Cellular Explanation of CAR T-cell Therapy

Immunotherapy is a type of treatment that uses the body's own immune system to fight cancer (Leukemia & Lymphoma Society, 2015). One type of immunotherapy is chimeric antigen receptor T-cell therapy. This treatment has been linked to curing acute lymphoblastic leukemia (ALL), the most common cancer in children (Pehlivan, Duncan, & Lee, 2018). An antigen is a substance on a cell that has the ability to trigger immune responses (Britannica, 2016). A chimeric antigen receptor (CAR) is a protein that can latch onto CD19 antigens, which are found on the cancer cells in ALL (Johns Hopkins Medicine, 2019).

T-cells are white blood cells that fight disease by latching onto antigens of diseased cells and injecting them with toxins (Dana-Farber Cancer Institute, 2017). Normal T-cells do have the ability to kill cancer cells, but not efficiently (MD Anderson Cancer Center, 2019). This is because cancer cells have been able to elude the immune system by disguising as healthy cells or altering their surface to make it nearly impossible for cells to bind to them (Dana-Farber Cancer Institute, 2017).

During CAR T-cell therapy, the doctors will draw blood from a patient with leukemia.

From there, they perform apheresis, the process of isolating the T-cells from the rest of the blood (MD Anderson Cancer Center, 2019). Afterward, an inactive virus is put into the T-cell to genetically modify them to kill leukemia cells. These T-cells are now called CAR T-cells because they contain CARs on their surface (Dana-Farber Cancer Institute, 2017). The CAR T-cells are then grown so there are more of them, then cryopreserved in liquid nitrogen until they are ready to be infused back into the patient (Weinkove, 2019). Cryopreservation is the process of preserving at low temperatures (Pegg, 2007). It allows the doctors to run more tests and ensure the CAR T-cells are safe for the patient (Weinkove, 2019). Finally, the CAR T-cells are infused into the patient's bloodstream. The hope is that they will bind to CD19 antigens on leukemia cells then eliminate them by releasing toxins called cytokines (Benmebarek et al., 2019).

While CAR T-cell therapy has been a successful treatment for many patients, there are side effects. The main side effect is cytokine release syndrome (CRS). T-cells release cytokines as part of their function to help the immune system. But in CRS, cytokines are released in excessive amounts (National Cancer Institute, 2016). As a result, the patient may experience fever, low blood pressure, difficulty breathing, and difficulty handling fluid. CRS can occur within the first week after receiving CAR T-cell therapy (Johns Hopkins Medicine, 2019).

Another side effect of CAR T-cell therapy is B-cell aplasia. Like leukemia cells, B-cells also express CD19 antigens on their surface. Thus, CAR T-cells will target B-cells in addition to the cancerous ones. Patients with B-cell aplasia may receive immunoglobulin therapy. This is because it provides antibodies to fight off infection, doing the job that a normal B-cell would do (National Cancer Institute, 2016). Although CAR T-cell therapy comes with side effects, they are not as severe as the prolonged side effects that can arise with chemotherapy and transplants (Johns Hopkins Medicine, 2019).

Bibliography

Benmebarek, M.-R., Karches, C. H., Cadilha, B. L., Lesch, S., Endres, S., & Kobold, S. (2019). Killing Mechanisms of Chimeric Antigen Receptor (CAR) T Cells. International Journal​ of Molecular Sciences​, 20​ ​(6), 1283. https://www.ncbi.nlm.nih.gov/pubmed/3087573​ 9

This article is from the National Center for Biotechnology Information (NCBI), which contains many scientific abstracts on medical and biological topics. The authors of this abstract work are members of the German Center for Lung Research in Munich, Germany. They explain the release of cytokines in CAR T-cells, which was helpful in understanding what CAR T-cells do to kill leukemia cells.

Dana-Farber Cancer Institute. (2017). CAR T-Cell Therapy: How Does It Work? [YouTube Video]. Retrieved from https://www.youtube.com/watch?v=OadAW99s4I​ k

This video was made by the Dana-Farber Cancer Institute, a group of oncologists in Boston who have been doing research on CAR T-cell therapy for curing leukemia. It provided an overview on how CAR T-cell therapy works using animations that added a clearer understanding. It was a good source to go to first because the information was all introductory and to-the-point.

Johns Hopkins Medicine. (2019). CAR T-Cell Therapy | FAQ with Dr. Patrick Brown [YouTube Video]. Retrieved from https://www.youtube.com/watch?v=RpD69Z-Xco​ 4

Dr. Patrick Brown is the director of the pediatric leukemia program at Johns Hopkins Medicine. In this video, he answers many frequently asked questions that people have about CAR T-cell therapy for ALL treatment. While he did have a lot to say about the treatment process, I mainly used this video for information on the risks that can arise from this treatment, especially the CRS side effects.

