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Overcoming the Challenges of Manufacturing Therapeutic Mesenchymal Stem Cells

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Mesenchymal stem cells (MSCs) have broad anti-inflammatory and immune-modulatory properties and have been identified as promising therapeutics for a range of diseases, including osteoarthritis, graft versus host disease, and heart disease. However, the challenges associated with manufacturing donor-derived MSCs have so far impeded their commercial use and more recently have proven to be a fundamental concern for the US FDA.

Cynata Therapeutics is developing a therapeutic stem cell platform technology, Cymerus™, with the aim of overcoming these challenges. The platform uses induced pluripotent stem cells (iPSCs) from a single donor to generate mesenchymoangioblasts (MCAs), a precursor of MSCs. Results of the world’s first human clinical trial of an iPSC-derived MSC cell –  Cynata’s CYP-001 –  were recently published in
Nature Medicine.

Technology Networks
had the pleasure of speaking with Ross Macdonald, CEO of Cynata Therapeutics, to learn more about the trial, the challenges of manufacturing therapeutic MSCs, and how the Cymerus technology overcomes these. In this interview, Ross also discussed some of the other disease areas MSCs could benefit and the impact that the COVID-19 pandemic has had on the progress of clinical trials.

Anna MacDonald (AM): How have advances in stem cell research influenced the cell therapy and regenerative medicine fields in recent years?

Ross Macdonald (RM):
Focusing on the cell type of relevance to Cynata (mesenchymal stem cells or MSCs), we have seen very important recent advances in our understanding of the mechanisms of action of this very versatile and potent therapeutic modality.  This has implications for designing more robust clinical trials, for interactions with regulators, and for pricing and market access.  It has also helped in managing investor expectations and the expectations of patients, their families and their caregivers.  Clinical trials have demonstrated safety and, in many cases, very promising efficacy, in a wide range of diseases.  These trials have led to MSC product marketing approvals in major markets such as Japan and Europe. 

AM: Can you tell us about Cynata’s Cymerus technology and its origins?

Cynata Incorporated (a California registered company) was formed in October 2011 by two of the inventors of the Cymerus technology (Professor Igor Slukvin and Dr Maksym (Maxim) Vodyanik), in collaboration with Australian technology entrepreneur, Dr Ian Dixon. Skukvin and Vodyanik at the University of Wisconsin – Madison (where many seminal discoveries concerning stem cells had been made) had identified the biologic pathway for the generation of MSCs from precursor cells – the family tree of MSCs in simple terms.  Following the filing of patents in resepect of this discovery the core Cymerus technology was licensed exclusively to Cynata by the Wisconsin Alumni Research Foundation (WARF). 

Cymerus MSCs are uniquely derived from induced pluripotent stem cells or iPSCs, which are mature cells that are reprogrammed back into embryonic-like, pluripotent cells that can replicate themselves indefinitely and differentiate into any other type of cell in the body. The Cymerus manufacturing process ensures that cells for therapeutic use can be produced in virtually limitless quantities from a single donor. This provides a novel solution to the challenges associated with conventional MSC manufacturing approaches that depend on a constant supply of new tissue donors and the inherent product inconsistency that comes with sourcing starting materials from different donors.

In November 2013, Cynata Incorporated was acquired by an ASX-listed company called EcoQuest Limited which subsequently changed its name to Cynata Therapeutics Limited. The company is now headquartered in Melbourne, Australia, but the majority of its operations continue to be undertaken in the USA. The Cynata founders – Professor Slukvin, Dr Vodyanik and Dr Dixon - all still hold shares in the Company and Professor Slukvin remains closely involved with the company’s product development activities.

AM: Can you give us an overview of the steps involved in the MSC production? How are the iPSCs derived, and why was this method chosen? 

The following schematic illustrates the Cymerus process.

The iPSC starting material was derived from a blood donation from a single donor using a proprietary episomal reprogramming process originally developed at the University of Wisconsin – Madison and Cellular Dynamics International (now Fujifilm CDI).  This method was chosen as it was undertaken without the use of viruses or transgenes and also using good manufacturing practice (GMP), essential for the development of a human therapeutic product.

AM: What are the main challenges of manufacturing therapeutic MSCs? How does Cymerus overcome the limitations associated with first-generation methods of production? 

