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FEATURE
Stem Cell Therapies — What Happened and Where Next?
John Dangerfield
Chief Operating Officer, SG Austria Pte Ltd / Austrianova Singapore Pte Ltd
Council Member, BioSingapore

Although the mainstream media hype about stem cells has noticeably calmed in the last few years this should not detract from the considerable success within the industry itself, which has surpassed the expectations of many scientists. This editorial aims to explain in lay terms the types of stem cell therapies currently being used to treat patients, the hurdles that exist before they can become standard, everyday treatments and a promising solution which can be used to overcome these challenges.

Without going into details about the various categorizations of stem cell types, their use for medical purposes can be broken down into two main areas. They can be extracted directly from a patient, or from his/her previously banked blood sample and, after various types of laboratory or manufacturing processes, be implanted or injected back into that same patient. This type of treatment is known as autologous cell therapy. The second broad category of treatment is when a patient receives cells from a third party source. These so called allogeneic treatments are when a single source of cells is expanded to generate a large quantity of one, identical cell-based product which can then be stored and shipped for use by any patient, anywhere and at any time.

Both autologous and allogeneic stem cell therapies are performed regularly at state hospitals as well private hospitals and specialized clinics outside of major regulatory control systems such as the USA Food and Drug Administration agency (FDA), the European Medicines Agency (EMA) or any particular country’s own equivalent thereof. However, most of such less or non-regulated treatments are autologous because it is easier from a safety and regulatory perspective to implant a patient’s own cells back. There are currently hundreds of such stem cell treatment centers all around the world, many of which offer unapproved treatments [1]. However, there are also a few properly regulated stem cell treatments which are approved by a country’s medical agency after undergoing the formal process of clinical trials and showing that manufacturing standards can be met. Such biological manufacturing environments are regulated under an internationally recognized code of Good Manufacturing Practice (cGMP). In the autologous setting, this usually just invokes the careful defining of a process whereby a patient’s stem cells are taken into a GMP environment for culturing and expansion to larger numbers. Allogeneic products of course need to be characterized in more detail for safety reasons and the path to official approval is a far more lengthy and costly one.

Whether it be for stem cells or any other kind of cell therapy, allogeneic treatments are the clear focus for industry, they are the basis of almost all large scale commercial cell-based therapy efforts. This is because the autologous process cannot be made into an “off-the-shelf” pre-manufactured product as the cells need to be individually manufactured for each patient. Autologous cell therapy is more amenable to be administered as a medical process, similar to bone marrow transplantation, at a medical center.

Although ideal from the perspective of having a one-for-all, storable, shippable treatment, allogeneic products are far more technically challenging from a number of perspectives. Any new treatment must firstly pass close scrutiny by professional authorities like FDA or EMA. For example that the cells are safe, both from the perspective of not carrying any adventitious agents (such as pathogenic bacteria or viruses from the source donor or picked-up during the developmental processes) and also that when freed into the body of another being that they will not grow out-of-control and potentially form a tumor. This is generally referred to as the tumorigenicity of a cell, whereby for a stem cell a type of tumor known as a teratoma can form; a well-known risk factor associated with stem cell infusion [2].

Secondly, a full-scale cGMP manufacturing process must be put in place. This is the case even for the earlier stages of development such as the first clinical trials in humans, before it’s even known if the product can work effectively. Of course this is the same for any pharmaceutical product; however, established systems are in place for drug manufacturing whereas the cell therapy industry is much younger meaning there are still significant risk factors in designing and setting up what is, in the vast majority of cases, a highly novel process. Apart from financial considerations there are technical challenges to be overcome since many kinds of stem cells can still only be grown in two-dimensional culture systems [3]. Stem cells are by nature very sensitive to changes in their environment or physical pressure upon them, meaning they can rarely be manipulated for production in large scale growth systems such as three-dimensional, stirred bioreactors which actuate stresses onto the cells, potentially changing their characteristics. This means the possibilities for large scale production are limited due to manpower intensiveness and costs.

