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Chimeric Antigen Receptors Cell Therapy (CAR-T) Explained

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The Problem

Whether you or someone close to you has cancer, knowing what to expect can help you cope. Having basic information about the disease and its causes to in-depth information on specific cancer types – including risk factors, early detection, diagnosis, and treatment options, provides essential comfort at a very difficult time. Chimeric antigen receptor (CAR) T-cell therapy[1] is a way to get immune cells called T cells (a type of white blood cell) to fight cancer by changing them in a laboratory to find and destroy cancer cells:

  • The National Health Service (NHS) is providing CAR-T therapies for children and young people with B cell acute lymphoblastic leukaemia.[2]
  • The National Institute for Health and Care Excellence (NICE) also recommended CAR-T therapy for adults with diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma in England.[3]

The therapy is one of the newest, most promising treatments for blood cancer, using your body’s immune system to help fight:

A picture containing text, clock Description automatically generatedPicture licensed under the Creative Commons Attribution-Share Alike 4.0 International license. Author: Reyasingh56, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0&gt;, via Wikimedia Commons.
File URL: https://upload.wikimedia.org/wikipedia/commons/b/b6/CAR_T-cell_Therapy.svg.

The diagram above represents the process of chimeric antigen receptor T-cell therapy (CAR) – a method of immunotherapy which is a growing practice in cancer treatment. The final result should be a production of equipped T-cells that can recognise and fight the infected cancer cells in the body. 1. T-cells (represented by objects labelled as ‘t’) are removed from the patient’s blood. 2. Then, in a laboratory setting, the gene that encodes for the specific antigen receptors is incorporated into the T-cells. 3. Thus, producing the CAR receptors (labelled as c) on the surface of the cells. 4. The newly modified T-cells are then further harvested and grown in the lab. 5. After a certain time period, the engineered T-cells are infused back into the patient.

CAR T cells destroy cells through several mechanisms, including extensive stimulated cell proliferation, increasing the degree to which they are toxic to other living cells (cytotoxicity) and by causing the increased secretion of factors that can affect other cells, such as cytokines, interleukins and growth factors.[4] The first CAR T cell therapies were US FDA-approved in 2017,[5] and there are now six approved CAR T therapies.[6]

Chimeric antigen receptor (CAR) T-cell therapy has been defined[7] as:

‘…a type of treatment in which a patient’s T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient’s blood. Then the gene for a special receptor that binds to a certain protein on the patient’s cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion. CAR T-cell therapy is used to treat certain blood cancers, and it is being studied in the treatment of other types of cancer. Also called chimeric antigen receptor T-cell therapy.CAR-T (chimeric antigen receptor T-cell) therapy is specifically developed for each individual patient and involves reprogramming the patient’s own immune system cells which are then used to target their cancer. It is a highly complex and potentially risky treatment, but it has been shown in trials to cure some patients, even those with quite advanced cancers, and when other available therapies have failed.’

The treatment is called chimeric antigen receptor because the receptors are chimeric in combining both antigen-binding and T cell activating functions into a single receptor. CAR T cell therapy uses T cells engineered with CARs for cancer therapy.

The interim service specifications for CAR-T therapy can be found at the following links:

  • Axicabtagene Ciloleucel Chimeric Antigen Receptor T Cell (CAR T) Therapy for the treatment of adult patients with relapsed or refractory large B-cell lymphoma.[8]
  • Tisagenlecleucel Chimeric Antigen Receptor T Cell (CAR T) Therapy for ALL and DLBCL.[9]

In total, NHS England[10] estimates that there will be about 150-180 patients per year eligible for treatment with tisagenlecleucel[11] within its licensed indication. There would be 5-10 children or teenagers who have diseases with similar biology to adults and who could also benefit from CAR T therapy in the event that off-label use is available in future. At present, there is no data to support this use and it is not licenced for such use.

