Written by: Maryam Isayeva
Edited by: Julia Holder, Izzy Medrano, Jessica Liu
Illustrated by: Hutch Viscardi
Introduction
Cancer is a vicious disease with equally fierce remedies. Decades of clinical trials have come up with somewhat effective ways of dealing with the diagnosis, including chemotherapy and radiation therapy. Chemotherapy is the use of anti-cancer drugs to target cancer cells (and others in the process) [1]. Radiation therapy involves high doses of radiation being aimed at the tumor [2]. These types of treatments are also often described as double-edged swords [3]. This is because of the strenuous side effects they tend to have on patients who are already struggling due to the side effects of the tumors themselves. According to oncologists, side effects from cancer treatments can include, but are not limited to “nausea and vomiting, fatigue, decreased appetite, changes in taste, hair loss, dry mouth, and constipation” [4]. The need for methods that are kinder to the patient is obvious, and so the world of cancer treatment was revolutionized in the 2000s with the development of immunotherapy. Instead of injecting a patient with aggressive drugs to destroy the cancer cells, the new approach focused on reprogramming the immune system to attack tumors [5, 6]. One of the most successful examples of immunotherapy is Chimeric Antigen Receptor (CAR) T-cell therapy, which uses T-cells, a type of immune cell, to fight blood-based cancer [6].
History
The idea of immunotherapy is associated with Gregor Mendel’s experiments on genetics in 1865 [7]. Mendel conducted systematic crossbreeding experiments with pea plants, focusing on seven distinct traits, such as seed shape and flower color, the results of which laid the foundation for genetic engineering [7]. The journey from the initial study of inherited genes in pea plants, to the first use of the term “genetic engineering” by microbiologist A. Jost in 1941, to the first completed draft of the human genome sequence in 2002 took almost 150 years [8]. In 2007, 142 years after the first experiment on inheritable traits, the first tumor-targeted gene therapy, Rexin-G, was recognized [8]. While immunotherapy and gene therapy are two different fields, the former includes genetically modifying patients’ immune cells, which is a gene therapy principle. Although there are currently multiple types of immunotherapy treatments, of particular interest is CAR T-cell therapy, a recent treatment approved by the U.S. Food and Drug Administration (FDA) in 2017 [6].
The process starts with a sample of blood being taken from the patient to obtain T-cells, a type of white blood cell that plays a vital role in the immune system [9]. The T-cells are then engineered under laboratory conditions to produce proteins called chimeric antigen receptors (CAR), hence the name CAR T-cell therapy [9]. These proteins bind to antigens, which are substances that the immune system recognizes as foreign, on the surface of the malignant tumor and begin self-replication [9, 10]. Upon binding, the CAR T-cells involve different regions of the immune system, including signaling proteins called cytokines. The cytokines attract other immune cells to the site, and the large amounts of the CAR T-cells cause significant inflammation concentrated on the tumor site [11]. Inflammation occurs when the immune system reacts to foreign factors [12]. It works by getting rid of these elements and starting the process of healing through further recruitment of immune cells. This effectively destroys the tumor [13].
While CAR T-cell therapy has its drawbacks that are yet to be mitigated, it is also undoubtedly full of potential for future research.
Main Advantage
The main advantage of CAR T-cell therapy is the successful treatment of specific types of blood-based cancers with significantly fewer side effects and in a shorter time when compared to alternative remedies [14]. Not only does it take less time to cause remission, which is the reduction or disappearance of symptoms caused by the cancer, but it also does so with a better overall quality of life for the patient [14, 15]. Compared to stem cell therapy, which requires a course of chemotherapy to transfer cells that can develop into a variety of other cells, patients tend to recover almost 2-3 months quicker with CAR T-cell therapy, as the treatment only needs to be administered once (not including initial blood sample procedures) [16, 17]. Moreover, the use of chemotherapy during stem cell therapy poses the same side effects as chemotherapy itself [18].
