The Science Journal of the Lander College of Arts and Sciences Volume 12 Number 2 Spring 2019 - 2019 CAR T-cell Therapy for Acute Lymphoblastic Leukemia Esther Langner Touro College Follow this and additional works at: https://touroscholar.touro.edu/sjlcas Part of the Biology Commons, and the Pharmacology, Toxicology and Environmental Health Commons Recommended Citation Langner, E. (2019). CAR T-cell Therapy for Acute Lymphoblastic Leukemia. The Science Journal of the Lander College of Arts and Sciences, 12(2). Retrieved from https://touroscholar.touro.edu/sjlcas/vol12/ iss2/6 This Article is brought to you for free and open access by the Lander College of Arts and Sciences at Touro Scholar. It has been accepted for inclusion in The Science Journal of the Lander College of Arts and Sciences by an authorized editor of Touro Scholar. For more information, please contact [email protected]. CAR T-cell Therapy for Acute Lymphoblastic Leukemia Esther Langner Esther Langner will graduate in June 2019 with a Bachelor of Science degree in Biology and will be attending Mercy College’s Physician Assistant program. Abstract Despite all the available therapies, Acute Lymphoblastic Leukemia (ALL) remains extremely difficult to eradicate. Current available therapies, which include chemotherapy, radiation, and stem cell transplants, tend to be more successful in treating children than adults .While adults are more likely than children to relapse after treatment, the most common cause of treatment failure in children is also relapse. Improved outcomes for all ALL patients may depend upon new immunotherapies, specifically CAR T-cell therapy. CAR T-cell therapy extracts a patient’s own T-cells and modifies them with a CD19 antigen. This modification allows the new T-cells to recognize and kill cancer cells that contain the antigen on their surfaces, like leukemia cells do .Although CAR T-cell therapy may cause toxicities such as Cytokine Release Syndrome (CRS), they are mostly short term and reversible .Trials indicate that almost all patients who undergo CAR T-cell therapy will enter complete remission .Though a large percentage of those patients will experience a relapse, relapse rates of CAR T-cell therapy are lower than other treatments . By reviewing the available research literature regarding CAR T-cell therapy, this paper examines the effectiveness of this therapy in different patient populations and demonstrates that CAR T-cell therapy significantly improves event-free survival rates in ALL patients. Acronyms Used: compared, and analyzed to evaluate if CAR T-cell therapy is an ALL - Acute Lymphoblastic Leukemia effective treatment for ALL. ACT - Adoptive Cell Transfer CAR T-cell Therapy CAR - Chimeric Antigen Receptors CAR T-cell therapy is relatively straight forward. T-cells, which CRS - Cytokine Release Syndrome play a critical role in orchestrating an immune response, are re- CSF - Cerebrospinal Fluid sponsible for killing cells that are infected by pathogens. In order Ph - Philadelphia chromosome to retrieve these T-cells, blood is drawn from a patient and the TKI - Tyrosine Kinase Inhibitors T-cells are separated from the rest of the blood. The T-cells then CNS – Central Nervous System undergo genetic modification via the insertion of genes that WBC – White Blood Count encode for tumor specific chimeric antigen receptors (CARs). These receptors allow the T-cells to recognize and subsequently Introduction attach to a specific antigen. The antigen CD19 was chosen be- The leading cause of disease related death in U.S. pediatric pa- cause it is universally expressed on all ALL tumor cells and not tients is cancer, most commonly Acute Lymphoblastic Leukemia on pluripotent hematopoietic stem cells (Tumaini, et. al., 2013). (ALL) (Tumaini, et. al., 2013). For many years, cancer treatments Once the T-cells have been successfully engineered to express were limited to radiation therapy, chemotherapy, or surgery. More the CD19 antigen, they are expanded in a lab to form hundreds recently, newer types of treatments called immunotherapies, have of millions of cells. This process has been refined and advanced become available. Cancer immunotherapies are therapies that over the years and can now quickly create large quantities of enlist and strengthen the power of a patient’s immune system to T-cells that have genetically engineered receptors on their sur- fight and attack the cancer. Of the immunotherapies discovered, face to treat both pediatric and adult ALL patients. The CAR adoptive cell transfer (ACT), in which a patient’s own immune T-cells are then infused back into the patient’s body where they cells are collected and used to treat their cancer, has achieved continue to multiply, recognize, and kill the cancer cells con- the most successful outcomes. The most effective ACT therapy taining the antigen on their surfaces (Tumaini, et. al., 2013). This is CAR T-cell therapy (Brentjens, et. al., 2013). In 2017, CAR T-cell step is considered to be an in vivo expansion, which requires therapy was approved by the FDA as a treatment for ALL and for the new host