First published in our Biotech Review of the year – issue 9.

What are cell therapies?

In the simplest of terms, one can think of cell therapies as living medicines. Traditional medicines work by directing and inducing a patient’s own cells, whereas cell therapy uses live cells that are injected or grafted into a patient where the cells work locally or systemically to restore the function of tissues or organs. Cell therapies can be used where a patient’s cells are compromised, or insufficient in numbers, and may bring significant improvement to a patient’s life or even be curative, depending on the condition being treated. Cell therapies can therefore be life-changing, but as a specialised treatment, every step of their development and use is expensive. However, because cell therapies are often used as a last resort in select patient populations after all other treatments have failed or where none are available to begin with, the cost-benefit ratio may be favourable.

How do cell therapies work?

The basic concept of cell therapies is to take healthy cells and implant them into a patient to cure or alleviate symptoms of a disease. In principle this is simple, however, getting to a stage of having suitable cells in sufficient amounts and of sufficient quality is extremely challenging. It may help to think about what the point of the therapy is: to make the transplanted cells do something that cures (or treats) an illness or condition. Cell therapies are powerful tools, but there are also significant risks. Cells used in cell therapies have the potential to transform into malignant cells, migrate to sites outside of the target area or tissue and can generate unwanted immunogenicity. Unsurprisingly, the mitigation of such risks is a core element in the applicable regulatory environment.

Sources of cells for cell therapies

There are two sources of cells for cell therapy; autologous and allogeneic cells. Autologous cells are harvested from a patient, stored, and treated before being re-implanted into the same patient, whereas allogeneic cells are harvested from a healthy donor before processing and implantation into a patient. A third form of cell therapy, xenogeneic, is possible where the cells to be grafted come from a different animal species. Currently, xenografts are limited to research settings in which human cells are transplanted into other species, but with the hope that, if problems such as rejection and endogenous retroviruses can be overcome, this methodology can be reversed and animal cells be used safely and effectively in the treatment of humans.

One of the benefits of autologous cell therapies is that the immunogenic response is minimal as the patient is being administered their own cells. This form of therapy is therefore particularly suitable for immunocompromised patients. However, unless the cells can be procured and re-implanted within the same surgical procedure, autologous therapy is by no means straightforward, because the therapy must be customised for each patient. The cells must be collected, processed to achieve the desired population, and then re-implanted. Following harvest, the cells may require weeks of isolation in culture and expansion before there are enough that are suitable for treatment, with each step between procurement and implantation conducted under strict quality and safety conditions.

This is time-consuming and there is no guarantee that a sufficient amount of cell product will be produced, nor that it will be available in time to treat a patient with an aggressive form of disease. Another drawback of autologous cell therapies arises from the fact that they are personalised for each patient so that the time and cost cannot be shared between patients by scaling the operation. Traditional quality and effectiveness testing is always applicable, but the relevant question is whether they make sense for all personalised cell therapy medicinal products. Despite this, there have been major advances in autologous therapies in the last few years, most excitingly CAR-T therapy, the first approved genetically modified cell therapy.

In contrast to autologous therapies, allogeneic cell therapies use cells harvested from a healthy donor, after which the cells are cultured and scaled to produce large amounts of cells over time. This can result in an off-the-shelf product that can be used for multiple patients. The drawback of using cells that are not the patient’s own is that a patient who receives allogeneic cells will need to undergo immunosuppressive therapy to prevent serious immunological complications such as graft versus host disease. Some of the benefits associated with the use of allogeneic cell therapies are the immediate availability of cultured cells and the availability of having multiple donors on file to match patients as well as possible. If allogeneic cell therapies can be sufficiently refined to be effective, and their manufacturing scaled appropriately, there might be a shift from using autologous to allogeneic cells in therapies. Although scaling may be done in theory and large batches of cells cultured, new issues arise such as the functional heterogeneity inherent in cells which introduces variability between batches of cells, and which will likely affect functional responses in patients.

Manufacturing

The manufacturing process for cell therapies is complex and highly specialised. Cell cultures are temperamental and can currently only be produced manually and in small batches, although there are attempts to automate the production. There is also a major manufacturing bottleneck around talent: a shortage of people qualified in cell therapies at all levels, from technical staff manufacturing the cells to scientists and clinicians. Another issue is around the facilities for the production of cells which are highly regulated environments to ensure microbiological purity of the cell-drug product.

This brings logistical issues. As an example, for patients in the EU who are to receive Novartis’s therapy Kymriah, the process involves harvesting autologous cells from patients in the EU, flying them to the USA for transformation into treatment cell therapy product, and then flying them back to be re-infused to patients as treatment. Due to the specialised facilities required, manufacture of cells is only done in a select few places. Manufacturers have been trying to address some of the bottlenecks. As an example, Novartis recently invested $90 million in a cell and gene therapy factory in Switzerland to establish an EU facility[1].

