THE HUMAN BRAIN
Your brain contains billions of auxiliary cells which ensure that your nerve cells work, but these cells can develop into cancer. Scientists have developed a strong weapon against sick cells.
In part one of a new series, we find out how scientists are training dedicated armies of immune cells to seek out cancer cells deep inside the brain.
Behind your skull, a huge army of nerve cells is at work. This is made up of 86 billion soldiers – but even this number does not give it a majority. Hidden between the nerve cells is another army that matches their numbers, an army of different cells with long, thin arms that wrap around nerve cells and blood vessels: the auxiliary cells of the brain.
The auxiliary cells decide which substances are allowed to enter and exit the brain; they supply the nerve cells with energy, make sure that the brain can send signals, control nerve cell activity, and protect the brain against viruses and bacteria. They are completely indispensable — but they could turn against you. About seven in 100,000 people each year develop severe brain cancer, and the auxiliary cells of the brain probably cause 80% of these cases.
Mutations can rapidly convert these important cells into cancer cells, and doctors lack efficient weapons to combat the cancer. Less than 10% of patients live more than five years after the diagnosis.
But a new treatment is being tested on people. Scientists send a group of highly 'trained' immune cells into the patient, and the focused elite unit seeks out the brain tumour, attacking the cancer cells. Early results are promising.
Barrier slows down medication
The brain’s auxiliary cells include a number of different cell types such as immune cells (microglia), oligodendrocytes that function as insulation of the brain’s electric circuits, and astrocytes, which carefully control the substances to which the nerve cells have access. Moreover, the brain contains different types of stem cells, which supply new auxiliary cells. Mutations in stem cells or
astrocytes are the most common causes of aggressive brain cancer.
The mutations make the cells divide out of control until they destroy the tissue around them – and in many cases, the result is death. Patients with brain cancer are generally worse off than other cancer patients, partly because it is difficult to perform brain surgery without harming healthy tissue or important blood vessels, and partly because the brain has a defence, the blood-brain barrier, that keeps out many drugs. The barrier surrounds the brain’s blood vessels and consists of close-set cells that only allow specific substances to pass from the blood into brain cells. Water-soluble substances such as salts have particular difficulty passing through the blood-brain barrier, whereas fatsoluble substances such as oxygen can pass relatively easily. The aim of the barrier is to
ensure the best conditions for the cells of the brain, but it is also the reason why 95% of the drugs that are tested in the struggle against brain diseases fail.
However, the challenges of brain cancer may not be impossible to overcome. Scientists are busy testing a new treatment that actively seeks to pass the brain’s barrier, attacking the cancer cells without harming healthy tissue.
Scientists train immune cells
Today, doctors have three weapons against brain cancer. The first one is surgery, usually an option only if the disease is discovered early. Surgeons must be extremely careful when they operate, and it can be difficult to remove all cancer cells, so the surgery is often supported by two other weapons – radiation and chemotherapy – which are aimed at killing the remaining cancer cells. Unfortunately, none of the treatments are very efficient, and only about 4% of the patients with the most aggressive type of brain cancer, gliobastoma, live for more than five years after the diagnosis.
So, cancer researchers throughout the world are now developing a fourth weapon for doctors: immune therapy. The treatment uses immune cells to kill the cancer, and in 2018 a variant of the treatment earned its inventors a Nobel Prize. Scientists can inject substances into the patient to activate the immune cells, or they can extract immune cells from the patient and train them to recognise specific proteins on the surface of the cancer cells. The immune cells are able to seek out and kill the tumour, sparing healthy tissue in the process. The method has proved to be efficient, and several types of immune therapy have already been approved.
The problem is that the treatment rarely kills all cancer cells, so that the cancer begins to grow again after a while. One possible explanation is that the immune cells have so far been trained to recognise only a few proteins on cancer cells. But the cells in a tumour can vary, and so there will often be some cancer cells that do not have the proteins which the immune cells have been trained to spot. These cells survive, and might begin to produce a new cancer tumour.
A new type of immune therapy developed by a group of Danish scientists, including physician Walter Fischer, could possibly solve the problem. The scientists train immune cells from the patient to recognise a long series of proteins on the cancer cells, and the likelihood of some cancer cells escaping this attack is smaller. The treatment has already produced promising results in human patients.
Cancer tumours shrink
Twenty-five patients volunteered to try the new immune therapy developed by Fischer and his colleagues. No previous treatments had effectively combated their brain cancer, and they had only a few months left to live. Fischer’s experiment was a phase 1 trial, its primary aim to study side effects, and the treatment involved three injections with immune cells over a period of five months. Unfortunately, only 10 of the patients survived long enough to complete the entire planned treatment. Seven of these continued the treatment, receiving more injections. The cancer tumour in one of the patients stopped growing, and in three other patients, tumours began to shrink considerably.
Major improvements in patients with advanced brain cancer are rare, and the phase 1 trial shows that the new immune therapy apparently succeeds without substantial side effects. While the experiment by no means proves that the treatment is more efficient than previous treatments – that would require a more extensive experiment – Walter Fischer is optimistic. He observed how an elderly woman paralysed by her cancer ended up getting out of her wheelchair. Examinations of her brain showed that 1.5 years after the first injection, the brain was completely free of cancer cells. (Unfortunately, she later died of heart disease. ) An elderly man went from having a huge cancer tumour in his brain to one that was markedly smaller. He became able to play music in his orchestra again, but after a few years his tumour grew back and proved terminal.
The scientists hope that the treatment will have an even better effect on patients where the cancer is not as advanced. So Fischer and his colleagues are now carrying out a phase 2 trial to test the effect of the immune therapy on 40 glioblastoma patients who are at an early stage of their disease. Aside from the immune therapy, the patients also receive a standard treatment consisting of radiation and chemotherapy. To be sure that any improvements in the patients are being caused by the immune cells, the scientists have included a control group of 20 people as part of the new trial, and these receive only the standard treatment.
Many scientists remain sceptical of the new immune therapy, so the results of the phase 2 trial are awaited eagerly by all parties involved. Fischer and his colleagues have already realised that the treatment might include weaknesses, believing that the lack of effect on some patients of the phase 1 trial could be because the cancer launches a counter-attack on the immune cells. This phenomenon is a challenge to all types of immune therapy – but a new discovery might produce a solution.
Gene change helps immune cells
Brain cancer makes the immune system’s killer cells hide in the bone marrow. A new study carried out by US and Japanese scientists has revealed that patients with advanced glioblastoma have very few of the immune system’s T cells in their blood. On the other hand, the T cells accumulate in the patients’ bone marrow – with the result that they cannot combat the cancer. Experiments on mice have also shown that injection of new, fresh T cells does not solve the problem. After 24 hours, these also ended up in the bone marrow. This problem is highly relevant to Fischer’s immune therapy and similar treatments.
The cause of the defective immune system is that the tumour forces the T cells to remove a specific receptor known as 'S1P1' from their surface. Normally, S1P1 helps the T cells find their way from the lymph system into the blood, but without it, they are stuck in the bone marrow. To solve the problem, the scientists created genetically-modified T cells that could not remove S1P1 from their surface. When the cells were injected into mice with cancer, they remained in the blood instead of hiding. Other types of genetically-modified T cells are already used in the struggle against cancer, so it is not unlikely that in the future we will see treatments against brain cancer that combine gene editing of S1P1 with the immune cells from Fischer and his colleagues.