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The development of stem cell therapies

Promising treatments are being developed, but a clear regulatory pathway is needed to ensure risks to patients are minimised 

The development of stem cell therapiesSince the first successful bone marrow transplantations in 1968, stem cell therapies have continued to fascinate the medical world. Their abundance and versatility encourage their development as treatments for a number of conditions; the possibilities seem endless. The two broad types of stem cells, embryonic and adult, play major roles in the body's repair system, through their ability to divide and differentiate on diverse specialised cell types, and their self-renewal ensures countless generations of new cells.

Through the introduction of stem cells into an area of disease or damage, the body can be encouraged to repair and replace tissues regardless of how old the trauma is, with minimal risk of rejection. Stem cells also show potential in inhibiting cell death caused by disease. Researchers anticipate that when fully developed, stem cell therapies have the potential to address leading causes of death, such as cancer and heart disease.

Despite their promise, the only US Food and Drug Administration (FDA)-approved stem cell therapy to date is haematopoietic stem cell transplantation (HSCT), commonly known as bone marrow transplantation. Strict regulations in the US and Europe seek to protect patients as there is still much to learn about the efficacy and tolerability of these therapies; however, these rules are relatively new and arbitrary in cases. As research in the area gathers momentum, regulatory guidance will become increasingly important.

Stem cell therapies are generally defined by the types of cells used, with all having advantages and disadvantages. Embryonic stem (ES) cells are pluripotent stem cells isolated from the inner cell mass (ICM) of blastocysts. They can differentiate into all derivatives of the three primary germ layers: ectoderm, endoderm and mesoderm - essentially all the cell types found in the body. However, isolation of the ICM results in the destruction of the fertilised human embryo, which raises ethical concerns.
ES cells have a potentially unlimited capacity for self-renewal, like adult stem cells. Adult stem cells are found in adult tissues but are mostly multipotent, meaning that they can give rise to cells from multiple, but a limited number of, lineages. They are generally referred to by their tissue origin e.g. mesenchymal stem cell or adipose-derived stem cell.

There is a third type of stem cell, the induced pluripotent stem (iPS) cell, which is being considered for therapeutic use. These are artificially generated cells, reprogrammed from somatic adult cells to reacquire both the stemness and differentation characteristics of ES cells. Research into iPS cells is less developed than that into the other types of stem cells and therefore their use poses significant risks.

Progenitor cells
HSCT involves the administration of progenitor cells capable of reconstituting normal bone marrow function and is used to treat conditions such as leukaemia. The progenitor cells can be sourced from the patient (autologous), a donor (allogenic), or donated umbilical cord blood. The traditional source of haematopoietic stem cells for autologous and allogeneic transplantations has been bone marrow, which requires collection by repeated aspirations of the posterior iliac crests of the donor.

Over time, the use of bone marrow has been replaced with peripheral blood, in which bone marrow cells can be mobilised and collected via leukocytapheresis. Peripheral blood stem cells have 10-fold more T-cells than bone marrow and therefore increase the risk of chronic graft-versus-host disease (GVHD). However, they speed engraftment and reduce toxicity in patients undergoing autologous transplantation.

Myeloablative conditioning regimens, which include total-body irradiation and chemotherapy, are applied to kill residual cancer cells and to cause immunosuppression in preparation for engraftment. Non-myeloablative regimens use chemotherapy drugs and radiation at lower doses. Several weeks of growth in the bone marrow following engraftment is usually sufficient to normalise blood counts and reinitiate the immune system.

Some of the risks involved with stem cell therapies are attributed to the two principal characteristics that define them. Due to their capacity to self-renew and differentiate, ES cells can be tumorigenic if cell growth is inadequately regulated. It is thought to be impossible to separate tumorigenic cells from non-tumorigenic cells due to the connection with pluripotency.

Even HSCT, despite its use for over 50 years, is not without risks. It is usually not attempted unless a patient has exhausted all other options and the condition is considered life-threatening. The transplanted cells must accept the body or GVHD will occur. Other complications include infection, mucositis, veno-occlusive disease and graft rejection. Further research will aim to reduce the toxicity of stem cell therapies, such as designing effective, reduced-intensity conditioning regimens and discovering targeted therapies to prevent and treat GVHD.

Despite the use of procedures such as HSCT for decades, only in the last 10 years have regulatory authorities started to establish rules governing the approval of such therapies. In the US, stem cell therapies are regulated by the FDA as biologic products, defined as 'articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient'. In Europe, stem cell therapies are classified as 'advanced therapy medicinal products' (ATMPs). In both regions, the products are subject to the same regulatory principles as other types of biotechnology medicinal products.

However, an emphasis is placed on the type and amount of preclinical and clinical data necessary to demonstrate the quality, safety and efficacy of the product. Developers must be able to address issues such as the risk of infectious or genetic disease transmission, risk of contamination and damage, the types of cells used and purity and potency of the final product plus, above all, the efficacy and safety of the product.

