the clinical trial, hundreds of millions of stromal cells are required. If the therapy is to enter the mainstream, we also need to be able to demonstrate that we will be able to produce cells in sufficient quantities to treat thousands of patients. If clinicians are to confidently prescribe cell therapy treatments, however, the cell therapies must be very pure and consistent.
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The cells used in VISICORT (and in the majority of stromal cell clinical trials) are extracted from bone marrow. The bone marrow is taken from the top of the donor’s hip-bone (the ‘iliac crest’) by an experienced haematologist. The cell therapy product is allogeneic since it is generated by isolation and expansion of plastic adherent human bone marrow (BM)-derived Mesenchymal Stromal Cells, (h-BM-MSCs) from healthy adult donors. The tissue is procured in accordance with EMA Tissues & Cells Directive, 2004/23/EC and the product is manufactured in accordance with Good Manufacturing Practices (GMP).
The manufacturing process for the cell product is continuous. The bone marrow is procured and transferred to Centre for Cell Manufacturing Ireland at the National University of Ireland Galway where it is washed, counted and plated directly onto T-175 tissue culture flasks. At the end of P0, the mesenchymal stromal cells are harvested and seeded on the QUANTUM CES bioreactor (P1) and all plastic adherent cells are harvested and cryopreserved – this P1 cell suspension is called the Drug Substance, (DS). The DS is resuspended in the product formulation buffer, filled in the primary container, and cryopreserved in the vapour phase of liquid nitrogen or in a freezer (≤ -150°C).
Cell isolation and expansion of the plastic adherent BM-derived mesenchymal stromal cells through filling and cryopreservation of the hMSC drug substance (DS) is performed in accordance with Good Manufacturing Practice (GMP). A description of the manufacturing process for DS is provided below.
SOPs and Regulatory Authorisation
The VISICORT cell production protocols comply with Good Manufacturing Procedure (GMP) standards; this is essential if the cells are to be accepted as mainstream therapeutic products. Such products require authorisation by national and international regulators such as the EMA (Europe), FDA (USA), MHRA (UK) and HPRA (Ireland). An essential part of securing this authorisation is a demonstration of GMP compliance. The cell isolation and production processes in VISICORT take place within certified GMP environments.
In VISICORT, we are preparing for the use of allogeneic bone marrow‐derived MSC (allo-hBM-MSC) as a novel immunomodulatory cell therapy for corneal transplant recipients at high risk for acute rejection due to loss of a previous corneal transplant.
Using CCMI Manufacturing Expertise
ADIPOA-2 has built on the work of ADIPOA to deliver a large-scale clinical trial in regenerative medicine for OA. The purpose of the project is to design and implement a phase IIb study to assess the safety and efficacy of autologous (patient-derived) ACSs in the treatment of advanced OA of the knee. The cells have been prepared from samples of adipose tissue harvested from patients by lipoaspiration. It is a randomised clinical trial across 10 hospitals in Europe and involving 150 patients. CCMI is currently manufacturing batches for the Galway Clinical Site and these are being used to treat osteoarthritis in patients. The recruitment of patients is currently active.
Horizon 2020 EU funding has been granted for NUI Galway to coordinate and carry out a four-year project. NEPHSTROM will study the use of next-generation stem cell therapies to combat diabetic kidney disease. Orbsen Therapeutics uses patented technology to purify stromal cells, and the trial is currently treating patients with diabetic kidney disease as part of the first-in-man trials. The trial is taking place in Galway, Belfast, Birmingham and Bergamo, with 48 people in the hope that the treatment slows or eradicates the patient’s kidney disease. The research project is a collaboration with 11 European partners and builds on the EU-funded project REDDSTAR which uses stromal cells to treat diabetes mellitus. CCMI currently manufacture stem cell batches as part of the NEPHSTROM project.
CRITICAL LIMB ISCHEMIA (CLI)
Approval was obtained from the HPRA in 2014 to carry out a phase 1b, open-label, uncontrolled, non-randomised dose-escalation CLI Stem Cell Trial. This study will examine the safety of intramuscular autologous transplantation of escalating doses of mesenchymal stem cells to patients with no-option critical limb ischemia (CLI). Patient enrolment has commenced and CCMI is currently manufacturing cell batches for this trial and this will continue on a phased basis over a two year period as the patients are selected.