Institution of Affiliation
Kymriah to Treat B-Cell Cancer
Kymriah is a chimeric antigen receptor (CAR) T-cell therapy that was developed by Novartis. The drug is able to produce prolonged complete responses with minor side effects in adults with relapsed or those with refractory diffuse large B-cell lymphoma (DLBCL). The drug is also used in the treatment of the B-cell acute lymphoblastic leukemia in the patients who are aged 25 years and below. It is used to treat individuals whose cancer treatment has not gotten better with other therapies or has relapsed for two or more times. Further studies are ongoing to test the efficiency of the drug I the treatment of different types of cancer. Kymriah is a drug that was developed using the patients T-cells, which happens to be one of the immune system cells. According to Gill, a gene for a specific receptor, chimeric antigen receptor, is added to the T-cell in the laboratory and the changed T-cell now the CAR T-cells are cultured in large numbers in the laboratory, and they are provided to the patients by infusion. The drug, Kymriah binds to the protein CD 19, that is found in some Lymphoma and Leukemia patient cells, aiding the body’s immune system in destroying the cancer cell.
Kymriah was the first cell-based gene therapy to obtain validation by the United States Food and Drug Administration (FDA). In accordance with Gardner views, the CAR-T drug was meant for the treatment of relapsing or refractory acute lymphoblastic leukemia and non-Hodgkin’s lymphoma among the pediatric and young adult patient of 25 years and below. Acute lymphoblastic leukemia is the most frequent type of leukemia in children. Acute lymphoblastic leukemia is marked by the bone marrow producing too many white blood cells, the lymphocytes to which fail to develop correctly. The excess development of the abnormal white blood cells causes swellings and damage to the internal organs preventing the body from producing other blood cells. The prevention of the formation of different blood cells especially the red blood cells that are responsible for the transport of oxygen around the body tissues, result to anemia and as well dampened immune response. It is in a similar manner that the diffuse large B-cell lymphoma, which is the most common form of non-Hodgkin’s lymphoma is an aggressive cancer of the lymphatic system that is caused by the accumulation of the abnormal B-cells.
The new analysis of the trial data on the Novartis Kymriah CAR-T therapy that were presented at the 59th American Society of Hematology annual meeting indicates that the drug sustained complete responses at six months in adults with a difficult to treat the form of leukemia cancer. The CAR-T therapy offers a new treatment approach in the sense that it is specially produced for the treatment of an individual patient. During the process of treatment, the T-cells are drawn from the blood of the patient and then reprogrammed in the laboratory to develop the T-cells to which are genetically programmed to hunt and kill the patient’s cancer cells.
According to the data obtained from the Juliet’s trail that was led by the researchers from the University of Pennsylvania indicate an overall response rate (ORR) of 53% in the patients taking the Kymriah medication, with 40% achieving a complete response (CR) and 14% achieving a partial response (PR) (Wohlfarth). At six months, 30 percent of the patients were in complete response, with a 74 percent relapse-free rate onset of response, while the median duration of response was not reached. According to the principal investigator, Stephen J. Schuster, at the time of the trial enrollment, the patients with the DLBCL had been through multiple rounds of chemotherapy, and a significant number had unsuccessful stem cell transplants, and this left the patients with few options and poor prognosis. With the availability of the Kymriah drug, the team was able to significantly increase the chances of achieving and maintaining a sustained response without the stem cell transplant, and this was a demonstration of the benefit caused by the Kymriah drug in the treatment of the lethal blood cancer.
Concerning safety, the cytokine release syndrome (CRS) that can result when engineered cells get activated into the body of the patient, occurred in 58 percent of all the treated patients with the Kymriah drug, with 23 percent of them experiencing three-quarters cytokine release syndrome. 21 percent of the patients experienced any grade neurologic events, and 12 percent of the patients possessed three-quarters neurologic adverse events that were managed by supportive care. Grade three-quarters cytopenias lasting more than 28 days, grade three-quarters infection and grade three-quarters febrile neutropenia occurred in 27 percent, 20 percent and 13 percent of the patients respectively. According to Samit Hirawat, while the immediate response to the treatment by the drug is a marker for efficacy, the physicians and patients require treatment options that provide sustained reactions over time with as consistency in the safety profile.
Additional analysis of the data obtained from the ELIANA clinical trial indicates impressive results in the 75 patients that were treated with the Kymriah drug (Thomas et al.). The investigation found the overall remissions rate within three months was 81 percent, the rates of the event-free survival were 73 percent at six months and 50 percent at 12 months. The overall survival rate was 90 percent and 76 percent over the same time intervals. The follow-up analysis of the results that were obtained from the ZUMA-1 trial that investigated the effectiveness of axicabtagene ciloleucel in the patients with the refractory non-Hodgkin’s lymphoma also indicated impressive outcomes. According to the analysis, more than one year after the treatment, 42 percent of the 108 patients enrolled in the ZUMA-1 trial had maintained remission while 40 percent of the patients exhibited no evidence that pointed them to have cancer. Besides more than half of the patients were alive at the median follow up of 15.4 months, and that is more than double the median survival for 6.6 months for the patients treated with the conventional therapy aside from the Kymriah therapy. Therefore the efficacy of the Kymriah drug can be said to be high, and that’s why the Food and Drug Administration opted to license the drug for commercial use.
