CARs designed to tackle cancer
Every so often you have a ‘wow’ moment in life. This may be from seeing one of the wonders of the world or witnessing a great performance on stage. For me, my common ‘wow’ moments are of the ‘Wow, how come I have only just discovered this when others have known about it for ages’ sort. I felt this way when I first read about CRISPR technology and how it can be used for precise gene editing only last year. The same feeling has occurred again recently when I discovered the latest successful cancer immunotherapy; CAR T-cell therapy.
What is CAR T-cell therapy?
Your body is truly a wonderful machine, so wonderful that it has its own defence system. There are several levels of this defence but an important component are T-cells that provide cell-mediated immunity. T-cells express receptors on their cell surface that recognise antigens of virus-infected cells allowing for their destruction. The issue is, a key hallmark of cancer cells is their evasion of the T-cells immune response.
CAR T-cell therapy provides a way this issue can be overcome. It involves modifying the T-cells by genetically engineering them to display cell surface markers that recognise antigens on cancer cells. The recognised cancer cells are then destroyed (Figure 1). This is where the name CAR comes from, standing for ‘Chimeric antigen receptor’. The gene for CARs can be introduced by a virus.
The reason for my ‘wow’ moment is partly because CARs were first described over 25 years ago! As CARs have been refined over time, they have been characterised into different generations. The 1st generation CARs were composed of the T-cell CD3ζ intracellular signalling domain linked via a transmembrane domain (TM) and hinge to an antibody fragment (the part that provides specificity of response). The design was improved in the 2nd generation with the addition of a co-stimulatory domain, with two of these domains added in 3rd generation CARs (2). (See Figure 1 of ref (2) to see images of the CARs!) The effect of the co-stimulatory domains is to regulate replication of the T-cells and improve their persistence allowing for an overall better response.
No, I have not just made up a word and neither have I randomly hit my keyboard. Tisagenlecleucal is the name of the recently FDA-approved CAR T-cell therapy for treating patients with B-cell acute lymphoblastic leukaemia (ALL). You may have heard of it by the name Kymriah, marketed by Novartis. The $475,000 treatment involves taking the patients T-cells and re-programming them to recognise the cell-surface protein CD-19, that is specifically expressed on B-cells. These introduced T-cells can therefore target and kill the cancerous B-cells.
The clinical trials were successful, with 82.5% overall remissions. However, 47% of patients developed cytokine release syndrome (severe inflammatory responses that can result in high fevers) although they were all managed and there were also reported temporary seizures and hallucinations (3). Nevertheless, the tailor-made therapy provides a major advance over previous treatments.
What about other cancers?
It may not be a coincidence that CD-19 was the first target antigen investigated. CD-19 is expressed throughout B-cell development and are specific to the cell lineage, making it an ideal target for cancerous B-cells, since other healthy cell types are unaffected by the modified T-cells. Moreover, since ALL is a blood cancer it allows for easier delivery of the T-cells. Finding tumour-specific antigens for other cancers is proving hard to find. This is especially the case for solid tumour malignancies such as lung cancer that show heterogeneous patterns of antigen expression and show inefficient homing of T-cells to tumour sites. Potential ways this issue can be circumvented involve choosing antigens that are present on other cell lineages but are dispensable or replaceable and by using combinatorial CAR T-cell therapy using other therapies such as systemic administration of antagonists to improve targeting (4).
With the FDA approval of Novartis’ approach for treating patients with ALL, it should be expected that CAR T-cell therapies to become more abundant in the future to tackle other cancers and more advanced to reduce any potential side effects.
(1) If you prefer animation over my description and cartoon then check out this video; https://www.youtube.com/watch?v=ivFCv2j3-mk (Novartis approach)
(2) S.Maude. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia Blood 125, 4017-4023 (2015)
(4) S.Kakarla. CAR T cells for solid tumours: armed and ready to go? Cancer J. 2, 151-155 (2014)