From PHG Foundation by Hayley Carr

CAR-T cell therapy involves genetically engineering T cells, a type of immune cell, so that they respond to a prespecified molecular marker, or antigen.

recent study has shown remarkable results from compassionate use of CAR-T cell therapy to treat severe lupus in five patients in whom multiple other treatments had previously failed.

Systemic lupus erythematosus (SLE), also known as lupus, is a chronic autoimmune disease. The most common symptoms are extreme fatigue and joint and muscle aches and pains but can also include inflammatory rashes, light sensitivity, headaches, hair loss, and depression. Uncontrolled disease can lead to organ damage, including to the kidneys, skin, heart, lungs, and brain, which can be life threatening. Due to the success of new treatments in recent decades, the disease does not get to this stage in most patients.

However, in some patients, conventional treatments fail to get their disease under control. This leaves them at risk of organ failure and with limited treatment options. Novel therapies are being explored to try to address this unmet need, including the use of CAR-T therapies.

What are CAR-T cell therapies?

CAR-T cell therapy involves genetically engineering T cells, a type of immune cell, so that they respond to a prespecified molecular marker, or antigen. This means they mount an immune response against cells with the chosen antigen, clearing them from the body.

Currently used CAR-T therapies are autologous, where a patient’s T cells are extracted, genetically engineered, and then given back to them. This avoids issues with rejection and graft-versus-host disease – when the donor cells attack the patients’ normal cells.

CAR-T therapies are currently in use for the treatment of some forms of late-stage blood cancer, including large B cell lymphoma and B cell acute lymphoblastic leukaemia. For this, the T cells are engineered to target cancerous cells, which for these blood cancers are derived from B cells, another type of immune cell. Targeting an antigen on B cells enables elimination of the cancerous cells.

Targeting B cells in lupus

In lupus, autoantibodies – antibodies that target the patients’ own cells and tissues – are produced by B cells and can lead to inflammation that may affect several organs. Although lupus is a complex disease with a multitude of disease processes involved, targeting B cells could be a treatment option to reduce B cell driven autoimmunity.

The use of treatments that block or deplete B cells has been explored previously, but these have had varying levels of success against severe disease. A possible explanation is that these therapies are not able to get into the organs or tissues that are being affected, so that B cells remain in these key areas contributing to disease.

CAR-T cells may be able to access these tissues, more effectively targeting B cells and leading to better, longer-lasting responses to treatment. As CAR-T therapies targeting B cells are already in use for other conditions, this study explored using them in severe lupus. It was given as a compassionate-use therapy for five patients aged 18-25 with severe disease that did not respond to conventional treatments.

The results of this study were remarkable, with all patients achieving sustained drug-free remission of their disease. CAR-T therapy initially resulted in reduced B cell numbers, which later recovered. However, the B cells no longer produced autoantibodies associated with lupus, or produced them at a greatly reduced level.

A new treatment for lupus?

There are several reasons why CAR-T cell therapies will not become widely used for lupus anytime soon.

The treatment process itself places a signficant burden on patients, requiring extended time in, or near to, the hospital or specialist CAR-T treatment centre, meaning some patients will have to travel and stay away from their home. The core treatment pathway took 23 days, not including initial screening or follow up visits. This creates access challenges, particularly for those who are unable to be away from home for extended periods, for example those with work or family commitments.

As part of the treatment, patients also need to undergo three to five days of chemotherapy to deplete their immune cells prior to receiving the CAR-T cells. The chemotherapy is generally not very strong, but may still be unpleasant for patients.

The severe side effects of CAR-T therapies sometimes seen in those with blood cancer – cytokine release syndrome (CRS) and neurotoxicity – were seen to a lesser degree in the lupus patients in this study. In blood cancer there are abnormally large numbers of B cells, which results in over-activation of the immune system when these are targeted, causing CRS and neurotoxicity. In lupus there are more normal B cell numbers, which is thought to reduce the overall level of activation of the immune system, as well as associated side effects.

However, for the majority of lupus patients, who have relatively mild disease and are able to achieve disease control using already available treatments, CAR-T cell therapies will not be suitable. The potential risk of side effects and burden on patients, alongside the hefty price tag due to the requirement for bespoke manufacturing, will likely not justify the end result when there are alternative treatment options available.

Hope for the future

Despite the drawbacks associated with CAR-T cell therapy, for the five patients with severe and life-threatening lupus, and others like them, this study represents a potential breakthrough. It shows that severe lupus affecting many organs can be treated and brought under control even following multiple other treatment failures. These patients will now need to be followed up to assess the long-term impacts of CAR-T therapy and to see how long their drug-free remission is maintained.

While promising, the results have only been seen in five patients, so clinical trials involving larger groups of patients will be needed. These should gather more evidence of how successful CAR-Ts are at treating severe lupus and fully assess the side effects, to find out whether more patients could benefit from this approach in the future.

Source – PHG Foundation

Mackensen A, Müller F, Mougiakakos D, Böltz S, Wilhelm A, Aigner M, Völkl S, Simon D, Kleyer A, Munoz L, Kretschmann S, Kharboutli S, Gary R, Reimann H, Rösler W, Uderhardt S, Bang H, Herrmann M, Ekici AB, Buettner C, Habenicht KM, Winkler TH, Krönke G, Schett G. (2022) Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med 28(10):2124-2132. doi: 10.1038/s41591-022-02017-5.

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