Moreover, CAR T-cell therapy shows lots of promise with potential treatments of various cancer types, and a few prominent steps have already been made to implement the therapy [19]. For example, the FDA has approved CAR T-cell therapy infusions for the treatment of acute lymphoblastic leukemia, a type of cancer that affects the blood and bones of a patient, as well as for diffuse large B-cell lymphoma, another common type of blood cancer [19]. The most notable mention should be the intravenously (i.e. inserted through the veins) administered CAR T-cell therapy infusion Tecartus from the pharmaceutical company Novartis which can be used to treat both lymphomas in kids and young adults [20]. While there is still a long way to go for CAR T-cell therapy, the advancements that have been made might give people who are unable to receive chemotherapy or radiation therapy hope.
Cytokine Release Syndrome
While CAR T-cell therapy is undoubtedly more innovative in treating cancer, it has its own side effects. One of the most widely associated adverse effects is the development of cytokine release syndrome (CRS) [21, 22]. Since the objective of CAR T-cell therapy is the production of cytokines in addition to activated CAR T-cells, it can often lead to elevated levels of different types of cytokines, some of which are toxic. Hence, the higher levels of cytokine proteins in the blood can effectively poison the patient as much as they help in defeating the tumor [21].
According to Dr. Noelle Frey, a clinical hematologist at the University of Pennsylvania Medical Center, most patients with CRS present with symptoms ranging from mild cases, such as a fever and low blood pressure, to severe conditions, including but not limited to hypoxia, the lack of an oxygen supply to a region, and multi-organ toxicities [21]. In most cases, the syndrome occurs within the first week of administration of CAR T-cell therapy, and symptoms peak within a week. The syndrome can be managed with certain types of “supportive care,” that often include acetaminophen drugs, like Tylenol, and hypothermia blankets for fevers. Low blood pressure and dehydration are also often treated with intravenous infusions of fluids [21].
It is important to note that while CRS is an adverse effect of CAR T-cell therapy, it can also be managed with immunosuppressants, drugs that reduce or inhibit the activity of the immune system [23]. Studies show that the use of certain immunosuppressants can reverse the syndrome, although the utilization of aggressive immunosuppressive therapy could also negatively affect immunotherapy outcomes in the first place [23]. Hence, CRS is treated on a case-to-case basis, in which doctors weigh the advantages and disadvantages of immunosuppressant administration.
Success Story
Overcoming cancer for the first time is incredibly tough and only gets more challenging if the disease returns. Rich Gingerelli is a former firefighter who, after his retirement, faced significant health challenges due to cancer [24]. At the age of 50, in 1998, Rich Gingerelli was first diagnosed with Waldenstrom Macroglobulinemia (WM), a type of non-Hodgkin's lymphoma, where a diverse group of blood cancers target immune cells called lymphocytes [24, 25]. He successfully beat WM with the help of chemotherapy, but that was not the end of his story [24]. In 2015, nearly 17 years later, he faced another alarming diagnosis: large B-cell lymphoma. Refusing to lose hope, Gingerelli battled the blood cancer, going through chemotherapy again and beating the odds just like he had before. The success was short-lived, as the lymphoma returned three years later when Rich was 78 years old. A stem cell transplant was unsuccessful, so the new, experimental CAR T-cell therapy, which had already shown success in the treatment of certain cancers, was introduced to the patient and his family. Despite the novelty, the Gingerellis decided to try the therapy, which ended up changing Rich Gingerelli’s life forever [24]. As Dr. Reshef, the clinical lead for the CAR T-cell program at Columbia University, states, “We’re seeing patients, who were once incurable, live for many years after a CAR T infusion. It’s unprecedented” [24, 26].
Conclusion
Cancer is a vicious disease with equally fierce remedies, but the advancements made in treatments give us hope. Patients with certain blood cancers now have promising treatments because of the groundbreaking development of CAR T-cell therapy. Moreover, even if the therapy initially gained prominence in treating certain blood cancers, such as leukemia and lymphoma, ongoing research and clinical trials are exploring its potential as a treatment for other types of cancers, including solid tumors [27]. Notable benefits include its tailored strategy and potential for long-term remission. Of course, the treatment also has drawbacks, such as the serious adverse effects discussed above. However, there is optimism that these drawbacks can be lessened with further study, making CAR T-cell therapy a more widely available and effective cancer treatment [28]. Perhaps, one day, it will be able to treat all types of cancers with virtually no side effects.
References
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