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Stem cell therapies - are we there yet?

Stem cell therapies have revolutionised how disease are treated by shifting the approach from ‘fixing what’s broken’ to ‘replacing what’s broken’. This raises the possibility of curing diseases by addressing their root cause, rather than trying to rectify downstream effects by administering treatment to alleviate symptoms or slow disease progression. Stem cells are pre-mature cells that have not specialised their function and have the potential to become any cell in the body given the right environment. These cells are mostly found in embryos but, luckily, they can also be found in certain tissues in the adult body, such as the bone marrow, fat and skeletal muscles, opening the possibility of collecting stem cells from adult individuals. What is even cooler, scientists have discovered a way to convert already ‘specialised’ cells back to their pre-mature stem cell form. Given all this, it is evident scientists got excited at the prospect of using stem cells from an adult body to replace damaged cells and regenerate organs. We have witnessed a few success stories in the history of stem cell treatment, with therapies that have been approved by regulatory authorities and are currently on the market. However, these examples are limited and this field still faces major challenges in getting robust clinical data and developing marketable regenerative therapies.

Regenerative therapy = medical treatment that restores the normal/healthy function of an organ by replacing or regenerating the tissue by promoting natural repair processes

Stem cell transplantation has been around since E. Donnall Thomas performed the first transplantation of bone marrow stem cells in patients treated with radiation and chemotherapy in 1957 (Donnall Thomas et al., 1957). His research developed into what is now the standard therapy for multiple blood and bone marrow cancers, and also got him a Nobel Prize in Medicine or Physiology. As a matter of fact, the transplantation of hematopoietic stem cells (HPC) is the only stem cell-based product authorised by the US health authority – Food and Drug Administration (FDA) to be used on the US market (FDA, 2019). The following paragraph explains the principles of these stem cell therapies and the underlying mechanism of action.

Hematopoetic stem cells = stem cells derived from the bone marrow that have the potential to develop into different types of blood cells (red, white, platelets)

The general HPC therapy involves the following steps:

  1. Chemotherapy or radiotherapy given in very high doses killing as many cancerous cells as possible. This high dose, however, is also toxic to the healthy bone marrow, which has the function of making blood cells. Damage to the bone marrow can lead to low levels of blood cells.

  2. Transplantation of bone marrow-derived stem cells. These healthy cells then substitute the damaged bone marrow, multiply and become various types of blood cells.

There are two types of cell transplantation in this procedure – illustrated in Figure 1 below: autologous (when the cells are collected from the patient before the chemo/radiotherapy, the cancerous cells are removed from the mixture, and the healthy cells are then transplanted back) and allogeneic (when the cells are collected from a matching healthy donor – often a relative).

Figure 1. Difference in autologous and allogeneic stem cell transplantation.

There are advantages and disadvantages to both methods. For example, autologous cells won’t trigger an unwanted immune response as the body will recognise its own cells. However, there is a small risk of transplanting undetected leukaemia cells back.

In contrast, allogeneic stem cells are derived from healthy donors, eliminating the risk of transplanting any diseased cells into the patient. Once these allogeneic cells are transplanted, they develop into immune cells that protect the donor, attacking and killing the patient’s cancer cells. Unfortunately, in some cases they may start attacking the patient’s healthy cells because they see them as foreign, resulting in side-effects that make the treatment difficult to tolerate. In leukaemia, allogeneic stem cell therapy has been shown effective, resulting in 8 licensed HPC therapies on the US market, as of 2019. The success of HPC may be due to their combined approach of replacing damaged bone marrow and attacking remaining cancerous cells. It may be more challenging to show good evidence for a beneficial impact of stem cell therapy in a non-leukaemia context, when we don’t want stem cell-derived immune cells to attack the surrounding tissue.

Autologous cells = cells collected from the patient and transplanted back into the patient

Allogeneic cells = cells collected from a matching healthy donor

Outside of the US, other stem cell therapies that have been approved by health authorities. In Europe for example, stem cells are used to treat stem cell deficiency in the eye caused by burns (Holoclar), a type of immunodeficiency (Strimvelis), and perianal fistulas in Crohn’s disease (Alofisel).

  • In the eye, the transplanted stem cells act by becoming cells of the cornea, multiplying and forming a reservoir of stem cells that can regenerate the tissue.

  • In the case of the immunodeficiency, stem cells populate the bone marrow and secrete a molecule that these patients are lacking, reversing the immunodeficiency.

  • In the case of perianal fistulas, a highly inflamed area on the perianal skin surface, stem cells act to reduce the inflammation by secreting anti-inflammatory molecules.

In the two latter examples, we describe another interesting stem cell mechanism of action – production and secretion of beneficial molecules that send signals to surrounding tissue to promote the repair process. Even if it is not the previously described ‘replacement’ therapy, it is potentially a complementary or an even better mechanism of action promoting organ regeneration.

Immunodeficiency = condition in which the immune system is weakened and unable to defend the body against harmful germs.

Perianal fistula = A condition which often manifests as an abscess around the anus

Cornea = transparent tissue covering the eye that is essential in vision

These stem cell therapies have been extremely challenging to develop: scientists have been investigating stem cell therapies for decades and these products have only been approved in the past 10 years for a limited number of diseases. There are thousands of clinical trials worldwide investigating the clinical benefit of stem cells for diseases such as heart failure, stroke and diabetes. Unfortunately, many of them are showing inconclusive results at this stage and are very difficult to compare. In addition, bringing stem cell treatment to the market will face additional challenges from a manufacturing perspective. We may have had standards for research and manufacturing of small molecule therapies but bringing cells into the picture will require a lot of process optimisation and standardisation, because they are alive and living things tend to have many more sources of variability. Finally, the regulatory framework of various markets is constantly evolving in this era of advanced treatments (including stem cells), and guidelines may change as we learn more about the nature of this therapy. This means that stem cell therapy programs will have to be flexible and adapt to the changing regulations.

Overall, stem cell therapy is clearly an extremely exciting field with great promises and hopes. However, even if there is plenty of research focused on this field and a lot of media hype, only few made it successfully through the scrutiny of pre-clinical and clinical testing to be approved by regulatory bodies. It is still a very recent development in the healthcare space, and much more research needs to be done to understand how stem cells work before these ground-breaking therapies are widely available and become the new standard.

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