T cells[12]
To understand CAR T-cell therapy more, it helps to understand what T cells do: White blood cells called lymphocytes play an important part in fighting infection and diseases, including cancer. There are different types of lymphocytes. T cells are one type. T cells move around the body to find and destroy defective cells. The body makes T cells to fight that specific infection or disease when you come into contact with a new infection or disease. It then keeps some in reserve so that if you encounter the infection again, your body can recognise it and attack it immediately.

What is CAR T-cell therapy?
T cells are good at fighting infection. But it can be difficult for them to tell the difference between a cancer cell and a normal cell. So the cancer cells can hide away and not be recognised. Scientists are trying to find ways to get T cells to recognise cancer cells. One possible way to do this might be CAR T-cell therapy.

The treatment involves several steps over several weeks and can be summarised as follows:

  • First, the patient’s blood is taken and sent to the manufacturer’s laboratory.
  • The patient’s blood is ‘trained’ to fight the cancer cells.
  • The CAR-T blood is then transported back to the hospital, and the patient is administered with the CAR-T to treat their condition.

What conditions can CAR-T Cell Therapy treat?
Currently, NICE has approved CAR-T use in the NHS, where all other treatment options have been unsuccessful for relapsed or refractory B-cell acute lymphoblastic leukaemia (ALL) in people up to the age of 25 years. A second one has been approved for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more systemic therapies.

Diagram Description automatically generated
Depiction of adoptive cell transfer therapy with CAR-engineered T cells

Attribution: Caron A. Jacobson and Jerome Ritz, Public domain, via Wikimedia Commons. The file has been identified as being free of known restrictions under copyright law, including all related and neighbouring rights.
File URL: https://upload.wikimedia.org/wikipedia/commons/a/a2/CAR-Engineered_T-Cell_Adoptive_Transfer.jpg

Side Effects/Risks[13]
Chimeric antigen receptor (CAR) T-cell therapy is a recent promising therapeutic development for the treatment of various relapsing blood and bone marrow cancers, including lymphoma, myeloma, leukaemia, and sarcoma.

Whilst the therapy itself has shown incredible therapeutic responses in patients, the side effects are significant and toxic. The two major adverse effects of CAR T-cell therapy are Cytokine Release Syndrome (CRS) and Neurotoxicity.

Cytokine Release Syndrome
Cytokine Release Syndrome[14] is caused by a large, rapid release of cytokines into the blood from immune cells affected by immunotherapy. Cytokines are immune substances that have many different actions in the body. Signs and symptoms of cytokine release syndrome include:

  • Fever
  • Nausea
  • Headache
  • Rash
  • Tachycardia (abnormally rapid heartbeat)
  • Low blood pressure
  • Trouble with breathing

Most patients have a mild reaction, but sometimes, the reaction may be severe or life-threatening.

Neurotoxicity
Some of the common neurotoxic effects of the treatment include[15]:

  • Headache
  • Cerebral oedema
  • Delirium (mental confusion)
  • General weakness
  • Cognitive changes
  • Encephalopathy (brain-damaging disease)
  • Seizures
  • Tremors
  • Ataxia (uncoordinated balance)
  • Capillary leakage (fluid and proteins leaking out of tiny blood vessels and flowing into surrounding tissues, resulting in dangerously low blood pressure)
  • Cardiac arrest
  • Cardiac arrhythmias
  • Cardiac failure
  • Hemophagocytic lymphohistiocytosis (life-threatening immune system activation) /macrophage activation syndrome (life-threatening activation of macrophages) (HLH/MAS)
  • Hypoxia (lack of oxygen reaching the tissue)
  • Renal insufficiency (poor kidney function)
  • Poor lung oxygenation
  • Multiple organ failure

History and Timeline
What many people might not realise is that this innovative therapy is the culmination of more than 60 years of dedicated research using knowledge of the immune system, genetic engineering, antibody therapy, and a deep understanding of the underpinnings of blood cancers. In the 1950s, medical knowledge of the procedure known as bone marrow transplantation laid the groundwork for developing this therapy. This was the first concept of infusing cells into blood cancer patients to control cancer and understanding that T cells have the power to kill cancer cells.[16]