As with most areas of life, COVID-19 also touched upon cell therapies. The viral vectors used in their production are also used in vaccine production, as is explored elsewhere in this year’s Biotech Review. Viral vector manufacturing is already at capacity, and demand is unlikely to decrease in the next few years. There is therefore an urgent need to implement scaling of viral vector production to increase their yield as soon as possible to enable increased cell culture manufacturing capacity.

The regulatory environment of cell therapies

The regulatory landscape for cell therapies varies from country to country, which in and of itself is problematic for the development of therapies, standards, and clinical trials.[2] In the EU, cell therapies the manufacture of which involve substantial manipulation are regulated as ‘Advanced Therapy Medicinal Products’ (ATMPs) for purposes of medicines law[3]. There are three types of ATMPs: gene therapy medicinal products, somatic cell therapy medicinal products and tissue-engineered products. In addition to needing to meet the donation, procurement and testing requirements of the EU’s blood cell and tissue regulations,[4] they are also regulated by the ATMP Regulation[5]. Before being brought to market, all medicines (including cell therapies) must be authorised by the relevant regulator: getting a marketing authorisation is demanding, especially when it comes to ATMPs[6]. In the UK the licensing authority is the MHRA; in the EU, applications are addressed centrally, to the European Medicines Agency (EMA).

Are cell therapies correctly classified as ATMPs?

The problem is that although the ATMP Regulation accommodates cellular and genetic medicinal products within the European medicines regime, they do not quite fit a framework designed around mass-market pharmaceutical products. For example, when the Regulation was proposed in the early 2000s, embryo-derived cell products and other allogeneic products were expected to dominate. Things have, however, turned out quite differently. Most therapies are not derived from embryonic cells, and the vast majority of them are based on the patient’s own cells[7].

The awkwardness of the ATMP Regulation becomes apparent as soon as one thinks of autologous cell therapies: products designed and manufactured solely for one person. As the ATMP Regulation is intended to govern products placed on the market, can it truly be said that a product like cell therapy intended for one person is truly placed on a market? Despite this, autologous therapies do get authorised, but is the process fit for purpose? With the development of more accessible cell therapies, there seems to be a gradual acceptance that the current framework needs to be reconsidered. After MEPs approved, in November 2021, a new EU medicines strategy which expressly refers to the position of new and innovative medicines^[8], we anticipate that the European Commission will publish proposals in due course. Whether these address such issues remains to be seen. There are no plans for Great Britain.

The EU’s blood cell and tissue regulations[9] already address quality and safety frameworks for cells, so is it legitimate to argue that the autologous cell therapy market would be better regulated as a service than based on a framework for mass-market products? Some of the fundamental questions asked during market authorisation preparation for mainstream small molecule medicines are questions such as, “what is the mechanism of action?” and “what is the dose?” But questions such as these do not fit products like cell therapies where the mechanism of action is the cells themselves. The European Commission is undertaking a review of the blood cell and tissue regulations, although as above, there are no plans for Great Britain.

Trends in the coming years

With the scientific advances made in recent years, we are likely to see increased use of personalised medicine and cell therapies in the coming years. There are currently over 1,300 active cell therapy clinical trials globally, with the majority of trials being CAR-T cell therapies[10]. Although increased use and development of these therapies will require manufacturers to address the manufacturing bottlenecks to meet growing demand, one can be positive about future developments. In parallel, regulatory authorities will need to address the inappropriate classification of cell therapies to enable their use. As therapies for more conditions become available, the cost of therapies and how health systems cover them (or not) will likely be a heated subject.

[1] Novartis’s $90 million Swiss factory to help solve cell therapy bottleneck | Reuters

[2] Two Decades of Global Progress in Authorized Advanced Therapy Medicinal Products: An Emerging Revolution in Therapeutic Strategies (nih.gov)

[3] Regulation 726/2004/EC, Regulation (EC) No 1394/2007, and Directive 2001/83/EC

[4] Directive 2002/98/EC and Directive 2004/23/EC

[5] Regulation (EC) No 1394/2007.

[6] https://www.gov.uk/guidance/advanced-therapy-medicinal-products-regulation-and-licensing

[7] The development of stem-cell-based embryo models may make even embryos unnecessary.

[8] See https://www.europarl.europa.eu/doceo/document/A-9-2021-0317_EN.html#title1 (paras 96 to 102); and https://www.europarl.europa.eu/doceo/document/ENVI-PR-681109_EN.pdf

[9] Directive 2002/98/EC and Directive 2004/23/EC

[10] https://www.nature.com/articles/d41573-021-00100-z