CAR T-cells: giving our own bodies the battle plan against cancer
20th May 2022 - Last modified 19th October 2023
20 years of Alto. 20 years of science. #4
By Olivia Hillson, Science writer
As part of Alto Marketing’s 20 year celebrations, we’re looking back at some of the most important advances in science over this time in our blog series “20 years of Alto. 20 years of science.” Here we take a look at CAR T-cells and how they came to be one of the most promising cancer therapies of our time.
I think every scientist has the moment.
The one where you realise how important and life-changing scientific research can be. For me this moment was in 2019.
During my undergraduate degree – somewhere around 2016 – I attended a seminar at the Institute of Child Health (ICH – the research institute attached to Great Ormond Street Children’s Hospital). There were several lectures by different researchers at the institute and, as is usual for a university student, I sat and listened as information filtered slowly into my brain and I wondered about many other things like where we would go for cocktails that night or what was on television later. But, on the 31st of January 2019 I saw a news article on the BBC that shot me right back to the ICH lecture hall. The headline read: “First child given pioneering CAR-T cancer therapy” [1].
For the first time in my life, research I had been privy to was now out in the real world and making a difference. Suddenly, I could recall the lecture as if it was yesterday and the excitement of the researchers made so much more sense.
Mobilising the Immune System
CAR T-cells are the elegant answer to the immune system’s inability to recognise cancer cells. Since cancer cells are very similar to healthy cells, usually your immune system ignores them as if they are healthy cells.
CAR T-cell technology utilises the T-cell (the immune cell which seeks out and destroys foreign invaders) and genetically engineers them using chimeric antigen receptors (CARs). CARs provide the T-cells with instructions for how to find the cancer, inducing an immune attack.
Patients eligible for CAR T-cell therapy have their own T-cells removed from their blood, which are then genetically engineered with CARs for their specific cancer, These CAR T-cells cells are multiplied in vitro and then administered to the patient via a drip where, once inside the patient’s system, they begin to attack the cancer [2].
30 Years in the Making
While the concept is simple in theory, the process of creating these cells proved to be much more complicated. Although hailed as a ‘revolutionary new pillar in cancer treatment’ in Nature just last year, the technology actually dates back as far as 1989 when the first CAR T-cells were developed [3]. These first-generation cells weren’t clinically effective and so triggered decades of further research. Second generation T-cells were developed to be more robust and efficient but eventually these gave way to the third generation, which built even more on the efficacy of the previous incarnation.
The current fourth generation cells are more potent again and come with the added advancement of being able to more easily target solid tumours. Increased treatment safety is a key theme in the development of a fifth generation of CAR T-cells and new research is being conducted all the time [4].
As recently as last month, the American Association for Cancer Research announced that the mRNA vaccine technology created by BioNTech for the Covid-19 vaccine can be used effectively to improve CAR T-cell efficacy against solid tumours [5].
“Off-the-Shelf”
However, despite this scientific progress, CAR T-cell therapies still face major barriers to widespread use… time and money. Current CAR T-cell treatments are engineered personally for each patient’s cancer by expert scientists. This individualisation means they take weeks to produce for a patient and are extremely expensive. Reports of the therapy costing £280,000 are not hard to understand when you consider the complexity and specificity of the work involved [6]. In the UK, this is a huge barrier to use on the NHS. As a result, research has focused on the idea of off-the-shelf versions to try to bring CAR T-cells to a wider group of patients.
Creating an off-the-shelf CAR T-cell line is somewhat of a holy grail in cancer immunotherapy. Research in the last few years has developed several possible ways to produce allogenic CAR T-cells, which are cells donated from a source other than the patient such as genetically engineered adult donor cells and umbilical cord stem cells. But allogenic cells come with their own set of risks. Patients receiving cells that are not their own would be at risk from Graft Vs. Host Disease in much the same way as a transplant patient, where the immune system would attack the CAR T-cells. This is a life-threatening complication, that is even more of a concern if the patient already has immune complications from their cancer [7-9]. I remember off-the-shelf cells being a key goal of the researchers back in my lecture in 2016 and they remain elusive to this day. Alas though, there is hope. If CAR T-cells took close to three decades to be first used in UK hospitals, it would be no stretch to imagine that these advances are waiting for us in the very near future.
Since my first moment I have come to learn, through my own experiences as a researcher and from ground-breaking publications, just how fast life science and healthcare research continues to progress.
References
1. Fergus Walsh. First child given pioneering CAR-T cancer therapy. 2019; Available from: https://www.bbc.co.uk/news/health-47058069.
2. Cancer Research UK. CAR T-cell therapy. 2021; Available from: https://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/immunotherapy/types/CAR-T-cell-therapy.
3. Robert C. Sterner and Rosalie M. Sterner, CAR-T cell therapy: current limitations and potential strategies. Blood Cancer Journal, 2021. 11(4): p. 69.
4. Jan Styczynski, A brief history of CAR-T cells: from laboratory to the bedside. Acta Haematologica Polonica, 2020. 51: p. 2-5.
5. American Association for Cancer Research, New CAR T-cell Therapy for Solid Tumors Was Safe and Showed Early Efficacy. 2022.
6. Duncan Sim. ‘Cutting edge’ CAR T cell immunotherapy approved in England. But is the NHS ready? 2018; Available from: https://news.cancerresearchuk.org/2018/10/05/cutting-edge-car-t-cell-immunotherapy-approved-in-england-but-is-the-nhs-ready/.
7. Darel Martínez Bedoya, Valérie Dutoit, and Denis Migliorini, Allogeneic CAR T Cells: An Alternative to Overcome Challenges of CAR T Cell Therapy in Glioblastoma. Frontiers in Immunology, 2021. 12.
8. Cynthia Perez, Isabelle Gruber, and Caroline Arber, Off-the-Shelf Allogeneic T Cell Therapies for Cancer: Opportunities and Challenges Using Naturally Occurring “Universal” Donor T Cells. Frontiers in Immunology, 2020. 11.
9. Kenneth J. Caldwell, Stephen Gottschalk, and Aimee C. Talleur, Allogeneic CAR Cell Therapy—More Than a Pipe Dream. Frontiers in Immunology, 2021. 11.
