CAR T-cell Therapy: A new approach to enhancing the immune response to blood cancer

By Cristina Riquelme V.

An ageing world population has brought with it a growing cancer occurrence rate, thus placing cancer as one of the leading public health crises in the 21st century; 2018 saw 9.6 million deaths worldwide attributed to cancer (Cancer research UK, 2019). This has, however, spurred scientists and disease specialists across the globe into collaborative action, developing novel therapies and approaches with the aim to improve the prospects of cancer patients. In the last few decades, immunotherapy has become an important part of treating some types of cancer – new immunotherapy treatments are being trialed, and new ways of working with the immune system are being discovered at a very fast pace. One of the recent immunotherapies has been Chimeric antigen receptor (CAR) T-cell therapy, also known as a type of adoptive cell transfer, primarily for blood cancers such as leukaemia and lymphoma (Hucks and Rheingold, 2019).

CAR T-cell therapy is a very complex treatment whereby doctors take T-cells from a patients’ body and genetically modify these cells in the lab to better target cancer cells. Then, millions of these target-seeking cells are put back into the cancer patients’ body to effectively fight the cancerous cells. However, before delving into CAR T-cell therapy itself, it is very important to understand what T-cells are and the importance of their role in the immune system.

T cells or T lymphocytes are white blood cells that take part in the cellular response of the immune system. In other words, T cells move around the body to identify and destroy defective cells, amongst which are cancer cells. T cells search for cells marked as being ‘foreign’ through their lack of self-antigens. Once they flag a non-self antigen, they activate mechanisms to kill it. However, in some cases, this is not always effective –  one such case is when the defence mechanisms are not fully activated, allowing the cancer cells to rapidly proliferate and spread; another case is when the cancer cells are very similar to normal cells so the T cells do not fully act on them as they should – allowing the cancer cells to hide away and remain unrecognised.

Scientists are trying to find ways to improve the recognition ability of T cells to cancer cells. This is where CAR T-cell therapy comes in, which works by powering up your immune system through the addition of a specific receptor, making it easier for T cells to find and attack your cancer cells (Hucks and Rheingold, 2019). CAR T-cell therapy has several steps. It starts with leukapheresis or T-cell collection from the patient’s blood using an apheresis machine. Then T-cells are genetically modified in a lab, where a new gene is added. This causes T-cells to sprout special proteins, known as chimeric antigen receptors (CARs), on their cell surface. CARs allow the identification of cancer cells and thereby the attack on the surface antigens of cancer cells. A few weeks are required for these modified T cells to grow and multiply to have a reasonable amount to attack cancer cells, and during that time the patient is given a low dosage of chemotherapy to reduce the numbers of unmodified T cells and other immune cells in their body. This is known as lymphodepleting chemotherapy, where decreasing competition between immune cells makes it easier for the new CAR T-cells to function on the cancer cells. CAR T-cells are then inserted into the patient’s body through a vein in the arm, much like in a blood transfusion (WebMD, 2020).

CAR T-cell therapy has been approved to treat acute lymphocytic leukemia (ALL) in children and young adults and certain types of adult non-Hodgkin’s lymphoma, following the decisions taken by the National Institute for Health and Care Excellence (NICE) in England in December 2018 and January 2019 and the Scottish Medicines Consortium (SMC) in 2019 (Cancer Research UK, 2020). However, chemotherapy and stem cell transplants remain the first choice of treatment for these diseases. However,  if they show no promising effects or the cancer returns after treatment, CAR T-cell therapy is considered an alternative treatment option. Although it is a relatively new approach, this treatment has already been observed to have some known side effects such as cytokine-release syndrome, neurological side effects and no or decreased numbers of B cells that target the antigen CD19 after CAR T-cell treatment (Gust et al., 2017). Moreover, the price of this treatment lies in the hundreds of thousands, which remains a limiting factor to its accessibility to the general population, particularly in developing countries.

Overall, although CAR T-cell therapy offers promising results in the fight to cure cancers such as acute lymphocytic leukemia, the treatment itself is fairly new and untested in a broader range of settings. This naturally raises concerns on the longevity of results following treatment, as well as other yet-uncovered drawbacks to the health of a patient treated with CAR T-cell therapies.

References:

Cancer Research UK. 2019. Worldwide Cancer Statistics. Available at: https://www.cancerresearchuk.org/health-professional/cancer-statistics/worldwide-cancer#heading-One [Accessed 30 August 2020].

Hucks, G. and Rheingold, S.R. (2019). The journey to CAR T cell therapy: the pediatric and young adult experience with relapsed or refractory B-ALL. Blood Cancer Journal, [online] 9(2). Available at: https://www.nature.com/articles/s41408-018-0164-6.

WebMD. 2020. What Is CAR T-Cell Therapy? Immune Cell Therapy For Cancer. Available at: https://www.webmd.com/cancer/guide/what-is-car-t-cell-therapy#1 [Accessed 30 August 2020].

Cancerresearchuk.org. 2020. CAR T-Cell Therapy | Immunotherapy | Cancer Research UK. Available at:https://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/immunotherapy/types/CAR-T-cell-therapy [Accessed 31 August 2020].

Gust, J., Hay, K.A., Hanafi, L.-A., Li, D., Myerson, D., Gonzalez-Cuyar, L.F., Yeung, C., Liles, W.C., Wurfel, M., Lopez, J.A., Chen, J., Chung, D., Harju-Baker, S., Özpolat, T., Fink, K.R., Riddell, S.R., Maloney, D.G. and Turtle, C.J. (2017). Endothelial Activation and Blood–Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells. Cancer Discovery, 7(12), pp.1404–1419. Available at: https://cancerdiscovery.aacrjournals.org/content/7/12/1404 [Accessed 6 September 2020].

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