Q&A: PROF JOHN GRIBBEN
Consultant haematologist at The London Clinic on CAR T cell therapy, which has the potential to revolutionise cancer treatment
Interview: Viel Richardson
Portrait: Christopher L Proctor
Where does CAR T therapy sit within the field of cancer treatment?
CAR T therapy is a recently developed form of immunotherapy. The concept was born out of the question, why do T cells—which our immune system uses to identify and fight infections—not recognise and kill cancer cells? It turns out that some cancers can be pretty much invisible to the immune system or switch off the T cells that attack them. With CAR T cell therapy, you genetically introduce what we call chimeric antigen receptors (CAR) into the patient’s own T cells. What’s new about it is the way we are combining the fields of gene therapy and immunotherapy.
What is a CAR and what does it do?
Antibodies are one of the body’s ways of fighting foreign and diseased cells. We have known for some time that we can use these antibodies to treat cancer. We also developed the ability to make in the laboratory antibodies that attack cancer cells. There is a protein in the surface of lymphomas called CD19, for which there is an antibody. The CAR has two distinct parts, each with a different task. The outside of the receptor is the CD19 antibody: this recognises and latches onto the CD19 protein, attaching the T cell to the tumour cell. The other part is inside the CAR T cell, and this sends a signal for it to activate and kill the tumour cell. What the gene we introduce does is ensure that the CD19 antibody expresses on the surface of the CAR T cell and that the T cell is fully activated.
So, you then re-introduce the modified cells to the patient?
Yes. The cell now recognises the CD19 protein on the surface of the lymphoma cell and attaches to it. The tumour cell also cannot switch off the modified T cell. As well as switching on the CAR T cell, another signal instructs the cell to send out a signal for any CAR T cells that receive it to multiply. You then get an extremely rapid expansion of the number of these cells, which then attack other lymphoma cells and, if all goes well, eradicate the cancer.
Is it difficult to introduce the genetic material?
It is quite difficult and there are also several things you need to be very sure of, as with any gene therapy. Once you genetically modify a cell, you have to make sure it does precisely what you want and nothing else. The whole field of gene therapy was put back by years when a gene therapy treatment designed for children with immune deficiency syndrome went wrong. One of the children developed leukaemia and died, because the gene they introduced switched on processes it was not designed to affect. A lot of work was needed to fully understand what the new gene is doing to the rest of the cellular machinery. We are always looking at safer and better ways to introduce new genes.
Have CAR T cells advanced since their introduction?
Yes, they have, and real progress is being made. In fact, the product we are using is second-generation CAR cells. The first CARs recognised and attached to the tumour cells, but activation performance was not what we wanted. This is why we added what we call a ‘co-stimulation’ modification—the part that sends the signal to activate the CAR T cell. There are now third generation CAR T cells and others on the way.
As it is quite new, is access to the treatment limited?
Yes, it is operating under a limited licence at the moment. The CAR T cell we are using at The London Clinic is supplied by a company called Gilead Sciences and is licensed to treat two conditions: diffused large B-cell lymphoma and primarymediastinal lymphoma, two subtypes of non-Hodgkin’s lymphoma. There is another CAR T cell that has been licensed to treat acute lymphoblastic leukaemia, but we are not using that treatment here as yet. The license also places limitations on the patients we can treat. At the moment, it is for people for whom chemotherapy and stem cell transplant therapy have failed, or for people who were not fit enough to have a stem cell transplant. These are cases where the prognosis is very poor. One very large study suggested that 95 per cent of these patients would otherwise die within a year.
Some people have concerns about genetically modifying cells. How safe is this procedure?
Everyone is very focused on making this as safe as it can be. The geneticists are working very hard to ensure that the introduced gene does not integrate into the normal part of the genome in ways that cause unintended genetic switching within the cell. Also, the way this gene is delivered into the T cells means it should never migrate to other cells, and so far no-one has found any evidence of the gene migrating elsewhere. In fact, the gene modification remains restricted just to the CAR T cells and has not been found in any other T cells in the immune system.
