That the body’s own immune system can fight off cancer was discovered in the late 1980s, knowledge that inspired new studies. In brief, the idea was to remove immune cells (T-cells) from the patient’s tumour and multiply them in the lab, and then return them a few days later. In a small number of cancer patients, this treatment resulted in the shrinking of metastasised tumours. In the subsequent decades, the technology was developed further into CAR T-cell immunotherapy.
This therapy is built around the patient’s immune cells (figure 1). The first step is the isolation of T cells from human blood, using a blood cell separator. The cells are transported to a special processing facility. An extra piece of DNA is built into the cells, allowing them to better recognise and clean up tumours. Subsequently, the modified cells are given some time to multiply, until there are millions of them. The live cells are transported back to the hospital and given back to the patient via an infusion.
Combatting diseases with the patient’s own cells is the ultimate example of personalised medicine: a single person is the supplier of the starting material for the manufacturing process and the recipient for the final product. This process is significantly different from common manufacturing and logistics processes for pharmaceutical products, where a medicine is made for thousands of patients.
White blood cells are taken from the patient.
T cells are isolated from these white blood cells.
The T cells are transported to a facility where they are genetically modified.
They are given an additional piece of DNA coded for CAR (chimeric antigen receptor), which will later be able to detect cancer cells.
Then millions of T cells are cultivated at the facility until they are sufficient in number for a treatment.
The cells are then transported to the hospital.
They are administered to the patient by infusion.
Thanks to the integrated CAR gene, the newly formed CAR T cells are able to detect certain proteins on the exterior of the cancer cell (antigens). The CAR T cells then bind to the cancer cell and kill it.
In the autumn of 2018, two CAR T-cell therapies were authorised in Europe for the treatment of specific blood tumours that do not respond to other medicines. These CAR Ts are classified as ATMP: Advanced Therapy Medicinal Products, a new generation of medical therapies based on cells, genes, tissues or a combination thereof. The patient’s own cells or tissues are often the starting point. ATMPs are interventions at the gene, cell or tissue level that aim to provide a permanent solution to a wide range of conditions, such as cancer, eye conditions, blood coagulation disorders or joint complaints.
A characteristic of cell and gene therapy is that they can add (for example missing) genetic properties to cells that have a direct effect in the patient’s body. They can add additional properties, or block existing properties. In gene therapy, the patient’s genetic code is modified. This allows errors in the DNA to be repaired (figure 2). Errors in the DNA can lead to incorrect or blocked protein creation in a cell. If this protein plays an important role, lack thereof can lead to severe, sometimes even lethal conditions. The technology can also be used to give cells a boost. This is used to treat cancer, where gene therapy is used to strengthen the patient’s immune system. Cell therapy is the administration of viable, often purified cells in a patient’s body in order to grow, replace or repair damaged tissue. These cells may be obtained from the patient, or from a donor. Many cell therapies are being developed with the use of stem cells. These are cells that can divide and specialise into specific cell types. Tissue technology attempts to repair, maintain, improve or replace damaged organs and tissues.
Over 900 companies worldwide are working on new cell or gene therapies, over 200 of which are located in Europe. Together, they are running over one thousand clinical trials. In mid-2019, 93 of these studies were in the final phase prior to marketing authorisation. The main goal is finding applications for various forms of cancer, cardiovascular diseases and nervous system disorders.
OVER 1,000 CLINICAL TRIALS WITH CELL AND GENE THERAPIES ARE BEING CONDUCTED WORLDWIDE.
Through mid-2019, fourteen cell and gene therapies have received marketing authorisation in Europe for a variety of conditions. These include a gene therapy product that is injected into the eye, intended for patients that gradually go blind due to an inherited condition. The therapy includes a virus-like particle containing a gene that can add missing properties to cells. After injection in the back of the eye, the crippled virus penetrates the light-sensitive cells and helps them work better. Eyesight is not completely restored, but patients can distinguish objects in their environment more easily and their mobility is improved.
