The Triple Helix @ UChicago

Spring 2018

"Chimeric Antigen Receptor T Cell Therapy" by Rose Cytryn

 

Typically, especially as highlighted in movies and TV, chemotherapy and transplantation are the treatments of cancer.  The foundation for these treatments is the removal of harmful cells using an agent from outside the body. Chemotherapy and radiation treatments often follow the idea that once a cancer has begun to affect the body through rapid proliferation introducing new agents is advantageous because the body is compromised. 

Generally, chemotherapy treatments use cytostatics to prevent the uncontrollable proliferation of cancer cells. Typically given intravenously, chemotherapy targets rapidly dividing cells, like cancer cells, to rid the body of cancer.  Chemotherapy treatments aim to bring about remission by targeting and eliminating rapidly dividing cells, an important hallmark of cancer.  This inhibition of division occurs at various levels of the life of a cancer cell.  Certain chemotherapies target cells during mitosis, cell division, aim to prevent enzymes and hormones from providing nutrition to cancerous cells, trigger apoptosis, or block the growth of blood vessels to support further tumor suppression. The various aims of chemotherapy treatments allow them to generally be split into one of four categories, alkylating agents, antimetabolites, plant alkaloids, and antitumor antibiotics.  Alkylating agents and antitumor antibiotics, both of which target the DNA of rapidly dividing cells, as well as plant alkaloids, work to block synthesis and reproduction of cancerous cells, while antimetabolites aid in cell death through the mimicry of proteins cancerous cells rely on for survival. 

It is, however, this generality of chemotherapy treatments which also makes them harmful.  The ability of chemotherapy treatments to effectively kill rapidly dividing cells often extends to normal and healthy cells in the human body which, by nature, divide rapidly, specifically cells of the blood, mouth, stomach, bowels, and hair.  The indirect effect chemotherapy has on these cells produce varying side effects from alopecia (hair loss) and nausea, to issues with blood clotting and anemia.  They are shown to lead to problems with short term memory and depression. The introduction of such drugs into the system of a patient with cancer and the following behaviors of chemotherapy therapies and subsequent side effects helped to pave the way for the search for new methods of treating cancer.

The basis of CAR (chimeric antigen receptor) T cell therapy, is that T cells, which are a type of immune cell, can provide a more direct and specific targeting approach to the elimination of cancerous cells, while not subjecting a patient to foreign and often simultaneously harmful medication.  The hope is that through CAR T cell therapy, the patient’s own body can recognize and eliminate their own cancer.  The foundation for T cell therapy lies in the removal of T cells from a patient with cancer and the modification of these immune cells to contain cancer-recognizing proteins.  These cells are then grown and given back to the patient with the goal of persisting within the body as a drug which continuously grows.  

In 1989, Zelig Eshhar made the first CAR T cell.  The goal of his work was to redirect the specificity with which T cells typically operate and, in doing so, focus the T cell engineering on a cancer-specific antigen.  This idea meant that a patient’s very own cells could be modified in such a way that the patient could host the cells curing their own cancer.

The first T cells synthesized were composed of an extracellular binding domain, a section which exists externally from the cell and recognizes and responds to ligands, usually neurotransmitters or hormones.  The extracellular binding domains aid most in the specificity in relation to the tumor antigen.  That is, the ability of T cells to be able to recognize foreign substances – antigens – and present them in such a way that they are recognizable by processes in the body which can eliminate them.  Hinge regions are also present and as stretches of amino acids, allow for flexibility and construction within the cell.  The initial CAR T cell also had transmembrane and signaling domains which aided in the recognition of foreign species outside the cell, as well as a CD3 intra cellular signaling domain, which allowed for the transmitting of signals.  This was a main point of evolution for future generations of CAR T cells.  

While it seems that the introduction of this treatment to the medical world, which occurred over 30 years ago, should reduce the excitement which surrounds it, the Food and Drug Administration (FDA) did not approve CAR T cell therapy until October 18, 2017.  At this point, they approved the release and use of CAR T cells for specific types of non-Hodgkin lymphoma, marking an incredible moment in the work of gene modification and use in treatment of serious and fatal diseases.

The present-day structure and specification of CAR T cells has evolved greatly from Eshhar’s lab in 1989.  In CAR T therapies such asAxicabtagene ciloleucel (Yescarta), the second of such therapies to be approved, T cells are removed from a patient and grown in the lab to produce an immune cell containing anti-CD19.  CD19 is a marker of B cells and is useful as many malignancies originating in B cells present with high levels of this antigen.  When T cells are modified to express anti-CD19 immunotoxins, their chimeric antigen receptors, and introduced to a patient with non-Hodgkin lymphoma, the modified receptor signals a cascade which leads to lysis of the specifically targeted CD19 B cells – the cancerous cells.  Trials conducted observing treatment using Yescarta showed that, out of over 100 adult patients with B-cell lymphoma, 51% experienced complete remission after treatment.

The novelty of such treatments, however, makes them expensive.  Yescarta treatment for adults stands at $373,000 for one treatment. The funds needed to continue CAR T cell research are incredibly high despite the groundbreaking results being seen in multiple studies, and the specificity of each dosage as well as the 2-4 weeks each dosage takes to prepare make each round of treatment that much more rare and expensive. It is the immensity and potential to heal which these therapies have that push insurance companies, leading cancer organizations, and research centers to work to structure payment plans and models which will allow patients to afford this treatment.  Still, this is an immensely significant moment in cancer’s history.  Therapies of this nature are reworking and redefining the way cancer is treated, not only physiologically but also with regard to the experience of the patient.  Chemotherapy, while still effective, is slowly being replaced by individualized treatments, as cancer treatment becomes more personal.

  

References

[1] “Chimeric Antigen Receptor (CAR) T-Cell Therapy.” Leukemia & Lymphoma Society. n.d. http://www.lls.org/treatment/types-of-treatment/immunotherapy/chimeric-antigen-receptor-car-t-cell-therapy

[2] Hussel, Tracy. “T Cells.” British Society for Immunology. n.d. https://www.immunology.org/public-information/bitesized-immunology/cells/t-cells  

 
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