A revolution is occurring in the treatment of leukaemia. While more than 80% of children diagnosed with leukaemia will be cured, the treatment options of the remaining 20% have been close to none. However, an exciting new treatment called T-cell therapy has been shown to dramatically improve the prognosis of terminally ill leukaemia patients who may only have a few months to live.
These superlatives do not appear exaggerated since numerous studies have reported that 80–90% of participants with acute lymphoblastic leukaemia (ALL) have seen symptoms vanish completely. T-cell therapy is a new class of treatment which augments the response of the patient’s own immune system to help it recognise and fight the cancerous cells.
Like all cancers, leukaemia is a disease caused by some of the body’s cells growing and dividing uncontrollably. Confusingly, in the case of leukaemia, the rogue cells happen to be some of the white blood cells that normally patrol the body looking for bacteria, viruses or cancer cells.
Normally, potentially malignant cells which are detected by the immune system are programmed to self-destruct. However, cancerous cells can look like normal cells, so the body does not recognise them as foreign and no immune attack occurs, leaving the cancer cells free to grow.
Chemotherapy drugs, alone or in combination, are used to kill most types of leukaemia cells. After chemotherapy patients are sometimes given blood, platelets or even a bone marrow transplant to help replace damaged cells.
Definitions
Antibody
Little protein tags which will stick very specifically to a target. Antibodies are produced by the immune system to identify and kill things such as bacteria and viruses.
Antigen
A substance which the immune system recognises as foreign; it is capable of producing a specific immune response – often something on the outside of an invading bacteria or virus.
Receptor
Most cells have specific proteins on their surface which can lock onto passing molecules. When something binds to the receptor it passes a signal to the inside of the cell so the cell can respond.
T-cell receptor
Every T-cell has a specific set of receptors on its surface which are on the lookout for a particular antigen, in other words a particular threat. When that specific antigen is bound to the T-cell it kicks the T-cell into action.
Q&A
In order to understand T-cell therapy, we need to consider a few frequently asked questions regarding white blood cells, immunity and immunotherapy:
What are white blood cells?
There are a few types of white blood cells which we need to know about:
• T Lymphocytes (also known as T-cells) cruise around looking for things which might harm the body such as viruses, bacteria or any foreign cells (e.g. transplant). Each T-cell is on the lookout for a particular threat and has one specific set of receptors on its surface which are on the lookout for one specific antigen. When the receptors bind to that particular antigen it kicks the T-cell into action, sending messages to other cells nearby and replicating itself so that the body can fight off the threat.
• B Lymphocytes (also known as B-cells) are responsible for producing antibodies.
• Natural killer cells (what a great name) attack and kill certain tumour cells and virus-infected cells.
• Granulocytes ingest foreign cells such as bacteria, viruses and other parasites.
• Monocytes carry out surveillance for the immune system.
How do T-cells contribute to immunity?
T-cells are produced in the bone marrow and go to a sort of ‘finishing school’ in the thymus where they start producing their own particular surface receptors. T-cells continuously patrol the blood and lymphatic system looking for trouble.
When a receptor on the T-cell binds to their particular antigen it initiates a cascade of events that activates the T-cell. Activation causes the T-cell to divide and produce copies of itself and also to produce effector T-cells which help to kill the intruder and memory T-cells which recognise the intruder if it shows up again in the future.
The effector T-cell releases cytotoxic proteins which act on the intruder cell, eventually killing it. Once the intruder cells have been eliminated the effector T-cells disappear, whilst memory T-cells remain and can retrigger the cycle if the antigen reappears.
What is immunotherapy?
Immunotherapy is a treatment that enables the body’s immune system to detect and destroy cancer cells more effectively.
Monoclonal antibody-based treatments are one example of immunotherapy. Monoclonal antibodies have successfully been developed to target specific antigen features on leukaemia cells. For example, rituximab (Rituxan®/MabThera®), ofatumumab (Arzerra®) and obinutuzumab (Gazyva®/Gazyvaro®) are now commonly used, alone or in combination with chemotherapy, to treat leukaemia. The antibodies stick to cancer cells and help the immune system home in and attack.
T-cells and immunotherapy
T-cells, with their specific receptors, can recognise and eliminate intruder cells, but are unable to recognise some cancer cells because they do not look foreign (remember they are just normal cells which have turned to the dark side). However, if receptors on the T-cell are modified so they recognise receptors on the outside of cancer cells, then the natural power of the T-cell can be unleashed on the cancer cells. It is this process that is now being used so successfully to treat patients with advanced leukaemia (see Figure 1).
For the engineered T-cells to have maximum impact, identification of a good target antigen is key. Ideally the antigen targeted would only be found on cancer cells. To date, most have been designed to recognise a specific protein on the cancer cell surface called CD19. However, a downside to targeting CD19 is its presence on both cancerous B-cells and normal B-cells – more on this later.
Figure 1: T-cell therapy for advanced leukaemia patients
Evidence
Remarkable success has been demonstrated using engineered T-cell therapy to treat blood-borne tumours. Numerous clinical trials have been conducted to target the B-cell-specific antigen CD19; complete remission rates as high as 90% have been routinely reported in patients with ALL who had not previously responded to treatment, or were suffering a relapse.
These results are unprecedented in patients without other curative options. Whilst clinical trials have been small, the results demonstrate the principle of this type of immunotherapy. The number and size of clinical trials continues to increase which will facilitate our understanding of T-cell therapy. Already the engineered T-cells have been found to persist in the body helping to guard against the cancer reoccurring, which has contributed to long-term remission in several patients.
Side effects of CAR T-cell therapy
While chimeric antigen receptor (CAR) T-cell therapy offers hope for many individuals, it does have some undesirable side effects.
Cytokinerelease syndrome is a potentially fatal condition caused by the death of so many cells. Patients experience dangerously high fevers and substantial drops in blood pressure, but the condition can be managed with steroids.
Another common problem is B-cell aplasia, in which normal B-cells are killed as well as the cancerous B-cells. This condition can be managed by intravenous administration of replacement antibodies.
In June 2016 it was reported that three patients had died during an engineered T-cell therapy clinical study due to swelling in the brain. The deaths do not mean the end of engineered T-cell therapy, but show that this treatment is not a quick fix and researchers are still working to understand its safety and efficacy.
The future
Immunotherapy is attracting a great deal of interest from clinicians, academics and the pharma/biotech industry. Work is ongoing to address the side effect issues, particularly the ongoing damage to healthy B-cells, for example, building an ‘off-switch’ into the modified cells so that they can be eradicated once they have done their job.
Solid tumours pose a greater challenge because the cancer does not consist of individual circulating cells, but is a solid mass which is not easy to access. However, progress is being made and immunotherapy is likely to find niches with treatment of other cancers.
“Currently, each lab is only allowed to culture one patient’s cells at any given time to prevent the risk of cross contamination”
Commercialisation of T-cell therapy is presenting significant challenges to an industry that is used to selling mass-produced drugs; in particular the task of scaling up the highly laborious and technical process of harvesting, manipulating, transforming and multiplying the cells. This requires a lab environment with tightly controlled, good manufacturing practices and arduous quality assurance procedures – including genetic profiling of the cells. Currently, each lab is only allowed to culture one patient’s cells at any given time to prevent the risk of cross contamination, and since it takes almost a month to make each treatment this creates a huge bottleneck.
Human cells dislike being shipped, even when frozen, so it seems likely that a network of regional laboratories will be required to provide treatment across a country. However, despite these challenges T-cell therapy offers an almost miracle cure for some otherwise incurable leukaemias, and hopefully it will find application for treatment of other cancers in the near future.
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