Finally there are challenges once the final stem cell product is implanted into the patient. When injected into any area, even muscle or other solid tissues, the cells disperse very quickly. One reason for this is because living cells are independently mobile. It may also be because they are being cleared by the patient’s immune cells or because they are dying due to natural cell-cycling processes such as apoptosis or necrosis. Thus, a combination of events determines the acute and chronic fate of stem cells in the body [4]. Due to this fast disappearance, a huge number of cells need to be implanted. For a typical stem cell product, 20-200 million cells must be implanted to have the desired effect [5]. Implanting such numbers of cells into a patient is a worry especially when one considers that multiple treatments may be necessary for certain indications.

Fortunately, there is a highly promising technology known as microencapsulation or bioencapsulation designed to overcome many, if not all, of these issues [6, 7]. A Singapore based company SG Austria Pte Ltd has developed a unique process called Cell-in-a-Box® which they use for their own products in the area of oncology and stem cell therapeutics but they also offer as a platform technology to other companies or researchers [8, 9]. By means of this and similar bioencapsulation processes, any living cell, including stem cells, can be physically immobilized into biologically inert beads or capsules and produced according to GMP guidelines [10]. Typically such capsules are in the size range of one millimeter (one tenth of a centimeter) and can hold up to ten thousand cells each. Implantation of encapsulated cells using this method has been shown to be safe and well tolerated in 27 patients in clinical trials [11, 12]. Depending on a number of factors such a potency of the cells and severity of the indication, typically between 100 and 1000 capsules are implanted to treat a condition. Due to the characteristics of the cell friendly material inside the capsule, stem cells which will normally only grow in two-dimensional culture systems can be cultured in large scale industrial stirred bioreactors (see Figure 1B). As such, the general benefits of the bioreactor system can be gained, such as high oxygenation levels and fast processing times. This allows GMP up-scaling without the associated drawbacks which would negatively affect most types of stem cells, such as when the stirring vortex of the bioreactor causes sheer stresses as the cells physically bang into each other and the walls of the bioreactor.

Further down the line, the capsules are also able to help out once implanted into the patient. Instead of being able to wander off, encapsulated cells are now fixed at the desired location because of the relatively large size of the capsules. This allows the cells to act at the chosen site of implantation for longer periods in time, in turn meaning that far fewer cells in total need to be implanted to have the same action. Of course, the capsules also protect the cells from attack by the patient’s immune cells. Although many types of stem cells are considered non-immunogenic, at some point there will be interactions with the patient’s cells which will in turn cause changes to (or clearance of) the implanted stem cells [4]. Due to the porous nature of the capsule outer-wall, which allows nutrients and well as cellular signaling factors to go in as well as therapeutic factors to come out of the capsules, the necessary interactions with the implantation site (e.g. wound factor signaling) can still take place, but the cells themselves cannot be cleared allowing longer lasting therapeutic activity (see Figure 1A). Finally, capsules can be removed after treatment is complete, a consideration which makes them especially attractive to the patient and authorities alike due to safety reasons as well as making multiple rounds of treatment viable if necessary.

Currently, there are at least three approved allogeneic stem cell-based therapies on the market world-wide and stem cells have been or are being tested in more than 4600 other clinical trials. It’s interesting that these treatments still exist despite the issues and challenges mentioned above. Indeed one could fairly challenge most if not all current stem cell therapy approaches about these concerns. However, due to the great therapeutic potential they are already showing, they are still fast emerging in biomedicine today. Most experts would agree that stem cell products will benefit from enhancing technologies, such as bioencapsulation, in order to enable cheaper and faster manufacturing, improve storage and shipping options, enhancing their efficacy in the patient as well as making them safer.

About the Author

Originally from the UK, John completed his PhD in molecular biology in Vienna in 2001. After a further 6 years in Austria doing fundamental research, he side-stepped into the biomedical industry working for Austrianova Singapore Pte Ltd (SG Austria), a company based at the Biopolis. Initially he was Head of Laboratory and he went on to be Chief Operating Officer in 2010. He is also co-founder and Managing Director of the early stage, life-science start-up company Anovasia Pte Ltd and an active council member for the bio-industry alliance organisation BioSingapore. John has co-authored over 15 peer-reviewed journal articles and book chapters and has edited two books.

 

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