Kymriah: FDA Approves First Gene Therapy in the United States

Kymriah: FDA Approves First Gene Therapy in the United States

“The approval of Kymriah is an exciting development for the field of gene therapy and holds great promise for the treatment of many rare diseases.”

On August 30, 2017, the Food and Drug Administration (FDA) approved the first gene therapy in the United States.1 The therapy is known by its commercial name Kymriah (tisagenlecleucel) and is used for the treatment of lymphoblastic leukemia in pediatric and young adult populations. Lymphoblastic leukemia affects 3,100 new patients annually and is traditionally treated with a chemotherapy regimen to eradicate leukemia cells, followed by stem cell transplantation to regenerate new blood cells.2 However, for a small group of patients whose cancer has not responded to traditional treatment, Kymriah is now available as an alternative therapy. The safety and efficacy of this treatment are supported by a recent clinical trial examining 63 pediatric and young adult patients suffering from relapsed or refractory lymphoblastic leukemia. The study found that 83% of participants responded to Kymriah when no other therapy worked.1 Thus, the approval of Kymriah is an exciting development for the field of gene therapy and holds great promise for the treatment of many rare diseases.

Gene therapy involves inserting genes into a patient's cells rather than using drugs or surgery. We can manipulate genes by inactivating a mutated gene, introducing a new gene to fight disease, or replacing a defective copy. There are two methods of introducing genes into a human cell. Approximately 70% of clinical trials use transduction, which is a method of gene transfer mediated by viral vectors.3 Retroviruses are combined with the target cells so that the virus can inject the beneficial gene into the cell, where it will be integrated into the cell's genome (Figure 1). Every time the cell divides, each daughter cell will carry copies of the beneficial gene. However, retroviruses are more compatible with cells that frequently undergo cell division, allowing the healthy genes copies that they carry to permeate the organism. For these well-differentiated and quiescent cell types, adenoviruses are the preferred choice of vectors. In this case, the healthy gene is independent and outside of the chromosome of the target cell. The limitation is that when the target cell divides, only one daughter cell will inherit the beneficial gene. As a result, the relative number of healthy genes present will remain constant. Approximately 30% are completed with non-viral vectors through plasmid DNA through transfection.3 This method is protective against vector insertional mutagenesis, the mutation caused by the insertion of new genetic material into a gene. However, it is extremely inefficient compared to its viral counterpart.


  Figure 1: Integration of retroviruses into the genome.

Figure 1: Integration of retroviruses into the genome.

The most clinically relevant gene therapy treatments are for immune deficiency because it is relatively easy to extract, proliferate, and re-introduce immune cells. For treatments like Kymriah, T cells are removed from patients by leukapheresis, which uses a dialysis-like machine to remove white blood cells as blood is drawn from the vein.4 The extracted T cells are then sent to a lab to be genetically altered to produce receptors on their surface called chimeric antigen receptors (CAR). These receptors allow T immune cells to have new antigen specificity. The genetically modified cells are left to proliferate before being reintroduced into the patient, where the T cells will multiply within a patient's body. Genetic modification of immune cells is also being investigated as a treatment for Sjogren's syndrome, an autoimmune disease that affects between one and four million people in the US.3 It is believed that the transfer of immunomodulatory genes can reduce sialadenitis and provide relief from symptoms. In 2012, there have also been two successful cases of children with Severe Combined Immunodeficiency who were brought out of isolation after undergoing treatment.3 These examples testify to the success and potential of gene therapy in the field of immunology.

More broadly, gene therapy has the potential to target systemic single-protein deficiency disorders, including insulin deficiency in diabetes and erythropoietin deficiency for anemias related to chronic kidney failure.3 By being able to stimulate the production of these proteins in the pancreas and kidney, we can eliminate the hassle of many long-term medications like metformin and insulin. However, progress in this field has not always been smooth. Most notably, in 1999, the death of 18-year-old Jesse Gelsinger lead to public concern over the safety of viral vectors.5 Jesse had an ornithine transcarbamylase (OTC) deficiency that made it difficult for his body to eliminate ammonia. While most people with OTC deficiency die at a young age, he was fortunate to be able to live on a concoction of drugs and a strict diet. In a clinical trial, Jesse was given an adenovirus vector to deliver a hepatic enzyme. Four days after the injection, he died from complications due to an immune reaction to the vector. His lawyer would later argue that a deadly immune response to the vector was not listed as a side effect, but at the time in all 400 clinical trials enrolling 4,000 patients, his death was the only one attributable to the vector.5 The media frenzy would incite public fear for the potential of vector-induced events for many years.

As of June 2012, there are 1,843 clinical trials for gene therapy being undertaken in 31 countries, showing the expansion of this technology.6 Much of this is a result of a better understanding of the etiology of diseases, as well as better understanding of the technique that allows for improved trial design. The improved trials focus on treating early symptomatic and even presymptomatic individuals rather than individuals with advanced and irreversible disease. The establishment of better vector safety protocols allows vector doses to be set at higher levels that promote therapeutic efficiency rather than minimal biological activity. Lastly, anti-inflammatory drugs are being administered as part of the gold-standard treatment to suppress the immune system in the case of adverse effects.7 Collectively, these three practices have been fundamental to improving the safety and efficiency of new gene therapy trials.


“With recent progress in genetics, epigenetics, and disease etiology, we can better examine the potential applications for immune disorders, inherited conditions, and even chronic malignancies.”

We have come a long way since the first human patient treated by gene therapy in 1990, but the field is still in its experimental stages.8 We have struggled with clinical application because of the lack of knowledge of the natural history and genetic relationships of many of the rare diseases that we are trying to treat. However, with recent progress in genetics, epigenetics, and disease etiology, we can better examine the potential applications for immune disorders, inherited conditions, and even chronic malignancies. Evidently, this field holds tremendous promise for rare disease patients. With FDA approval, the treatment has been given a stamp of safety and is a step towards greater public acceptance.


Works Cited:

1. FDA. FDA approval brings first gene therapy to the United States. FDA News Press Release. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm. Published 2017.

2. Dunkle M. FDA Announces First Gene Therapy in the US. National Organization for Rare Disorders. https://rarediseases.org/fda-announces-first-gene-therapy-u-s/. Published 2017.

3. Cotrim AP, Baum BJ. Gene Therapy: Some History, Applications, Problems, and Prospects. Toxicol Pathol. 2008;36(1):97-103. doi:10.1177/0192623307309925.

4. The Lancet. CAR T-cells: an exciting frontier in cancer therapy. Lancet. 2017;390(10099):1006. doi:10.1016/S0140-6736(17)32395-4.

5. Sibbald B. Death but one unintended consequence of gene-therapy trial. C Can Med Assoc J = J l’Association medicale Can. 2001;164(11):1612.

6. Ginn SL, Alexander IE, Edelstein ML, Abedi MR, Wixon J. Gene therapy clinical trials worldwide to 2012 - an update. J Gene Med. 2013;15(2):65-77. doi:10.1002/jgm.2698.

7. Naldini L. Gene therapy returns to centre stage. Nature. 2015;526(7573):351-360. doi:10.1038/nature15818.

8. Health NI of. Gene Therapy. A Revolution in Progress: Human Genetics and Medical Research. https://history.nih.gov/exhibits/genetics/sect4.htm. Published 2016.


Cite This Article:

Zhang B., Chan G., Palczewski K., Lewis K., Ho J. Kymriah: FDA Approves First Gene Therapy in the United States. Illustrated by L. Nguyen. Rare Disease Review. April 2018. DOI:10.13140/RG.2.2.17277.26086.

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