The Kymriah drug just like other drugs has it is own mechanism of action. The primary purpose of the CAR-T therapy is to eliminate the CD-19 expressing malignant and normal cells with specificity and increased chances of remission. According to Anton, the Tisagelecleucel also known as CTL019 is a CD19 that is directly genetically modified immunotherapy that is genetically targeted to the treatment of specific patients. CTL019 is an adoptive immunocellular cancer therapy that is programmed to use the autologous peripheral blood T- cells that have been coded with a transgene encoding in chimeric antigen receptor (CAR) to identify and eliminate the CD19 cells that express that malignant and non-malignant cells. The CAR is comprised of a murine single-chain antibody fragment that recognizes the CD19 cells and is fused to the intracellular signaling domains from the 4-1BB (CD137) and CD3-zeta. The CD3-zeta component is significant for the initiation of the T-cell activation and anti-tumor activity while the 4-1BB enhances the expansion and most fundamentally the persistence of the tisagenlecleucel. Upon the binding to the CD19 expressing cells, the CAR transmits a signal to promote the T- cell expansion, activation, target cell elimination as well as the persistence of the tisagenlecleucel. The transduced T-cells expand in vivo to engage and as well eliminate the CD19 expressing cells and may inhibit immunological endurance to assist in supporting a long-lasting remission.
Concerning dosage, the treatment course consists of the fludarabine and cyclophosphamide lympho-depleting chemotherapy that is followed by the infusion of Kymriah drug. According to the directions provided by Bachmeier, Kymriah is provided as a single dose unit that contains the chimeric antigen receptor (CAR) viable positive T- cells. The dosage is based on the patient’s weight that is reported at the time of leukapheresis that includes: For the patients below 50kgs, the dosage is 0.2 to 5.0 x 106 CAR-positive T-cell per kg body weight while for the patients above 50kgs the standard dosage is 0.1 to 2.5 x 108 CAR-positive viable T cells. For the Lympho-depleting chemotherapy: Fludarabine (30 mg/m² intravenous daily for four days) and cyclophosphamide (500 mg/m² intravenous daily for two days starting with the first dose of fludarabine). Infuse Kymriah drug for 2 to 14 days after completion of the lympho-depleting chemotherapy.
Despite the effectiveness of the Kymriah drug, there are lots of side effects are said to accompany its administration such as cytokine release syndrome, hypogammaglobulinemia, fever, decreased appetite and infections of unspecified pathogens. A headache, bleeding episodes, low blood oxygen, vomiting fatigue, delirium, and acute kidney injuries are just among the side effects of the administration of the Kymriah drug in accordance with Jones.
The advancement in the field of medicine has enabled and as well led to the development of drugs that are capable of curing diseases that for a long time disturbed and threatened the extinction of the human race. The Kymriah drug, as a chemotherapy for cancer treatment, is one of the many such drugs that have restored hope to the people especially the patients of cancer. Kymriah is a drug that was manufactured by the Novartis Company, directed to the detection and elimination of the CD19 cells. The clinical trials have proved the efficacy of the drug with over 80 percent success, and this led to its approval by the Food and Drugs Administration proving it safe for commercialization. The Kymriah as well can increase the risk of life-threatening infections that may lead to death and therefore it is advisable to seek medical attention upon the development of symptoms such as fever, chills or bleeding just after the drug use.
Gill, Saar, and Carl H. June. “Going viral: chimeric antigen receptor T‐cell therapy for hematological malignancies.” Immunological reviews 263.1 (2015): 68-89.
Gardner, Rebecca A., et al. “Intent to treat leukemia remission by CD19CAR T cells of defined formulation and dose in children and young adults.” Blood (2017): blood-2017.
Wohlfarth, Philipp, Nina Worel, and Georg Hopfinger. “Chimeric antigen receptor Tcell therapy—a hematological success story.” memo-Magazine of European Medical Oncology (2018): 1-6.
Hirawat, Samit, and Langdon Miller. “Methods for dosing an orally active 1, 2, 4-oxadiazole for nonsense mutation suppression therapy.” U.S. Patent No. 9,877,952. 30 Jan. 2018.
Thomas, Xavier, and Etienne Paubelle. “Tisagenlecleucel-T for the treatment of acute lymphocytic leukemia.” Expert opinion on biological therapy just-accepted (2018).
Anton, Roman. “Advances in Cancer Immunology and Immunotherapy.” Global Journal of Medical Research (2018).
Bachmeier, Christina. “Tisagenlecleucel Kymriah Novartis Pharmaceuticals Corp.—all entries with PAPs.”
JONES, DOW. “Novartis: receives first ever FDA approval for a CAR-T cell therapy, Kymriah (TM)(CTL019), for children and young adults with B-cell ALL that is refractory or has relapsed at least twice.”