to support these engineered T-cells. Therefore, the adults with advanced forms of lymphoma. However, while it may administration of the T-cells is preceded by a lymphodepleting seem that CAR T-cell therapy is poised to revolutionize cancer regimen, as lymphopenia (the condition of having an abnormally therapy, some of the optimism surrounding it is tempered by con- low level of lymphocytes in the blood) generates changes that cerns about its safety and potentially severe toxicities (Lim, June, support T-cell expansion and survival (Klebanoff, et. al., 2005). As 2017), calling into question if CAR T-cell therapy is an improved a result, most adoptive cell therapy protocols incorporate some treatment for ALL and relapsed ALL. version of lymphotoxic therapies prior to cell transfer. Like most cancer treatments, CAR T-cell therapy has serious Methods side effects. The most common side effect that patients usually The research used in this paper was located and compiled experience is cytokine release syndrome (CRS). Notably, CRS from papers obtained through Touro College’s access to on- has been seen in patients treated with other immunotherapies line publications. Google Scholar and Blood Journal were used and is therefore not limited to CAR T-cell therapy (Lee, et. for additional references. The articles were critically selected, al., 2014; Teachey et al., 2013). CRS is caused by the cytokines 32 CAR T-cell Therapy for Acute Lymphoblastic Leukemia released from the T-cells as CAR T-cells rapidly expand within Ironically, CRS is considered to be an “on-target” effect of the patient’s body. It can also be caused by other immune cells, CAR T-cell therapy, as the presence of the cytokines show that such as macrophages that might produce cytokines in response the T-cells are working in the body. Various grading systems for to the cytokines produced by the infused CAR T cells. CRS the “CRS-related adverse events” caused by immunotherapies patients have high levels of IL-6 (the cytokine secreted by the have been proposed. They depend on many things, such as the T-cells) and is characterized by systemic symptoms that usually temperature of the fever, the number of severe signs of toxici- begin with a fever (Giavridis, et. al., 2018). The onset of the fever ties, and cytokine levels in the patient. A category of severe CRS can range from a few hours after the treatment to more than is defined as CRS requiring pharmacologic and medical inter- a week after CAR T-cell infusion (Brudno, Kochenderfer, 2016). vention. In such cases, tocilizumab, an IL-6 receptor antagonist The fever is followed by nausea, chills, headaches, muscle pain, that is used to treat rheumatologic disorders, is used as a first and difficulty breathing (Maude et al., 2014). line agent. While not approved for this use by the FDA, it has CRS can lead to many different related toxicities that attack effectively treated CRS-related toxicities in clinical trials with no organ systems. Cardiovascular toxicities most commonly cause life threatening or toxic effects (Maude, et. al., 2014), and is now tachycardia, although more severe cases of CRS have prompted a widely used off-label for the patients who have received CAR hypotension, arrhythmia (irregular heartbeat), and decreased T-cell infusions. (Brudno, Kochenderfer, 2016). cardiac ejection fraction. CRS can lead to pulmonary edema Systemic corticosteroids have also been used for CRS-related and hypoxia, the deficiency in the amount of oxygen reaching toxicities. However, there is some evidence that corticosteroids the tissues that may require mechanical ventilation. It can also can possibly inhibit CAR T-cell persistence and anti-malignancy lead to reduced renal perfusion, the volume of blood delivered efficacy. For this reason, corticosteroid therapy is only used as a to the kidneys per unit time, which can cause a kidney injury. last resort if the tocilizumab does not succeed in ameliorating However, CAR T-cell related renal injuries are mostly reversible. the CRS. However, because neurologic toxicities may not come The same goes for other laboratory abnormalities that CRS along with CRS, these toxicities may differ from that of CRS causes, such as elevated levels of bilirubin and/or serum trans- alone. It is unclear if tocilizumab has any beneficial effect on neu- aminases. Patients also commonly become neutropenic and rologic toxicities, as severe neurologic toxicities are commonly lymphogenic when undergoing and following CAR T-cell therapy treated with systemic corticosteroids right away, rather than because they are severely immunocompromised and are not initially beginning with tocilizumab. protected against opportunistic infections, such as salmonella, Toxicities caused by CAR T-cells are diverse. Management bacteremia, and urinary tract infections. Viral infections such as of these toxicities requires continuous and vigilant monitoring, influenza, respiratory syncytial virus, and herpes zoster virus, aggressive supportive treatments, and, in some cases, intensive have also been known to affect patients following CAR T-cell care.