From cancer to autoimmunity: Could CAR T cell therapy cure scleroderma?

CAR T cells are an exciting and emerging therapy which have been used to treat certain cancers, giving hope to those for whom no other treatments have worked. A recent study carried out in Germany, published in Nature Medicine, which studied patients with lupus suggests that this therapy could be of use in treating a host of autoimmune conditions including scleroderma. 

What is CAR T cell therapy?

CAR (Chimaeric Antigen Receptor) T cell therapy is an innovative treatment which was developed with the aim of engineering a patient’s immune cells, to ‘wipe out’ their cancer. This treatment was first studied in mouse models of cancer in 2003. The first trials in just two adult leukaemia patients followed in 2010 and indicated the promise of this therapy where others had failed; within months of treatment their cancers vanished, and the pair remain leukaemia free to this day.   

Based on these encouraging results there was a massive investment from pharmaceutical companies into this novel approach of cellular therapy. This led to the development and clinical trials of several CAR-T therapies. Today these therapies are approved for use to treat leukaemia and lymphomas, cancers of a type of white blood cell called the B cell, in the US, Europe and the UK.

How could CAR-T help in autoimmune disease like scleroderma?

The cancers mentioned above are cancers caused by B cells, white blood cells which are part of the immune system. B cells are ‘factories’ pumping out specialised proteins called ‘antibodies’. Antibodies are usually made in response to a person becoming infected with an infectious agent like COVID-19, or the chicken pox virus, and they serve to neutralise the infectious agent preventing it from infecting more cells. After initial infection or vaccination these antibody producing cells persist, usually preventing further infections from taking hold should the person encounter the same infectious agent in the future.   

Lupus and scleroderma are autoimmune conditions, and in people with these conditions their immune systems begin to attack healthy tissues within their body. This includes the presence of rogue, self-reactive B cells which make ‘auto-antibodies’. These autoantibodies target normal molecules found in the body, and an example of these are the anti-nuclear antibodies found in patients with scleroderma.  

Given the success of CAR T therapy in ‘wiping out’ B-cell cancers, the researchers led by Professor Georg Schett based at the Friedrich-Alexander University in Erlangen-Nuremberg hypothesised that this treatment might also work in patients with autoimmune diseases.

In this landmark study five patients with lupus, all with multi-organ involvement, were granted compassionate use of CAR T cell therapy. All these patients were deemed to be severe cases having tried several lines of treatment with limited success, including immunosuppressant therapy.  

Doctors carried out a procedure to remove T cells from individual patients’ blood, which were then engineered to become CAR-T cells able to recognise a molecule called ‘CD19’ found on rogue, autoreactive B cells. The CAR-T cells were grown for several days in the lab before undergoing quality testing to check vital things such as their purity and that they are contaminant free, before being injected back into the same patient - allowing the ‘killer’ CAR T cells to do their job of taking out the patients’ rogue, auto-antibody producing B cells.

What did the researchers find?

Excitingly, researchers found that CAR T- cell therapy wiped out rogue B cells in all five patients, leading to marked improvements in their condition and allowing them to discontinue use of the immunosuppressant therapies they had previously been using. Patient symptoms such as fatigue, arthritis, fibrosis of heart valves, lung involvement, and nephritis (kidney inflammation) disappeared after CAR T cell therapy.  

Blood samples taken 3 months after treatment showed that patients’ autoantibodies were absent or dramatically reduced. Given these effects, the researchers wished to check that the treatment only affected ‘rogue’ B cells and did not also destroy any B cells which might be important in protecting the patients from infection. To do this they looked at patient vaccination responses to common viruses before and after CAR-T cell therapy. Importantly, these were unaffected by CAR-T cell therapy showing that CAR-T cell therapy is targeting auto-antibody producing B cells rather than healthy B cells.

What does this mean for people with scleroderma?

The findings of the study are undoubtedly very exciting. However, these patients will need to be followed for an extended period to ensure that they remain lupus free.

However, CAR T cell therapies are bespoke treatments, unique to each patient, and are labour intensive to produce and quality check, making them an expensive treatment option. It is also not without risk which is why in the case of cancer it is only used as a treatment of last resort when all other treatment options have been exhausted. However, initiatives like the Innovative Medicines Fund, a scheme which will give NHS patients living in England the chance to have ‘early’ access to cutting-edge treatments, along with their counter parts in the devolved nations, could make potentially lifesaving treatments like this more accessible to patients with rare diseases like scleroderma and lupus.

In brief, more research is needed in this novel area. Nonetheless, SRUK are encouraged by the findings of this very exciting study and the hope that it may offer hope to those living with treatment resistant scleroderma.