Advancements in cancer immunotherapies: CAR-T cell technology

By Yuki Agarwala

We encounter over 60,000 germs every day, yet we do not find ourselves falling sick every day due to the efficiency of our immune system.¹ We have an innate and adaptive immune system – the innate response is a general reaction that occurs early during infections, whereas the adaptive response is antigen-specific and involves the recruitment of B-lymphocytes and T-lymphocytes.² T-lymphocytes have receptors on their surface which help the cells detect the presence of non-self signals.³ This identification of pathogens and malignant cells is crucial as it helps initiate an immune response and defend the body against foreign or pathogenic substances.

One of the body’s immune responses to tumors involves infiltrating them with tumor-infiltrating lymphocytes (TILs). Such T-cells contain receptors that detect the specific mutated proteins that are present on cancer cells. To improve the body’s anti-tumor response, scientists have considered isolating the patient’s TILs from their tumor tissues, expanding them in numbers, and then transplanting them back into the patient. However, the number of TILs that are isolated from the patient may not be enough for specific cancers as their expansion may be slow. A broader approach would be to collect polyclonal T cells and genetically engineer them by inserting genes encoding for T cell receptors that are specific to the tumor antigen. This would allow scientists to target both membrane-bound and cytoplasmic proteins. Nevertheless, tumors have been shown to evade patrolling T cells by downplaying the major histocompatibility complexes (MHCs) proteins which are essential for the T cells to detect the tumor cells as non-self. Scientists overcome this by creating T cells specific to tumor-associated antigens (TAA), such that it is independent of MHCs.³

CAR-T cells or T cells modified with chimeric antigen receptors (CARs) have been used to combine the highly specific recognition domain with the T cells. Studies involving the investigation of CAR-T cell therapies have shown 50~90% complete response rates in B cell malignancies and led to the US Food and Drug Administration (FDA) approving the first CAR-T cell therapies in 2017. This triggered a revolution of cancer immunotherapies, showing the great potential that CAR-T cells have as therapeutics.³ CAR-T cells have shown very high efficiency in treating B-lineage acute lymphoblastic leukemia in patients who have previously tried other therapies including hematopoietic stem cell transplantation. In this, the CAR-T cells are engineered to target the pan-B cell marker CD19. However, up to 39% of patients relapse are shown to relapse with only CD-19 directed therapy. Fousek et al investigated the potential of combinatorial CAR-T cell therapies, which target other markers such as CD20 and CD22 which are expressed in 50%, and 80-90% of cases, respectively.⁴ In solid tumors such as glioblastomas, targeting three glioma antigens for CAR-T cell therapies has shown to be more effective than targeting two or fewer antigens, due to variability in the precise tumor antigens of the patients.⁵ While combining CAR T-cell therapies has shown higher effectiveness, studies have also shown that patients treated with anti-CD22 antibodies relapsed with CD22 negative disease, suggesting the possible resistance that could emerge from such therapies.⁴

In another study, this form of immunotherapy was used to treat patients with diffuse large B-cell lymphoma, the most common type of non-Hodgkin lymphoma. The patients involved had previously undergone multiple lines of chemotherapy and had few options when their cancers relapsed. Such patients who completed the infusion of the CAR T cells had high initial and ongoing responses. However, patients also experienced side effects in the form of cytokine release syndrome, which is characterized by a variety of symptoms including high fevers, multi-organ dysfunction, and delirium.^6-7

While CAR-T cell therapy has shown tremendous potential, especially in combating cancers in patients with disease remissions, many questions remain. The two current CD-19 specific therapies that have been approved by the US Food and Drug administration are some of the most expensive therapies, with costs reaching approximately US $400,000. With such high costs, widespread use of such personalized medicine is currently in debate, as organizations express concerns towards the large amounts of taxpayer funds that are used in the initial stages of such research.⁷ Since this therapy involves harvesting T cells from the patient, expanding, and genetically engineering them before infusing them back into the patient, it is currently unclear whether this form of personalized medicine will be available to treat large numbers of patients in clinical settings.⁸

CAR-T cell therapy shows great promise for solid and liquid tumors, where traditional approaches have been deemed ineffective in patients with cancer relapse. Recent advancements have led to the development of combinatorial treatments which target more than one tumor antigen and have shown promising results. Despite this, the high levels of cost and potential side effects associated with such technology imply that further developments will be required for CAR-T cell therapy to be regularly applied in clinical settings.

References:

1. Brownstein J, Chitale R. [Online] ABC News. ABC News Network; Available from: https://abcnews.go.com/Health/ColdandFluNews/story?id=5727571&page=1 [Accessed: 20th October 2021]
2. Parkin J, Cohen B. An overview of the immune system. The Lancet. [Online] 2001;357(9270): 1777–1789. Available from: doi:10.1016/s0140-6736(00)04904-7
3. Labanieh L, Majzner RG, Mackall CL. Programming CAR-T cells to kill cancer. Nature Biomedical Engineering. [Online] 2018;2(6): 377–391. Available from: doi:10.1038/s41551-018-0235-9
4. Fousek K, Watanabe J, Joseph SK, George A, An X, Byrd TT, et al. CAR T-cells that target acute B-lineage leukemia irrespective of CD19 expression. Leukemia. [Online] 2020;35(1): 75–89. Available from: doi:10.1038/s41375-020-0792-2
5. Bielamowicz K, Fousek K, Byrd TT, Samaha H, Mukherjee M, Aware N, et al. Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma. Neuro-Oncology. [Online] 2017;20(4): 506–518. Available from: doi:10.1093/neuonc/nox182
6. Hay AE, Cheung MC. CAR T-cells: costs, comparisons, and commentary. Journal of Medical Economics. [Online] 2019;22(7): 613–615. Available from: doi:10.1080/13696998.2019.1582059
7. Shimabukuro-Vornhagen, Alexander, et al. “Cytokine Release Syndrome.” Journal for ImmunoTherapy of Cancer, vol. 6, no. 1, 2018, https://doi.org/10.1186/s40425-018-0343-9.
8. Tran, Eric, et al. “A Milestone for CAR T Cells.” New England Journal of Medicine, vol. 377, no. 26, 28 Dec. 2017, pp. 2593–2596., https://doi.org/10.1056/nejme1714680.