CAR-T cell therapy is a very exciting treatment modality for patients with a number of haematological conditions. It is in its infancy and we're likely to see an explosion of new products coming into trials and then into the clinic. I'm focusing here on relapsed and refractory diffuse large B-cell lymphoma.
What are CAR-T cells?
CAR stands for 'Chimeric Antigen Receptor'. Basically, T-cells are immune system cells which can be taken out of the body in a fairly simple way by a process called apheresis (similar to how we get stem cells from patients). Once collected, they can be sent to specialised laboratories where they can be genetically engineered to produce a receptor on the cell surface (a Chimeric Antigen Receptor) which makes the T-cells recognise lymphoma cells. Currently, the protein they are made to recognise on lymphoma cells is called CD19. This is also found on normal B-cells. The T-cells are then grown in the lab, sent back to the patient and re-infused. Just before this, the patient receives some chemotherapy which enables a 'niche' in which the new T-cells can grow. Once inside, the T-cells can hunt down the lymphoma, attack it and also expand in numbers. This is why they are often called a 'living drug' in that the cells can potentially survive and grow within the patient.
How good are they?
In early trials of patients with difficult diffuse large B-cell lymphoma which has come back several times despite good treatment, about 60-70% of patients had a response i.e. their lymphoma shrank by more than 50% in volume. What's more, around 30-40% had a fairly long lasting complete response i.e. there was no detectable lymphoma on a PET scan. This is a very good response for patients with this sort of difficult disease. However we must remember that patients who are eligible for trials don't necessarily represent all patients. When used in the so-called 'real world', some centres have replicated the trial results, whereas others (notably the early data coming from the UK) have not.
What are the problems with CAR-T cells?
There are several.
1. Relapse. This is the most common problem with CAR-T cells. Although the response rates are higher than with other agents seen in this setting, most patients who receive the cells do not benefit in the medium to long term. It is important this is explained to patients. Some people relapse because the lymphoma cells lose the target for the CAR-T (so called CD19 negative escape) whilst others don't work well because the lymphoma cells produce proteins which are immunosuppressive (such as PD-L1). However there are also unknown mechanisms. Much work is underway to try to circumvent these resistance mechanisms.
2. They can cause side effects which in some cases are serious. In particular, cytokine release syndrome is when the T-cells work almost too well so that as they grow and attack the lymphoma they release chemicals into the blood. This can feel like very bad 'flu and can cause the body's blood pressure to drop. This in turn can threaten vital organs such as the kidneys. Sometimes patients need support in the intensive care unit, and an antidote drug called tocilizumab. The other main side effect is neurotoxicity. For reasons we don't properly understand, the CAR-T cells seem to irritate the brain in some patients causing side effects such as confusion, problems with writing or speaking and even coma and brain swelling (although this is not common). Usually these side effects are reversible but some occasional deaths have been reported.
3. The long term effects are unknown. We haven't been using CAR-T cells for long and there maybe long term unwanted side effects. This is NOT a reason not to use them, but it is a reason for continued data collection on the initial patients given these cells, and underlines the need for an appropriately cautious tone as the therapy is described to patients.
4. In some instances, patients have to travel far from home to get the cells. This is really important as most patients who get the cells will relapse and if this happens life expectancy is often short. It is far from ideal for a patient who maybe in the last few months of their life, to be in a hospital, suffering sometimes severe side effects, far away from home, with few visitors due to travel distances. Unfortunately currently we cannot predict which patients will do well and which will do poorly.
What does this mean in practise
CAR-T cell therapy does represent an important advance and offers probably the best chance of a response and of a durable remission for patients with multiply relapsed high grade lymphoma. It is important that this therapy is discussed with potentially eligible patients. However they must be discussed within the right context and other options outlined in detail. Other options for patients include:
(i) Clinical trials. Although by definition, the outcome of a trial is unknown, these maybe available closer to home and maybe using agents with already proven activity such as bispecific antibodies or an anti-CD47 antibody combination. These agents however are unlicensed.
(ii) Alternative chemotherapy approaches. Although unlikely to produce meaningful benefit, some combination such as bendamustine, rituximab and polatuzumab do appear promising. Whilst not wanting to suggest it's curative, remissions are frequent and fairly durable in some. If reimbursed, treatment would be able to be close to home for most patients.
(iii) Supportive / palliative care. It's really important we discuss this as an option with patients. Several times I have recommended a patient has no further active treatment and I've been surprised by how well they do - living with a very good quality of life, ticking off 'bucket list' items and living for longer than I expected. It enables good quality time with family and the necessary sorting out of affairs. It's important not to suggest this is 'giving up' but simply moving to a different phase of treatment whereby the disease isn't the focus, but the symptoms it produces and impact on quality of life are.
Conclusion
CAR-T cell therapy is here to stay. But it's not right for all patients and a major strand of research should be trying to delineate the patients likely to do well and to do poorly with this approach. For now, let's be appropriately cautious in our conversations with patients considering this therapy - not to take away hope, but to present all the options in a fair and balanced way helping the patient to make the right decision for them.