How effective is this therapy?
After this treatment, the condition of around 50 per cent of patients stops deteriorating, then plateaus. This is a real advance, but we still have much to learn. As the treatment is relatively new, we do not have longterm follow-up data on a large cohort of patients. However, we know that these can be aggressive diseases that tend to return quite quickly, so having patients who have been on that plateau for several years is hugely encouraging. We cannot say they are ‘cured’, because we do not know what will happen 10 or 20 years into the future, but at the moment the data from the test results is stable. This is especially encouraging because if the patient responds as we hope, we are unlikely to see a very late return of the cancer. There are no guarantees, but the fact that there is some uncertainty about the future is still a vastly better scenario than we have ever been able to offer these patients before.
Are there side effects?
When we give the CAR T cells to a patient, there is a 1,000-fold increase in the number of cells. The cells trigger this expansion through chemical signalling using proteins called cytokines. The scale of this chemical release can lead to something called cytokine release syndrome, as this flood of chemicals enters the patient’s system. Patients can get high spiking fevers, feel very flulike and extremely unwell. In some individuals, the effects can be serious enough for them to need careful monitoring in an intensive care unit. There is also a second potential problem: a neurological toxicity that significantly impairs the patient’s ability to think clearly. What seems to happen is that the brain swells. This needs medication to combat, requiring time in an ICU. You need a neurologist involved in monitoring patients during treatment as part of a multidisciplinary team.
How dangerous can these side effects be?
When you can support the patient through both these side effect complications, as is the case here at The London Clinic they are fully reversible. A longerterm side effect is caused by the fact that the CD19 protein we are targeting is also expressed on your normal B cells, which are a type of white blood cell that works as part of the immune system by secreting antibodies. The treatment can deplete the patient’s healthy B cells, leaving them with low antibody levels and more prone to infection. Some people need to have immunoglobulin replacement therapy until these B cell levels recover.
It seems extended multidisciplinary support is vital?
Absolutely key. The treatment would not work without it. In fact, in order to get approval to offer this treatment, the company that produces the CAR T cells has to visit and evaluate your facility. A very rigorous inspection process takes place to ensure that you have all the clinical and technical resources in place to offer the necessary support. Gilead Sciences inspected The London Clinic as part of our approval process.
How often do you have to give the modified cells to the patient?
You only plan to give it once. This is because the cells multiply enough to eradicate even large amounts of tumour. T cells are also very long lived and ideally will be around long enough to kill all the cancer cells. After this, they either disappear or fall back to very low background levels and become part of the normal immune surveillance system. The huge advantage over chemotherapy is that while chemotherapy kills the cancer cells, it only lasts a day or so, leading to repeat treatments.
Is this treatment chemotherapy-free?
No, and it is extremely important for potential patients to realise this. We have to use chemotherapy to kill some cells and create room for the implanted CAR T cells to expand into. If we don’t, they die out, so a small dose of chemotherapy at the beginning is a vital part of the process. It also reduces the patient’s own immune system, so it doesn’t fight the new cells. Another factor is that these can be very aggressive cancers and the patient may need chemotherapy to keep their situation stable while their T cells have been sent away to be modified, which can take several weeks.
What excites you about this treatment?
The ability to adapt the patient’s own immune system to fight cancers is hugely exciting. While chemotherapy can be very effective and has saved many lives, it is a very toxic process which can take a real toll on some patients and be too much for others to go through. CAR T cell therapy is one of a group of therapies called adoptive cellular therapies, where we make targeted modifications to the patient’s immune system to fight specific cancers. We are in the very early days, but this could be transformative for cancer treatments. It will be a long and difficult road to get there, but I can see a time when we will look back at the use of toxic chemotherapy chemicals in treating cancer in the same way as the concept that leeches were once considered good medicine. Now we wonder how anyone ever thought that.