Leukemia & Lymphoma Society. (2015, September 10). Chimeric Antigen Receptor (CAR) T-Cell Therapy | Leukemia and Lymphoma Society. Retrieved from Lls.org website: https://www.lls.org/treatment/types-of-treatment/immunotherapy/chimeric-antigen-recept or-car-t-cell-therapy

The Leukemia & Lymphoma Society provides credible information on leukemias and lymphomas while also providing support for patients with these diseases. Their page on CAR T-cell therapy contained graphics explaining the steps of the treatment in good detail. Like Johns Hopkins, the Leukemia & Lymphoma Society went over the risks that can arise with CAR T-cell therapy. Both sources explained CRS, but the Leukemia & Lymphoma Society was the only one that provided detailed information on B-cell aplasia.

MD Anderson Cancer Center. (2019). CAR T-cell therapy for cancer treatment: How it works [YouTube Video]. Retrieved from https://www.youtube.com/watch?v=UZpHu0gl6L​ U

The MD Anderson Cancer Center is involved in various types of cancer research, including leukemia. Similar to the video by the Dana-Farber Cancer Institute, this​ provided a brief overview of CAR T-cell therapy. Dr. William Wierda, a physician at the MD Anderson Cancer Center, was the narrator of this video. In addition to the brief overview, he mentioned the side effects of CAR T-cell therapy, but did not go into detail like the Leukemia & Lymphoma Society did.

National Cancer Institute. (2016). CAR T Cells: Engineering Immune Cells to Treat Cancer. Retrieved from National Cancer Institute website: https://www.cancer.gov/about-cancer/treatment/research/car-t-cells

Like the Leukemia & Lymphoma society, the National Cancer Institute is devoted to​ providing credible information on various cancers and support for patients with cancer. Their page on CAR T-cell therapy was helpful in explaining how CAR T-cells are made and how their structures are used to perform the function of destroying leukemia cells. There was quite a lot of information in this article that was easy to understand, and the pictures added more understanding to the text.

New York Presbyterian Hospital. (2019). Why CAR T-cell therapy is a "fast, furious and focused" cancer treatment [YouTube Video]. Retrieved from https://www.youtube.com/watch?v=LNX-ywebx-0

This video was made by the The New York Presbyterian Hospital's hematology & oncology department. The narrator of the animation, Dr. Satwani, did a lot of comparison​ between CAR T-cells and normal T-cells. Similar to Dana-Farber, the visual animations added a clearer understanding. This was helpful when the video was comparing CAR T-cell structures to normal ones, and how their abilities to kill cancer cells are different.

Pegg, D. E. (2007). Principles of Cryopreservation. Cryopreservation and Freeze-Drying​ Protocols​, 39–57. https://www.ncbi.nlm.nih.gov/pubmed/1808046​ 1

Similar to the first source, this abstract also came from the NCBI. It was written by David E. Pegg, a student in the biology department at the University of York. Though this source isn't about CAR T-cell therapy, it provided an explanation on what cryopreservation is. Cryopreservation was mentioned in Dr. Weinkove's TEDx Talk, but he never specified what it was. Thus, I needed to use this to elaborate on the subject.

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

This abstract was written by three pediatric physicians of the University of Virginia's University Hospital. Two of them specialize in hematology & oncology. The abstract focused on how CAR T-cell therapy has been efficient in treating ALL specifically, compared to how most of the others were centered around the steps of the treatment.

TEDx Talks. (2019). CAR T-cell therapy: Reprogramming the immune system to treat cancer | Rob Weinkove | TEDxTauranga [YouTube Video]. Retrieved from https://www.youtube.com/watch?v=rZRsqin3lwY&t=696s

TED is an organization made for sharing ideas and education around the world. The speaker of the TEDx Talk, Dr. Robert Weinkove, works for the Malaghan Institute in New Zealand. His main studies include immunotherapies such as CAR T-cell therapy.

Weinkove was the only source who mentioned the usage of cryopreservation in CAR T-cell therapy.

The Editors of Encyclopedia Britannica. (2016). Antigen | biochemistry. In Encyclopædia​ Britannica​. Retrieved from https://www.britannica.com/science/antige​ n

Britannica is an encyclopedia with credible information on many different educational topics. Britannica provided a clear definition of an antigen, which is important to know when learning about CAR T-cell therapy. It even provided a diagram with examples of antigens being used to further enhance understanding.