The 2000s marked the emergence of targeted therapies like imatinib (Gleevec) and trastuzumab (Herceptin) -drugs that find and kill cancer cells by homing in on specific molecular changes seen primarily in those cells. Dozens of targeted therapies are now standard treatments for many cancers. And over the past decade, immunotherapy—therapies that enlist and strengthen the power of a patient’s immune system to attack tumours—has rapidly become what many call the “fifth pillar” of cancer treatment. That’s because immune system–boosting drugs have shown the ability to shrink and even eradicate tumours in some people with advanced cancer. These treatment responses can last for years in a small percentage of patients. Drugs called immune checkpoint inhibitors, for instance, are already in broad use to treat people with many types of cancer, including melanoma, lung, kidney, bladder, and lymphoma. But another form of immunotherapy, called CAR T-cell therapy, has also generated considerable excitement among researchers and oncologists. Although CAR T-cell therapies are not as widely used as immune checkpoint inhibitors, they have shown the same ability to eradicate very advanced leukaemias and lymphomas and to keep the cancer at bay for many years. Since 2017, six CAR T-cell therapies have been approved by the US Food and Drug Administration (FDA). All are approved for treating blood cancers, including lymphomas, some forms of leukaemia, and, most recently, multiple myeloma.[17]

The first chimeric receptors[18] containing portions of an antibody and the T cell receptor was described in 1987 by Yoshihisa Kuwana et al.[19] at the Institute for Comprehensive Medical Science in Aichi, Japan and independently in 1989 by Gideon Gross and Zelig Eshhar[20] at the Weizmann Institute in Israel.[21] Originally termed “T-bodies”, these early approaches combined an antibody’s ability to specifically bind to diverse targets with the constant domains of the TCR-α or TCR-β proteins.[22]

Specific Information about the History and Timeline of Chimeric Antigen Receptors Cell Therapy (CAR-T)

Who is eligible for the treatment?
A panel of expert clinicians will decide the decision on which patients are eligible following a referral from a specialist doctor. You should speak to your consultant about whether CAR-T is the right treatment; if so, they will advise you on the referral route. NHS say that the treatment will be available to patients across the country (UK).

Where is the treatment available, and which centres will be providing the treatment?
NHS England has been working with The Joint Accreditation Committee ISCT-Europe and EBMT[23] (JACIE) and the life sciences companies to get centres up and running and have been working with nine centres across the country, According to the NHS website, the following centres will be able to provide CAR-T for acute lymphoblastic leukaemia for children and young people (up to the age of 25)[24]:

  • Cambridge University Hospitals NHS Foundation Trust
  • Great Northern Children’s Hospital (Newcastle)
  • Great Ormond Street Hospital
  • King’s College Hospital
  • Leeds Teaching Hospitals NHS Trust
  • Manchester Royal Infirmary
  • Queen Elizabeth Hospital (Birmingham)
  • Royal Manchester Children’s Hospital
  • Royal Marsden Hospital
  • The Christie NHS Foundation Trust
  • University College London Hospital
  • University Hospitals Bristol NHS Trust

The following centres will be able to provide CAR-T for adults with large B-cell lymphoma[25]:

  • Cambridge University Hospitals NHS Foundation Trust
  • King’s College Hospital
  • Leeds Teaching Hospitals NHS Trust
  • Manchester Royal Infirmary
  • Newcastle Hospitals NHS Foundation Trust
  • Queen Elizabeth Hospital Birmingham
  • Royal Marsden Hospital
  • The Christie NHS Foundation Trust
  • University College London Hospital
  • University Hospitals Bristol NHS Trust

Therapies currently[26] available
Examples of CAR T cell therapies currently approved[27] include:

  • Tisagenlecleucel, also known as tisa-cel (Kymriah)
  • Axicabtagene ciloleucel, also known as axi-cel (Yescarta)
  • Brexucabtagene autoleucel, also known as brexu-cel (Tecartus)
  • Lisocabtagene maraleucel, also known as liso-cel (Breyanzi)
  • Idecabtagene vicleucel, also known as ide-cel (Abecma)
  • Ciltacabtegene autoleucel, also known as cilta-cel (Carvykti)
Sources and Further Reading

