Teaching an Old Dog New Tricks: Repurposing Cancer Therapies for Autoimmune Diseases
It may seem counterintuitive to treat autoimmune diseases with the immune system seeing as it is the part of the body malfunctioning in the first place, but some researchers have been doing just that. This type of treatment, appropriately named immunotherapies, use the immune system to fight disease. Chimeric Antigen Receptor T (CAR-T) cells, a method which is becoming increasingly common in the treatment of blood cancers, is one immunotherapy that is beginning to be used for autoimmune diseases.
CAR-T cell therapy had its beginnings in the early 90s, but it wasn’t until 2017 that a CAR-T cell therapy received FDA approval. Since then, a total of five CAR-T therapies have been approved, primarily for lymphomas but also some leukemias and myelomas. CAR-T cells work by exploiting one of the body’s natural immune mechanisms, T cells. These cells, also known as T lymphocytes, can recognize antigens on the surface of diseased cells and either release toxins that kill the target cell or recruit other immune cells that will do the dirty work.
T cells identify cells that are infected with pathogens or otherwise diseased based on the fragments of proteins displayed on the cell surface. This detection occurs through the T-cell receptors which have two components: the variable region, and the constant region. The constant region is anchored to the T-cell membrane, and the variable region extends outward from there and can bind antigens. Chimeric Antigen Receptors (CARs) essentially act as artificial T cell receptors with the variable region modified for a specific cellular antigen. Scientists have been able to modify T cells and add CARs targeting cancer antigen, triggering the selective destruction of these cancer cells via T cell activation. The ability of CARs to both recognize antigen and activate T cell response is what makes them chimeric as they have a dual function.
At this point you may be thinking that this sounds like the work of science-fiction but allow me to explain how all of this is possible. To begin, T cells must be retrieved from the patient using the process of apheresis, which involves filtering the blood for a specific component and then returning the filtered blood to the patient. Once the T cells have been retrieved, the gene necessary to produce the receptor is inserted into the T cells using a viral vector. This vector has been modified to contain the gene that encodes for the chimeric antigen T cell receptor. The virus then conveniently injects the gene into the cell where it then travels to the nucleus and inserts itself into the DNA of the T-cell, a process known as transduction. After the introduction of the gene the T cells will begin to produce CARs. These T cells are then grown to create a large number before being reintroduced into the patient through an intravenous injection. You now have a patient with many T cells that are specific to your antigen of interest and can kill cells containing this antigen.
So how could CAR-T cell therapy work for autoimmune diseases? Essentially, if one could identify an antigen that was expressed on self-reactive immune cells then you could target these cells and destroy them using CAR-T cells. The main problem is that there have been few identified antigens that are specific to these self-reactive cells. Current treatment of autoimmune disorders focuses heavily on broadly suppressing the immune system. Although suppression leads to a reduction in symptoms it can also lead to infection by common pathogens and cause more frequent illness. It is hoped that the specific targeting of problematic immune cells with CAR-T cells will minimize these systemic responses and off-target effects, but the data to support this theory is still being gathered. It is noteworthy that the effects of CAR-T cells can last for years, making it a better option than repeated dosing of traditional therapeutic agents such as corticosteroids.
There are two main antigens of interest for the development of CAR-T cell autoimmune therapies: CD20 and CD19. Both antigens are highly expressed on the surface of B cells, the cells responsible for making antibodies. B cells are associated with many autoimmune diseases because they produce the unwanted antibodies that attack the body. Unlike CD20, CD19 is expressed on immature B cells and a larger expression profile typically means a more effective target for therapies. We will also choose to focus on CD19 as it was the target of interest in a recent case study where a patient was cured of systemic lupus erythematosus (SLE) using CAR-T cells targeting CD19.
SLE, like most autoimmune diseases, primarily affects women and is characterized by the formation of autoantibodies that attack one’s own cells and results in organ damage. If left untreated, SLE can lead to many complications such as kidney failure, blood clots, and increased risk of heart attacks. Previous treatments for SLE have used CD20 as a target but have had minimal success likely due to their expression occurring in select stages of B-cell production.
Our case study of interest involved a 20-year-old woman in Germany with severe SLE whose case could not be managed using typical immunosuppressants, including one that targeted CD20. In March of 2021 her healthcare team was able to use CD19 directed CAR-T cells, which are known for their use in treating some forms of cancer. Elevated levels of CD19 expression on B cells is associated with active SLE, making it an ideal target. The patient saw rapid remission of her SLE symptoms, both physical and in serum levels of autoantibodies and other markers indicative of the disease. The patient also reported no side effects while undergoing treatment. At the time of writing, only a six month follow-up was available, but during that time the patient reported zero symptoms. Additionally, she is on none of the drugs previously used to treat her SLE. These results show extreme promise for the use of CAR-T cell therapy outside of the realm of cancer.
As always, extensive follow-up and a larger study size is needed to show that this treatment will be effective and safe in the long-term. I am happy to report that an early Phase I clinical trial is currently recruiting patients for this study. It is hoped that further work in the area will show promise for not only SLE but other autoimmune diseases as well.
Your friend in science,
Kathleen
Further reading:
Clinical trial
Case study: CAR-T for SLE
CAR-T cell background