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CAR T-Cell Therapy: A New Fighter in the Cancer War

Chimeric antigen receptor (CAR) T-cell therapy has initiated a new era of treating reoccurring cancers and high-risk paediatric tumours. The use of CAR T-cells to treat cancer is a form of immunotherapy, that offers more long-term results than traditional therapies, like chemotherapy or surgery. This treatment is educating the patient’s immune system to recognize cancer cells and attack them. Renier J. Brentjens, M.D., Ph.D, has successfully used the term “living drug” to describe the action of CAR T-cells (National Cancer Institute, 2022). Since 2017, the FDA has approved six CAR T-cell therapies, which target blood cancers. For example, Kymriah targets leukemias, Yescarta targets lymphoma and Abecma treats adults with multiple myeloma.


Definition of T-Cells

To understand CAR T-cells, it is important to know the function of normal T-cells. T-cells are a group of lymphocytes in the blood or the lymph tissue, that support the adaptive immune system. They have a leading role in the immune responses of the organism because they target and kill pathogens that infect the organism. The most common types of T-cells are helper T-cells, also known as CD4+ T-cells and cytotoxic or killer T-cells, also known as CD8+ T-cells. Each type of T-cell recognizes specific pathogens. T-cells have proteins on their outer surface, called receptors and these receptors recognize specific proteins on the outer surface of the pathogen. Depending on the type of T-cell, after recognizing the specific pathogen, they are either killing the pathogen (killer T-cells) or signalling to other elements of immune system to attack the pathogen (helper T-cells). T-cells protect the organism both from infections and cancer (Kumar, Connors, & Farber, 2018). Although, the action of T-cells is a strong defensive mechanism against cancer, cancer cells proliferate much faster than the human immune system can handle and develop a tumour microenvironment that prevents the attack of T-cells (Labani-Motlagh, Ashja-Mahdavi, & Loskog, 2020).


Figure 1: T-cells attacking a pathogen (News-Medical, 2023)

CAR-T Cell Therapy

CARs redirect large populations of T-cells to attack cells that carry a specific antigen. In the case of cancer, CARs bind to a specific antigen on the surface of the cancer cell and initiate an immune response. For the creation of CAR T-cells, T-cells are collected from the patient’s blood. These are then genetically modified in the lab so that they can produce CAR proteins. These proteins will be located on the outer surface of the T-cell. Their most important feature is the antigen binding domain, the part of the protein that recognises the “enemy”, which in this case are the cancer cells. A viral vector is used to knock-out the original T-cell receptors and instead express the CAR construct on the surface of the cell. Millions of CAR T-cells are then grown and re-introduced into the patient's bloodstream (Jaspers & Brentjens, 2017). In the case of leukaemia, an excessive number of B-cell lymphoblasts is found in the bone marrow and in the blood. CD19 is an antigen exclusively present on the surface of B-cells. After engineering the T-cell to express anti-CD19 antibodies (CAR construct) on their surface, CAR will redirect them to target CD19 on leukaemic cells. This is an extremely elegant technique, that specifically focuses the immune response on the enemy cells (Maude et al., 2014).


Figure 2: Creation of CAR T-cell Therapy (National Cancer Institute,2022)

Some Recent Advancements

One of the benefits of CAR T-cell therapy is its specificity. This is achieved by optimisation of the CAR. Three generations of CD19 CARs have been produced, slightly altering the structure of the CAR. Researchers are aiming in adding co-stimulatory elements on the CAR T-cell. Co-stimulation enhances the in vivo expansion of T-cells and persistence in the blood of the patient (Savoldo et al., 2011). Second generation CARs are preferred to third generation as they are preserved for longer periods of time. For example, the FDA approved CAR T-drug, Tisagenlecleucel (Kymriah), uses the second generation CAR (Rosenbaum, 2017).


One of the major advantages of CD19 CAR T-cell therapy is that it successfully fights the relapse of some cancers, such as the B-cell acute lymphocytic leukaemia (ALL). Clinical trials have shown about 90% complete relapse, with no relapse beyond 12 months and long-lasting cure. Increased remission rates from various clinical trials, which use different CAR constructs and delivery methods, demonstrate the suitability and efficacy of this treatment. This immunotherapy is applicable in a wide range of patients with different molecular and clinical backgrounds. Moreover, studies have shown that it can also be applied to treat solid tumours, such as medulloblastoma (Donovan et al., 2020).


Current Limitations

Despite the elegance and the efficiency of the technique, there are some limitations in the use of CAR T-cells that need to be addressed. First of all, toxicity and targeting issues are still impeding the wider application of CAR T-cell therapy. After T-cells are activated, they produce cytokines that stimulate activation of other T-cells. This leads to a repeated production of cytokines, known as a cytokine storm. Accumulation of cytokines may produce a series of toxic events called Cytokine Release Syndrome (CRS), which generates symptoms of fever, hypoxia, and neurological disturbances (Davila et al., 2014). CRS is successfully being treated with Tocilizumab (Fitzgerald et al., 2017). Another drawback of CAR therapy is that non-tumour B-cells are often targeted. This is known as B-cell aplasia. This issue is usually addressed with Immunoglobulin supplementation, but there is no comprehension of the long-term consequences of B-cell aplasia (Pehlivan et al., 2018). Neurotoxicity is another side effect that usually arises after CRS and it causes confusion, hallucinations, seizures and cerebral edema. Research has not been successful in understanding the pathophysiology of neurotoxicity and treating it (Gardner et al., 2016). The correlation between dosage and efficacy of the CAR T therapy is still unclear and is also impossible to predict which patients will recover from relapse and which will not. Moreover, vectors are not always successful in transfecting all T-cells. Since genetic engineering is a technique that is still being investigated and improved, the techniques to target and edit T-cells have not been optimised yet.


