CAR-T can treat some blood cancers. So why not AML?

CAR-T for blood cancers

CAR-T therapy has transformed treatment for some people with blood cancer. By genetically modifying a patient’s own immune cells, scientists can effectively teach them to seek out and destroy cancer.

It has been particularly successful against some B-cell cancers, including B-cell acute lymphoblastic leukaemia (B-ALL). So why don’t we just do the same thing for acute myeloid leukaemia (AML)?

The problem isn’t that CAR T-cells are unable to kill AML cells. It’s getting them to kill all the cancer without killing healthy blood-forming cells too.

So, what makes AML such a difficult target?

How does CAR-T work?

T cells are a type of white blood cell that can recognise and destroy infected or abnormal cells. In CAR T-cell therapy, they are genetically modified to give them a new receptor called a chimeric antigen receptor (CAR).

As we’ve explained previously, the CAR acts a bit like a specially designed fishing hook. It recognises a particular protein, or antigen, on the surface of a cell. When it finds its target, the T cell attacks.

The important bit is choosing the right target.

For B-cell cancers, researchers have a particularly useful one: CD19, a protein found on the surface of B cells. CD19 isn’t unique to cancer, so CAR-T also kills healthy B cells. But the effects of losing B cells can be managed, including with replacement antibodies where needed.

A useful CAR-T target therefore doesn’t have to be completely unique to cancer. The damage to healthy cells just needs to be manageable.

For AML, that becomes much more difficult.

Why is AML different?

AML cells have plenty of potential targets. Two of the most studied are CD33 and CD123, proteins commonly found on their surface.

Unfortunately, they can also be found on healthy blood-forming cells.

That means a CAR-T cell designed to recognise CD33 or CD123 can do exactly what it was designed to do and still cause serious harm. As well as killing the AML, it may destroy cells the bone marrow needs to make healthy blood.

Other targets create different problems. CD7, for example, is found on AML cells in some patients and has been investigated as another possible target. But CD7 is also found on healthy T cells – the very cells being turned into CAR-T cells.

And AML has another trick up its sleeve. The proteins that can be used to identify AML vary enormously between patients, and even between cancer cells within the same patient. If a CAR-T treatment destroys cells carrying its chosen target but other AML cells don’t have it, those cells can survive and allow the cancer to return.

The ideal target would therefore be found reliably on AML cells, including the leukaemic stem cells that can regenerate the cancer, while avoiding the healthy cells we need to protect.

So far, researchers haven’t found one that ticks all those boxes.

Can we engineer our way around the problem?

If AML won’t give us one perfect target, researchers may have to make CAR-T cleverer.

One approach is to recognise more than one antigen. Researchers are also developing ‘logic-gated’ CAR-T cells, which respond to combinations of markers rather than simply attacking whenever they encounter a single one. This could make it harder for AML cells to escape treatment while helping CAR-T distinguish cancer from healthy cells.

Or, instead of changing the CAR-T cells, what if we changed the healthy cells?

Researchers have used gene editing to remove CD33 from healthy blood stem cells. In preclinical studies, these edited cells could still produce healthy blood cells but were protected from CD33-targeted CAR-T – while the AML cells kept the target that made them vulnerable.

And a similar idea is already being tested in patients with a different type of leukaemia, T-ALL (T-cell acute lymphoblastic leukaemia).

Remember CD7, which is found on both some cancer cells and healthy T cells? Researchers at UCL used base editing to remove CD7 from healthy donor T cells before adding a CAR designed to attack CD7. This prevents the resulting ‘BE-CAR7’ cells from attacking each other while allowing them to attack leukaemia cells with CD7 on their surface.

The donor cells used to develop BE-CAR7 for the first patient to receive the treatment came from an Anthony Nolan donor. In the latest results, nine of the 11 patients treated reached remission, with seven reported to be disease-free following treatment and a subsequent stem cell transplant.

Read more about Alyssa, the first patient in the world to receive this groundbreaking therapy – and who visited the Anthony Nolan Research Institute to find out more about our work.

How CAR-T and stem cell transplantation can work together

CAR-T and stem cell transplantation can play different roles at different stages of treatment. Often, CAR-T treatment can be offered after a patient has already received a stem cell transplant – although this will depend on several factors specific to each patient.

BE-CAR7 gives us a different example of how they can work together. For patients who respond to BE-CAR7, a donor stem cell transplant is used afterwards to rebuild their blood and immune system.

Researchers are investigating whether a similar approach could eventually help overcome the particular problems posed by AML. CAR-T could potentially be used to attack the leukaemia, followed by a donor transplant to restore healthy blood formation.

This is particularly interesting where targeting AML also damages healthy blood-forming cells. Some researchers have even proposed deliberately using this effect before transplantation, rather than treating it simply as an unwanted side effect.

It also reflects a wider shift in research at Anthony Nolan. Alongside improving stem cell transplantation, our researchers are investigating new immunotherapies and cell therapies that could help prevent relapse and improve outcomes.

Where next?

CAR-T is already an established treatment for some patients with specific blood cancers, and researchers are continuing to develop new ways to use it. For AML, however, the approaches described here are still experimental.

Researchers are tackling the problem from several directions: finding better targets, designing CAR T-cells that can make more sophisticated decisions, using gene editing to protect healthy cells, and exploring how these treatments could work alongside stem cell transplantation.

Anthony Nolan will continue campaigning for the uptake of cell and gene therapies like CAR-T through the NHS, to provide more options for patients. We won’t stop until every patient who needs treatment can survive and thrive.

Written by Jack Hooper. Reviewed for medical accuracy by Anthony Nolan’s clinical team.