Cancers kill around 160,000 people per year in the UK, with blood cancers (including leukaemia, lymphoma and myelomas) accounting for more than 13,000 of these. Although improvements in survival rates are being seen for many types of cancer, broad-ranging revolutions in treatment are few and far between. An exception to this appeared last year when patients in England became the ‘first in Europe’ to have access to two novel treatments for blood cancer, after they were approved for use on the NHS. These treatments are a form of regenerative medicine known as CAR-T (chimeric antigen receptor T-cell) therapies, and rely on genetically modified immune cells to fight a patient’s cancer.
Regenerative medicines for personalised treatments
Regenerative medicine (RM) featured as one of the PHG Foundation’s key transformational technology areas in our recent report ‘The personalised medicine technology landscape’. We described that although these highly personalised treatments have potential, they are technically complex to produce and the result of many years’ research effort.
Broadly speaking, RM therapies aim to replace, repair or regenerate the body’s cells, tissues or organs for the treatment of disease. Cancer immunotherapies are a broad class of RM therapies that use and modify cells of the body’s own immune system to detect and attack cancerous cells. These treatments make use of several sophisticated techniques, including genome editing, to generate cancer-fighting cells personalised to the patient.
A selection of the patient’s own, or a donor’s, T-cells are extracted from blood and genetically modified in the laboratory to express a particular protein on their surface. These modified cells are then reintroduced into the patient – where the modified protein allows them to better target and destroy the patient’s cancerous cells.
CAR-Ts for patients
In September 2018, the NHS announced that it would be providing the CAR-T therapy Kymriah for the treatment of B-cell acute lymphoblastic leukaemia (ALL) in children and young people. This represents one of the fastest funding approvals in NHS history, perhaps reflecting the promise of this rapidly advancing therapy area alongside clinical need. This was followed in quick succession by approval of a second CAR-T therapy, Yescarta, for the treatment of diffuse large B-cell lymphoma (DLBCL) in adults.
However, these therapies take time to develop and to personalise for each patient; when the patient’s own cells are used, it can take weeks for the treatment to be ready for application.
Because these therapies are adapted to the individual patient, there is reduced risk of rejection. In addition, the cells specifically target the cancerous cells, avoiding substantial harm to healthy cells. The modified T-cells are able to duplicate inside the patient, and the population can persist for some time, continuing to target the cancerous cells. In addition, the method by which T-cells operate allows them to signal to other immune system cells and bring them to the fight. However, these therapies take time to develop and to personalise for each patient; when the patient’s own cells are used, it can take weeks for the treatment to be ready for application. Advances in ‘off the shelf’ therapies using donor cells could facilitate the treatment of larger numbers of patients and are an active area of research
Benefits and challenges – more to do
Currently, treatments are intended to be given as a one-off and may also act as a ‘bridge’ to help move patients onto other treatments such as stem cell transplantation. Although relatively new, these treatments have shown to be successful in cases of advanced cancer where other treatments have failed. This is not to say that CAR-T therapy use comes without risk. At present, they can only be administered at specialist centres, due in part to the risk of potentially life-threatening side-effects such as cytokine release syndrome - where an excessive release of cytokines from the modified cells causes the immune system to ‘overreact’, resulting in symptoms such as fever and low blood pressure.
Although these treatments may offer hope for patients for whom other therapies have proven unsuccessful, they do not produce positive outcomes for every patient. More work is needed to fully understand how these therapies work in patients so that they can be refined and practitioners can better determine where they are more likely to produce positive outcomes. As with many new treatments, the base of evidence for these and other regenerative medicines is not as well established as for conventional treatments and there are gaps in understanding around efficacy and potential use in treatment of other cancers.
Developing delivery infrastructure
In the UK, steps are being taken to make delivery of these therapies a reality, for example through the establishment of more treatment centres. A long-term perspective will be required though, since the development of both infrastructure and expertise takes time.
Personalised treatments, like CAR-Ts, are expensive to develop and consideration should be given to reimbursement strategies to incentivise and support developers. In addition, therapy trials are (at least initially) likely to be conducted on a much smaller scale than for conventional treatments, meaning that evidence needs to be considered differently, sometimes down to a participant number of one. Once new treatments are approved, the health system will need tolook at delivery,and how to make the most of current infrastructure and pathways and ensuring that strategies can be easily modified for different types of therapy.
In time, more cancers are likely to be targeted by this type of therapy; investment is being made, but it remains to be seen whether techniques can be adapted to effectively target solid tumours or additional blood cancers. This is an exciting time not just for cancer treatment but also for the RM field as a whole and the next few years will be key to laying the foundations for the more standardised delivery of these therapies in years to come.