Figure 3: Electron micrograph of chronic lymphocytic leukaemia (Kolata, 2022)

Conclusion

CAR T-cells are beyond doubt a revolutionary treatment against cancer. Their main advantage against traditional treatments is their improved specificity, that reduces the risk of killing healthy cells in the patient’s body. Unfortunately though, the toxicity events are still high even with the use of CAR T-cells, but lab-research and clinical trials are currently trying to overcome this obstacle. Although CAR T-cells are not currently thought as a first-line treatment for cancer, this therapy promises long-term remission both for children and adult cancers, as the CAR T-cells can stay in the body for a long time to fight cancerous cells.



Bibliographical References

Davila, M. L., Riviere, I., Wang, X., Bartido, S., Park, J., Curran, K., … Brentjens, R. (2014). Efficacy and toxicity management of 19-28Z car T cell therapy in B cell acute lymphoblastic leukemia. Science Translational Medicine, 6(224). doi:10.1126/scitranslmed.3008226

https://www.science.org/doi/10.1126/scitranslmed.3008226


Donovan, L. K., Delaidelli, A., Joseph, S. K., Bielamowicz, K., Fousek, K., Holgado, B. L., … Taylor, M. D. (2020). Locoregional delivery of car T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and Ependymoma. Nature Medicine, 26(5), 720–731. doi:10.1038/s41591-020-0827-2

https://doi.org/10.1038/s41591-020-0827-2


Fitzgerald, J. C., Weiss, S. L., Maude, S. L., Barrett, D. M., Lacey, S. F., Melenhorst, J. J., … Teachey, D. T. (2017). Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Critical Care Medicine, 45(2). doi:10.1097/ccm.0000000000002053

https://journals.lww.com/ccmjournal/Abstract/2017/02000/Cytokine_Release_Syndrome_After_Chimeric_Antigen.37.aspx


Gardner, R., Wu, D., Cherian, S., Fang, M., Hanafi, L.-A., Finney, O., … Turtle, C. J. (2016). Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-all from CD19 car-T-cell therapy. Blood, 127(20), 2406–2410. doi:10.1182/blood-2015-08-665547

https://doi.org/10.1182/blood-2015-08-665547


Jaspers, J. E., & Brentjens, R. J. (2017). Development of CAR T cells designed to improve antitumor efficacy and safety. Pharmacology & Therapeutics, 178, 83–91. doi:10.1016/j.pharmthera.2017.03.012

https://doi.org/10.1016/j.pharmthera.2017.03.012


Kumar, B. V., Connors, T. J., & Farber, D. L. (2018). Human T cell development, localization, and function throughout life. Immunity, 48(2), 202–213. doi:10.1016/j.immuni.2018.01.007

https://doi.org/10.1016/j.immuni.2018.01.007


Labani-Motlagh, A., Ashja-Mahdavi, M., & Loskog, A. (2020). The tumor microenvironment: A milieu hindering and obstructing antitumor immune responses. Frontiers in Immunology, 11. doi:10.3389/fimmu.2020.00940

https://doi.org/10.3389/fimmu.2020.00940


Maude, S. L., Frey, N., Shaw, P. A., Aplenc, R., Barrett, D. M., Bunin, N. J., … Grupp, S. A. (2014). Chimeric antigen receptor T cells for sustained remissions in leukemia. New England Journal of Medicine, 371(16), 1507–1517. doi:10.1056/nejmoa1407222

https://www.nejm.org/doi/10.1056/NEJMoa1407222


National Cancer Institute (2022). Retrieved from

https://www.cancer.gov/about-cancer/treatment/research/car-t-cells


Pehlivan, K. C., Duncan, B. B., & Lee, D. W. (2018). Car-T cell therapy for acute lymphoblastic leukemia: Transforming the treatment of relapsed and refractory disease. Current Hematologic Malignancy Reports, 13(5), 396–406. doi:10.1007/s11899-018-0470-x

https://doi.org/10.1007/s11899-018-0470-x


Rosenbaum, L. (2017). Tragedy, perseverance, and chance — the story of Car-T therapy. New England Journal of Medicine, 377(14), 1313–1315. doi:10.1056/nejmp1711886

https://www.nejm.org/doi/10.1056/NEJMp1711886


Savoldo, B., Ramos, C. A., Liu, E., Mims, M. P., Keating, M. J., Carrum, G., … Dotti, G. (2011). CD28 costimulation improves expansion and persistence of chimeric antigen receptor–modified T cells in lymphoma patients. Journal of Clinical Investigation, 121(5), 1822–1826. doi:10.1172/jci46110

https://doi.org/10.1172/JCI46110


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Matina Laskou

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