by Saanvi Ganesh
Acute Lymphoblastic Leukaemia (B-ALL) is an uncontrolled expansion of a subset of immature immune cells or ‘blasts’ (or lymphoblasts, which normally would differentiate into either B or T cells) that are unable to mature or perform a useful function. Leukemia destroys the bone marrow by affecting its architecture and leaving no space for normal blood production.
Current treatments for leukemia is chemotherapy, including drugs like Aminopterin which is a folic adic antagonist (folic acid is critical for DNA replication during cell division and Sidney Farber linked this to Leukemia growth in a series of clinical trials to develop folic acid antagonsists for the treatment of Leukemia). However, around 20% of paediatric B-ALL patients will relapse with current treatments and the overall survival rate will be around 40-50%. This is worse in adult B-ALL where 50% of patients will relapse with around 7% surviving for 5 years. So, novel therapies are still needed and immunotherapy using Chimeric Antigen Receptor (CAR)-T cells could potentially lead to better treatments.
The building blocks of immunotherapy are B lymphocytes (B-cells) and T lymphocytes (T-cells). They are part of the adaptive (specific) immune system and provide specific immune responses to pathogens. Immunotherapies can be designed to exploit the anti-infection properties and functions of B and T cells. B-cells (or plasma cells) work by secreting specific antibodies to bind to foreign cells/tissue. These antibodies cause agglutination of similar antibody-pathogen complexes and ‘labels’ triggers phagocytosis by macrophages. T-cells selectively recognise foreign cells or host cells that have been invaded by viruses (by binding to specific antigens expressed only on these cells). T-cells then release perforin and cytotoxins to kill the target cells. Researchers have long sought to harness this cytotoxic potency and re-direct T-cells towards cancer cells and CAR-T cell therapy is an innovative new treatment that uses this principle.
CAR-T cell therapy uses T cells engineered with Chimeric Antigen Receptors (CARs) for cancer therapy. CAR-T cells can be either derived from T cells in a patient's own blood (autologous) or derived from the T cells of another healthy donor (allogeneic). Once isolated from a person, these T cells are genetically engineered to express a specific CAR, which programs them to target an antigen that is present on the surface of tumors. This is done by genetic transfer of B-cell genes into T cells, which leads to the expression of an antibody - the CARs. This forms a chimeric cell that has the specificity of the B cells and the toxicity of the T cells. For safety, CAR-T cells are engineered to be specific to an antigen expressed on a tumor that is not expressed on healthy cells.
CARs are composed of four regions: an antigen recognition domain (the variable region that is specific to the tumor cell CD19 antigen), an extracellular hinge region (for flexibility), a transmembrane domain, and an intracellular T cell signaling domain. Early trials of first generation CARs (like the one below) showed that although therpy was only moderately effective against B-ALL and that there was poor persistence of CARs for longer than 100 day after infusion. Further research then showed the reason behind this was that T cells required a co-stimulation mechanism, where multiple signalling proteins were needed (rather than only the CD3 protein endodomain in the image below). It was also found that lymphodepletion (killing all white blood cells already in the body) prior to treatment was needed to make CAR-T cell therapy more effective. This has led to many generations of CARs, each more effective than the last.
There have also been some problems with CAR-T cell therapy. The most common issue after treatment with CAR-T cells is cytokine release syndrome (CRS), a condition in which the immune system is activated and releases an increased number of inflammatory cytokines. CRS occurs in almost all patients treated with CAR-T cell therapy; in fact, the presence of CRS is a diagnostic marker that indicates the CAR-T cells are working as intended to kill the cancer cells. Neurological toxicity is also often associated with CAR-T cell treatment. The underlying mechanism is poorly understood and some deaths during trials have been caused by neurotoxicity. The possiblity of relapse is also still present as leukemia cells are unstable genetically and change their CD19 expression to outsmart CARs (antigenic variability). However, this is just the beginning for CAR-T cell therapy and there are many research groups planning larger trials and further development of the treatment and the hope is that CAR-T cell therapy will eventually be able to treat many types of cancer.
Sources:
https://pubmed.ncbi.nlm.nih.gov/29667553/
https://www.youtube.com/watch?v=DJfRkkSp5zY
https://www.bbc.co.uk/news/health-59771464
https://www.ucl.ac.uk/cancer/research/ucl-car-t-programme
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