CAUTION: This paper is not medical advice. No advice is implied or given in articles published by us but is only for general information. You should always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. This paper is compiled from the sources stated but has not been medically reviewed. It should never be used as a substitute for obtaining advice from your Doctor, a consultant Oncologist or Hematologist or other qualified clinician/medical practitioner. If you have already been given dietary advice, you should not make changes without first talking to your GP, consultant or dietitian. Any medications mentioned may include names for US drugs which may have a different name to those available in the UK. The facts are believed to be correct as at the date of publication, but there may be certain errors and omissions for which we cannot be responsible. There is no implied endorsement or promotion of any organisation by the writer. The hyperlinks were valid at the date of publication.

  1. Chimeric antigen receptors are also known as CARs, chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors. Source: https://en.wikipedia.org/wiki/Chimeric_antigen_receptor_T_cell ↑
  2. See: https://www.england.nhs.uk/2018/11/first-children-with-cancer-to-begin-treatment-with-revolutionary-car-t-therapy/ © Crown Copyright acknowledged ↑
  3. See: https://www.england.nhs.uk/2018/10/nhs-england-strikes-deal-for-ground-breaking-cancer-treatment-in-a-new-european-first/ © Crown Copyright acknowledged ↑
  4. Source: Tang XJ, Sun XY, Huang KM, Zhang L, Yang ZS, Zou DD, Wang B, Warnock GL, Dai LJ, Luo J (December 2015). “Therapeutic potential of CAR-T cell-derived exosomes: a cell-free modality for targeted cancer therapy”. Oncotarget. 6 (42): 44179–90. doi:10.18632/oncotarget.6175. PMC 4792550. PMID 26496034. ↑
  5. Source: Research, Center for Biologics Evaluation and (2019-04-05). “KYMRIAH (tisagenlecleucel)”. FDA. ↑
  6. Source: Research, Center for Biologics Evaluation and (2022-03-01). “Approved Cellular and Gene Therapy Products”. FDA. ↑
  7. Source: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/car-t-cell-therapy ↑
  8. See: https://www.england.nhs.uk/wp-content/uploads/2018/12/Axicabtagene-Ciloleucel-Chimeric-Antigen-Receptor-T-Cell-CAR-T-Therapy-for-the-treatment-of-adult-patients-wit.pdf ↑
  9. See: https://www.england.nhs.uk/wp-content/uploads/2018/12/Tisagenlecleucel-Chimeric-Antigen-Receptor-T-Cell-CAR-T-Therapy-for-ALL-and-DLBCL.pdf © Crown Copyright acknowledged ↑
  10. Ibid ↑
  11. Explanation: Tisagenlecleucel, sold under the brand name Kymriah, is a CAR T cells medication for the treatment of B-cell acute lymphoblastic leukemia (ALL) which uses the body’s own T cells to fight cancer (adoptive cell transfer). Serious side effects occur in most patients. The most common serious side effects are cytokine release syndrome (a potentially life-threatening condition that can cause fever, vomiting, shortness of breath, pain and low blood pressure) and decreases in platelets (components that help the blood to clot), hemoglobin (the protein found in red blood cells that carries oxygen around the body) or white blood cells including neutrophils and lymphocytes. Serious infections occur in around three in ten diffuse large B-cell lymphoma (DLBCL) patients. T cells from a person with cancer are removed, genetically engineered to make a specific chimeric cell surface receptor with components from both a T-cell receptor and an antibody specific to a protein on the cancer cell, and transferred back to the person. The T cells are engineered to target a protein called CD19 that is common on B cells. A chimeric T cell receptor (“CAR-T“) is expressed on the surface of the T cell. Source: https://en.wikipedia.org/wiki/Tisagenlecleucel#cite_note-Kymriah_EPAR-5 ↑