A second example of an authorised new therapy is a tissue therapy product for repair to damaged knee cartilage. This development is particularly useful for younger people who have had an accident or an athletic injury. Treatment begins with an arthroscopy, during which a small cartilage sample is collected and then cultured in a laboratory. Next, a mixture of balls of cartilage cells are injected into the damaged area during a second arthroscopy. The cells grow in place and over the next months contribute to the repair of the cartilage.
A similar technique is used to treat patients with a damaged cornea, the transparent layer on the outside of the eye. Normally, stem cells repair the cornea continuously, but if the damage is too great – for example due to burns or accidents with caustic substances – they can no longer manage. This affects eyesight. During treatment, a square millimetre of cornea is removed from the patient’s eye and grown in the laboratory. The cells are then placed on a transparent protein membrane and sent back to the hospital. Once returned to the eye, the cells continue to multiply and grow into a new cornea.
As of a few years ago, children who are highly susceptible to simple infections due to a deficient immune system (ADA-SCID) can be treated with a gene therapy product. Stem cells are collected from a patient’s bone marrow and modified genetically in the laboratory. This corrects the errors present in the body’s own bone marrow stem cells. Once they are placed back, patients develop a normally functioning immune system and are less prone to severe infections.
The recent new applications will be joined by a growing arsenal of advanced therapies in the coming years. There is a great deal of focused scientific interest, which is only expected to grow further. A review performed in early 2019 revealed over one thousand studies involving cell and gene therapy, most of which were in early stages of development, with over ninety studies in the final phases.
New cancer therapies are at the top of the list, with over six hundred clinical trials, followed by cardiovascular disease and nervous system conditions. Many of the conditions are rare, but research is also being performed into cell and gene therapies to cure HIV, or common hereditary conditions such as the blood disease thalassemia.
Most of these applications are being developed for life-threatening and disabling conditions, for which there is currently no good treatment, or which require regular hospital admissions. Cell and gene therapy often cures diseases, or at least results in a long-term improvement in quality of life. These properties are also reflected by the proportion of these new therapies in the PRIME list of the European Medicines Agency (EMA). PRIMA is an EMA programme designed to stimulate the development of innovative medicines. In mid-2019, the list included eighteen cell and gene therapies, including multiple products for hereditary blood conditions (haemophilia) and novel treatments for cancer.
With PRIME, the EMA wants to improve the chances for marketing authorisation for these new medicines, by consulting with the developers and cell and gene therapies at an early stage. This gives the EMA the opportunity to advise on the design of clinical trials, to ensure the correct data is provided and thus improve the chances of marketing authorisation. Clinical trial data also play a crucial role after marketing in discussions of added value and the cost of a new therapy.
While medical prospects of this new technology are often promising, introducing these therapies into everyday care for patients has proven difficult. There are various reasons for this, varying from manufacturing difficulties for the medicine, to organisational hurdles within the hospital and long debates about coverage for these therapies by insurance. This has even led to the withdrawal of marketing authorisation for four cell and gene therapies. These medicines are no longer available to patients.
This illustrates that innovative therapies do not necessarily become success stories following successful marketing authorisation. Acceptance and inclusion in daily practice, gradual growth in market share and turnover, and societal acceptance are not self-evident.
This is caused in part by the radical innovation represented by cell and gene therapies, which deviates strongly from traditional medicines. It has proved difficult to integrate these new applications within the traditional pharmaceutical frameworks which have been developed over the course of decades. There is a major difference between formulating a medicine based on an active substance, or transforming a patient’s cells into a medicine. There is little experience with previous authorisations.
The challenges not only lie in cell and gene therapies themselves, but also in the processes surrounding them, involving cells, viruses or a combination thereof. The starting point for these medicines are cells that are transported for a long stay in a laboratory or factory, and then finally returned to the hospital. Activities are performed at different locations, and logistics require good planning, training, checks and communication. Designing and certifying such a facility with strict requirements (in accordance with Good Manufacturing Practice, GMP procedures) and all processes inside and outside the laboratory is complex.
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