Author: Katie Birditt
With a formidable name like Chimeric Antigen Receptor T Cell Therapy, some incredible real-life success stories, and undeniably ingenious genetic engineering it’s no wonder there was so much hype surrounding the emergence of this novel T cell-based therapy. It seemed a worthy opponent of cancer, the devastating group of diseases that have confounded scientist for decades. However, does CAR T cell therapy, really have the potential to be a magic bullet against cancer or is it simply another well-aimed shot in the dark?
Reserving any further judgements on CAR T cell therapy it is probably best to first step back and get to grips with exactly what this therapeutic strategy is all about. It falls under the wider umbrella term of immunotherapy which is a type of treatment that essentially harnesses certain characteristics of an individual’s immune system and uses these aspects to fight cancer. In the case of CAR T cell therapy, it’s a certain type of immune cell that is used. Normally, the immune system, is tasked with the important role of protecting the body against illness, infection and even cancer. Unsurprisingly with this heavy workload, it can’t always detect and kill cancerous cells, who are notoriously devious. A way to ‘bio hack’ human immune cells and help the immune system chase down cancerous cells more efficiently was needed and this is how CAR T cell therapy was born.
T cells (without the CAR bit) are a type of white blood cell, known as lymphocytes. As an extremely important component of the immune system’s army, they patrol the body fighting off infections and disease. These cells possess special protein receptors, encoded by their genes, that are extremely specific to certain foreign antigens that get presented to them. By recognising and binding to the exposed antigen they are activated and subsequently initiate a series of steps that will ultimately kill the cell expressing it. Some populations of these cells, memory T cells, live on in the body ready to launch faster, more effective attacks on agents that have previously been encountered. It’s a brilliant little system really and scientists soon realised the potential that these T cells had from a therapeutic perspective. After all, they exhibited incredible specificity, toxicity, and memory; all characteristics which could be useful in generating tumour-specific T cells.
Now that the T and AR parts of the therapy’s acronym have been briefly discussed we are left with the C. The term chimeric comes directly and somewhat unsurprisingly from the Ancient Greeks (who it seems most important concepts can be traced back to). Chimeric is derived from the word Chimera which, in Greek mythology, was the name of a monstrous, four-headed beast. The CAR T cells have been engineered in such a way that they are three-headed beasts. In order for the synthetic receptors to work in a tumour-specific way they are each engineered to possess two different signalling domains, as well as an antigen binding site. A certain sneaky type of virus, known as a retrovirus, is used to successfully insert the genes that code for these three sites into the genomes of T cells. The incorporation of this genetic information then subsequently enables the T cells to produce and express functional chimeric antigen receptors which are capable of recognising target antigens on cancer cells and destroying them. (Sterner et Sterne, 2021)
Fig 1. An ordinary T cell is shown alongside a T cell that has been genetically altered to produce a chimeric antigen receptors.
So how on earth do we fiddle around with an individual’s cells? Well, first T cells have to be carefully collected from the blood. From there they are subject to the aforementioned genetic engineering that ensures they express the chimeric antigen receptor. The altered cells are allowed to grow and multiply under highly regulated conditions in the laboratory until their numbers are high enough for transfusion back into the bloodstream of the patient. Ideally, these new and improved CAR-T cells are now upgraded and ready to battle cancer!
Fig 2. A brief overview of the stages that make up CAR T cell therapy
(All images created with https://biorender.com/)
It’s easy to see why, on the surface, it seemed like CAR T cell therapy had emerged as a heroic saviour that would be able to rid us once and for all of cancer. However, when all the initial excitement surrounding the therapy inevitably died down, the reality of just how costly it was became known. To give you an idea of just how expensive we are talking, it is estimated that per-patient cost of the therapy can exceed 1 million US dollars! Additionally, it’s success rate does not span the broad heterogeneity of all cancers. It is currently only used to treat leukaemia and lymphoma, having a much lower efficacy against solid tumours. (Sterner et Sterne, 2021)
Whilst its therapeutic potency may be limited to a small niche of cancer, CAR T cell therapy is undeniably a scientific triumph. In the near future, with continued technological advancement there may be ways of addressing its shortcomings and expanding its impact. However, right now it just isn’t the cost-effective magic bullet needed to eradicate cancer.
Sterner, R.C., Sterner, R.M. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 11, 69 (2021). https://doi.org/10.1038/s41408-021-00459-7