  12. Source: https://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/immunotherapy/types/CAR-T-cell-therapy ↑
  13. See: https://www.news-medical.net/health/Neurotoxic-Side-Effects-of-CAR-T-Cell-Therapy.aspx ↑
  14. Source: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/cytokine-release-syndrome ↑
  15. Sources: https://www.news-medical.net/health/Neurotoxic-Side-Effects-of-CAR-T-Cell-Therapy.aspx, and https://www.lls.org/treatment/types-treatment/immunotherapy/chimeric-antigen-receptor-car-t-cell-therapy ↑
  16. Attributed to: https://www.lls.org/sites/default/files/National/USA/Pdf/LLS-CAR-T-cell-Therapy-Timeline.pdf ↑
  17. Source and Attributed to: https://www.cancer.gov/about-cancer/treatment/research/car-t-cells ↑
  18. Text referenced to: https://en.wikipedia.org/wiki/Chimeric_antigen_receptor_T_cell ↑
  19. Source: Kuwana, Y.; Asakura, Y.; Utsunomiya, N.; Nakanishi, M.; Arata, Y.; Itoh, S.; Nagase, F.; Kurosawa, Y. (1987-12-31). “Expression of chimeric receptor composed of immunoglobulin-derived V regions and T cell receptor-derived C regions”. Biochemical and Biophysical Research Communications. 149 (3): 960–968. doi:10.1016/0006-291x(87)90502-x. ISSN 0006-291X. PMID 3122749. ↑
  20. Sources: (1) Gross G, Gorochov G, Waks T, Eshhar Z (February 1989). “Generation of effector T cells expressing chimeric T cell receptor with antibody type-specificity”. Transplantation Proceedings. 21 (1 Pt 1): 127–30, and (2) Rosenbaum L (October 2017). “Tragedy, Perseverance, and Chance – The Story of CAR-T Therapy”. The New England Journal of Medicine. 377 (14): 1313–1315. doi:10.1056/NEJMp1711886. PMID 28902570 ↑
  21. Source: Gross G, Waks T, Eshhar Z (December 1989). “Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity”. Proceedings of the National Academy of Sciences of the United States of America. 86 (24): 10024–8. Bibcode:1989PNAS…8610024G. doi:10.1073/pnas.86.24.10024. JSTOR 34790. PMC 298636. PMID 2513569. ↑
  22. Source: Eshhar, Z.; Bach, N.; Fitzer-Attas, C. J.; Gross, G.; Lustgarten, J.; Waks, T.; Schindler, D. G. (1996). “The T-body approach: potential for cancer immunotherapy“. Springer Seminars in Immunopathology. 18 (2): 199–209. doi:10.1007/BF00820666. ISSN 0344-4325. PMID 8908700. S2CID 19872173. ↑
  23. See: https://www.ebmt.org/jacie-accreditation ↑
  24. Source: https://www.england.nhs.uk/cancer/cdf/car-t-therapy/ © Crown Copyright acknowledged ↑
  25. Ibid ↑
  26. As at July 2022 ↑
  27. Source: https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/car-t-cell1.html ↑

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Martin Pollins

Martin Pollins is a Chartered Accountant and MBA with wide experience in corporate finance and business management. He has served on the boards of several companies, including those listed on the London Stock Exchange, AIM and OFEX. He is the Chairman and Founder of OneSmartPlace and was a Council member of the Institute of Chartered Accountants in England and Wales from 1988 to 1996. He was managing partner of PRB Martin Pollins, based in Sussex, the first Accountancy firm to advertise on British television. He went on to create and launch the CharterGroup Partnership (the UK’s first Accountancy network) and then LawGroup UK (at the time, one of the largest networks of lawyers in the UK). In recent years, he helped to raise several £millions to fund British films such as The Da Vinci Code, Bridge of San Luis Rey, Head in the Clouds and Merchant of Venice with actors such as Charlize Theron, Robert De Niro, Al Pacino, F. Murray Abraham. Kathy Bates, Gabriel Byrne, Geraldine Chaplin, Tom Hanks, Ian McKellen, Audrey Tautou, Penélope Cruz, Steven Berkoff, Lynn Collins, Jeremy Irons, Joseph Fiennes and many more. He has written several business publications (see https://onesmartplace.com/resources/)

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