MSCs occur naturally in adult tissues such as bone marrow and fat. Conventional methods of manufacturing MSC-based products involve surgically collecting such tissue from a donor, isolating MSCs and then growing the cells in culture. However, there are a number of significant limitations with this approach that severely constrain the commercial development of MSC-based therapeutics:

· Expansion of MSC cultures derived from primary sources to produce even small numbers of doses face significant challenges.  The properties of MSCs are known to change with excessive expansion, and this could dramatically affect their efficacy or even safety. This means that only a limited number of reproducible, consistent doses can be generated from each tissue donation.  This in turn means that it is necessary to repeatedly collect new donations, posing major cost, supply and logistic challenges.

· Multiple donors pose major impediments to regulatory approval because it cannot be assumed that MSCs isolated from different donations are the same as each other. Each time a new tissue donation/new donor is used, it is necessary to demonstrate to the satisfaction of regulatory authorities that the end product remains the same. This process is time consuming and costly, and there is no guarantee that equivalence will be demonstrated.

These clear and fundamental product consistency shortcomings in conventional approaches to manufacturing therapeutic MSCs were dramatically highlighted recently by the FDA in its commentary around a decision not to approve a Biologics License Application (BLA) for a bone marrow-derived MSC product where substantial functional heterogeneity was noted.

Cynata’s Cymerus overcomes both of these challenges because it allows the manufacture of all of the cells that will ever be needed from a single Master Cell Bank of iPSCs – derived from a single donor. This has the potential to create a new standard in the emergent arena of regenerative medicine and stem cell therapeutics and provides Cynata with a unique competitive advantage.

AM: In a paper recently published in Nature Medicine, the safety and efficacy of CYP-001 was investigated. Can you tell us more about the study and the implications of the findings?  

The Nature Medicine paper describes the world’s first completed human clinical trial of iPSC-derived cells in any disease. The paper reviews the novel, iPSC-derived manufacturing process for CYP-001,  Cynata’s first Cymerus MSC product as well as results from the 100-day Primary Evaluation Period of the Phase I multi-centre, open label, dose escalation clinical study of CYP-001. Therapeutic use of MSCs for the treatment of GvHD was introduced by Le Blanc and colleagues in 2004 with positive results for a disease that is characterized by very poor prognosis and high mortality rates (~80%) using standard of care steroidal therapy. The results of Cynata’s clinical study have significant relevance not only to steroid-resistant GvHD but also to many other diseases in which MSCs are being clinically examined.  The clinical study confirmed that CYP-001 was safe and well tolerated, conferring an overall response rate and overall survival rate of 87.5% and 85.7%, respectively, by Day 100. This compares very favourably to previously published outcomes in this patient population and validates and supports the further development of CYP-001 for this challenging disease.

AM: The therapeutic potential of iPSC-derived MSCs is not limited to acute GvHD. Can you tell us about other trials that Cynata is currently involved in, or planning to commence soon?

RM: Cynata is investigating the therapeutic utility of its Cymerus MSC products in multiple clinical trials.
We recently announced the commencement of our Phase 3 trial of Cymerus MSC product CYP-004 in osteoarthritis, which is the first-ever Phase 3 trial of an iPSC-derived cell therapeutic and the largest randomized controlled trial of MSCs conducted in patients with osteoarthritis worldwide.

The company’s current product development pipeline is noted in the illustration below:

AM: What impact has the COVID-19 pandemic had on the progress of clinical trials?

The pandemic has had a dramatic and measurable impact on the majority of planned and current clinical trials around the world and Cynata is not immune to this situation.  Fortunately, Cynata was able to quicky take advantage of its compelling pre-clinical findings in acute respiratory distress syndrome (ARDS), sepsis and cytokine release syndrome (CRS), all of which are hallmarks of severe complications of COVID-19 and commence a clinical trial in such patients.  This trial is presently open for recruitment in Australia. We also are excited that we recently commenced our Phase 3 trial in osteoarthritis. Despite some temporary COVID-19-related restrictions that caused minor delays the largest randomized controlled trial of MSCs conducted in patients with osteoarthritis worldwide is now underway through our partnership with the University of Sydney. The Phase 2 critical limb ischemia trial, which was approved by the UK Medicines and Healthcare Products Regulatory Agency (MHRA) in January 2020, has been impacted by pandemic-related recruitment restrictions and it is at present uncertain when this trial might commence enrolling subjects.  Our corporate partner for CYP-001, Fujifilm, is planning a Phase 2 clinical trial in Japan, currently expected to commence by end 2020.  Whether the pandemic will have implications on the commencement of this trial is as yet unclear. 

Meanwhile Cynata has made very good progress during the COVID-19 pandemic on a range of pre-clinical programs with compelling data being reported in a range of animal models of diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome (ARDS), and in myocardial infarction (heart attack).

Ross Macdonald was speaking to Anna MacDonald, Science Writer for Technology Networks.