Despite the strict criteria, loopholes exist in the regulations, with many doctors stating that their therapies only involve the reinfusion of patients' own cells and therefore are not subject to regulatory approval. This has led to the establishment of stem cell clinics around the world, offering untested stem cell therapies that may be harmful to patients. Additionally, much late-stage development of these therapies is being conducted in regions outside the US and Europe, such as Asia and the Middle East, where rules concerning stem cell therapies are less established.

Mesenchymal stem cells are a seemingly popular choice for development, as they are found in the bone marrow and, due to procedures such as HSCT, much is known about their properties. Mesoblast's mesenchymal stem cell therapy is one of the most advanced stem cell therapies in development. It consists of allogeneic and autologous mesenchymal precursor cells (MPC) and is being developed for the regeneration and repair of bone, bone marrow and cartilage in patients undergoing bone marrow transplantation for haematological malignancies.

A phase III study is under way in the US, Europe and Australia. Additionally, the product has received clearance from the European Medicines Agency (EMA) to conduct a phase II clinical trial for the prevention of heart failure following myocardial infarction. The cells will be delivered by intracoronary infusion in conjunction with angioplasty and stent procedures. Similar trials in patients with cardiovascular disorders are scheduled to take place in the US, where phase II trials in degenerative disc disease and lumbar fusion are already ongoing.

Medipost's mesenchymal stem cell product (Cartistem) was approved by the Korea Food and Drug Administration for the treatment of osteoarthritis in January 2012. The therapy is based on adult mesenchymal stem cells derived from umbilical cord blood. The company is preparing to develop the product in other regions through licensing agreements with pharmaceutical companies in North America, Europe, Asia and the Middle East. FCB Pharmicell developed the first mesenchymal stem cell product (Hearticellgram-AMI) to be approved for clinical use in acute myocardial infarction. It was approved for sale in South Korea in July 2011, although concerns have been raised over the lack of independent validation of the treatment.

South Korea was once considered a global leader in human stem cell research, beginning with Hwang Woo-suk's experiments to generate ES cells through cloning. Until this breakthrough, therapeutic cloning of stem cells was thought to be impossible due to the complexity of primates. Subsequently in 2005, Hwang was found guilty of fabricating his research that was published in the journal Science. This highlights the importance of vetting research via independent experts, especially in a field where there is little regulation.

Other advances in the area of cardiovascular stem cell therapies include Cytori Therapeutics' adipose-derived stem and regenerative cells (ADRCs), which consist of autologous adult stem cells, endothelial progenitor cells and other growth factor-producing cells. This therapy is in phase II/III clinical trials for the treatment of myocardial infarction in the Netherlands. Long-term data from the phase I APOLLO trial showed that the mean reduction in infarct size at six months was preserved at 18 months, with a significant (p<0.05) mean reduction in left ventricular infarct size from baseline to 18 months in the ADRC-treated group. Cardio3 BioSciences is developing C-Cure, a human adult bone marrow derived somatic cell therapy. A phase III clinical programme is planned for 2012.

A promising stem cell therapy being developed in the US is carlecortemcel-L (StemEx; Teva/Gamida Cell) for the treatment of haematopoietic malignancies and myeloablative conditions. It is a cord blood-based therapy that is transplanted in combination with non-expanded cells from the same cord blood unit. The product has the ability to generate a stem cell population from umbilical cord blood that is large enough to increase significantly the chances of a clinically successful graft in both adults and adolescents.

A pivotal phase II/III clinical trial is evaluating the efficacy and safety of carlecortemcel-L and early results published in September 2009 suggest that the drug may be associated with favourable non-relapse mortality rates. Carlecortemcel-L received fast-track designation for use in bone marrow transplantation in patients with leukaemia and lymphoma and has been designated as an orphan drug by the FDA and EMA. Teva/Gamida Cell plan to submit a Biologics Licence Application to the FDA in 2012, pending positive final results from the trial.

Looking forward, as stem cells continue to hold considerable promise for various applications, clear regulatory guidance is needed to protect patients and encourage further research. As technology improves, patients may see safer and more effective stem cell treatments that are a specific match to the patient, with the ability to treat any type of ailment. For now, these therapies are still considered a radical form of treatment for patients who are unresponsive to conventional therapy, but it is hoped that even small developments will serve as a catalyst for global advancement in this research.

Chin-Hang Kong, Adis InternationalThe Author
Pipeline was written by Chin-Hang Kong of Adis International (Springer Healthcare), using data derived from Adis R&D Insight, Clinical Trials Insight and inThought.
For further information on Adis services, contact Daniela Ranzani on +39 02 423 4562 or Email:

12th April 2012


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