A team at University College London Hospitals (UCLH) has become the first in the UK to administer chimeric antigen receptor (CAR) T-cell therapy to a multiple sclerosis (MS) patient.
Emily Henders, 37, received the therapy as part of the global AUTO1-MS1 trial, which is one of the first of its kind in the world.
the limbic spoke to Dr Frederick Vonberg to find out about the procedure and how it might impact clinical practice in the future.
Dr Frederick Vonberg
Can you describe how CAR T-cell therapy works?
CAR T is a new and exciting treatment which has been amazingly effective for B-cell malignancies. First you extract a patient’s T cells, then genetically engineer them to express a chimeric antigen receptor, which is a receptor that can be directed against any antigen of your choice. This is usually a B-cell antigen, most commonly CD19, but it could also be a B-cell maturation antigen.
You then mature the T-cells in the lab and infuse them back into the patient, where they expand, recognise the target antigen – in this case a B-cell – and then secrete mediators to destroy it.
Can you describe the whole treatment process?
The team identified Emily because her disease was progressing despite high efficacy treatments. My team works very closely with the haematology team who run the CAR T service at UCLH. So the haematologist Dr Claire Roddie, Dr Wallace Brownlee [the study lead and MS neurology consultant] and I met with Emily and outlined the concept behind CAR T. After she consented to taking part in the trial, we screened her to determine whether she fitted all the eligibility criteria, which she did.
She then went through the same processes as all patients receiving CAR T. She underwent leukapheresis, where we removed the T-cells and then genetically engineered them to become CAR T-cells, which can take about four weeks. She then had chemotherapy, as we know from cancer patients that the CAR T-cells do best when there’s some immunosuppression to help them to take up residence and begin replicating. Then a couple of days later Emily was infused with the CAR T-cells. After that, the trial mandates that patients remain in hospital for 10 days while they’re monitored.
What are you hoping to find out from the AUTO1-MS1 trial?
It’s a Phase 1 trial so the main purpose is to assess safety. We want to be particularly vigilant with CAR T because we know it can be very toxic in patients with haematological malignancies. It causes a range of side effects, but the most common are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which can affect up to two-thirds of patients.
But the good news is that, from our very early data and from colleagues in other countries, we are not seeing the rates of toxicity that we see in the cancer populations. That’s very reassuring, particularly as the patient population is different. In patients with lymphoma and leukaemia, CAR T is often the only option they have left to treat a very lethal disease. But MS and other autoimmune conditions aren’t necessarily like that.
Regarding efficacy, we need to wait quite a long time to be confident that the CAR T’s been effective, really up to several years. Some of the very earliest people who were treated with CAR T globally for MS are reaching that point and the data looks quite encouraging. But they’ve all been Phase 1 trials, so they’re not designed to measure efficacy.
How might CAR T transform care for MS patients?
For one thing, CAR T could be more effective at switching off the more difficult to control degenerative component of the disease. The B-cell depletors we use currently are very good at damping down the relapse component of MS but, because they don’t cross the blood-brain barrier so well, they are less effective at treating the degenerative aspects. CAR T-cells, on the other hand, are actively shuttled across the blood-brain barrier, so they can exert their effect intrathecally. Our treatment options for progressive forms of MS are really quite limited, so CAR T offers a hope for slowing progression in these more difficult to treat subtypes.
Another aspect which is really appealing, particularly to patients, is that we think it will be a ‘one-and-done’ treatment. With current B-cell depletion therapies, patients either have to have a regular injection, which they can do at home, or they come in once every six months for several hours of therapy. These people are often young and trying to live their lives, so they understandably don’t want to do that. The beauty of CAR T-cell therapy is that you give the patient the CAR T cells once and then they’ll never need to come back for any further treatment. At least that’s the hope.
We’ve also looked at using CAR T for other autoimmune neurological conditions where we deplete or alter the function of B-cells, such as chronic inflammatory demyelinating polyneuropathy or myasthenia gravis. We haven’t treated any of these other conditions with CAR T yet, but one of the trials that we have open has an arm for myasthenia gravis and there’s a lot of interest in that.
What will be the biggest challenges to making CAR T widely available for MS patients?
The first challenge is that these studies require very close collaborations between neurologists, haematologists, cell therapists, and a whole multidisciplinary team. So you need centres that have those facilities, particularly, the large haematology and oncology departments, which not everyone has access to.
You also need to be able to take the T-cells and manufacture the CAR T cells, then you need to be able to give chemotherapy to the patient and monitor them in an in-patient setting for up to several weeks. That requires a lot of resources so there are concerns over ensuring that access to CAR T, if it proves to be safe and effective, is equitable. However, that’s true of a lot of aspects of healthcare and people are often willing to travel for their care, particularly, if it’s a one-and-done treatment.
Related to that are concerns around cost, as CAR T-cells are very expensive to manufacture. However, diagnosing and treating MS patients when they’re young can mean a lifetime – so 50 or 60 years – of regular hospital attendances and repeated treatments. So actually, CAR T-cell therapy could quite quickly end up being cheaper.
Another issue is selecting the right patients, as we don’t yet know who will benefit most from CAR T. We already have treatments that are very effective for MS, but there’s a proportion of patients who are much less responsive. So do we wait to find out whether the treatments fail, at which point someone’s MS will be more advanced and then the CAR T-cell might not be so effective? Or do we use CAR T-cell earlier? Those are questions that remain to be answered.
What’s next?
We are excitedly awaiting results of existing trials. We also anticipate further Phase 2 and 3 trials of CAR T in MS and trials of CAR T-cell therapy in other autoimmune neurological conditions. Ultimately, we hope that CAR T will become an important, safe and effective tool available to doctors treating MS, so it’s an exciting time to be involved in this field.