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What you should know about CAR T-cell therapy after FDA approval
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The FDA Tuesday approved the first chimeric antigen receptor T-cell therapy for the treatment of children and young adults with B-cell acute lymphoblastic leukemia.
Tisagenlecleucel T-suspension (Kymriah, Novartis) is indicated for patients aged up to 25 years with refractory B-cell precursor ALL, as well as those whose disease is in second or later relapse.
With tisagenlecleucel likely to become the new standard of care in this patient population – according to Stephan A. Grupp, MD, PhD, Yetta Deitch Novotny professor of pediatrics at Perelman School of Medicine at University of Pennsylvania and director of the Cancer Immunotherapy Frontier Program at Children’s Hospital of Philadelphia – it is important to shed light on what CAR T cells are.
How CAR T-cell therapy works
According to the Leukemia & Lymphoma Society, T cells – a type of immune system cell – are collected via a process that withdraws blood from the body and removes one or more blood components, such as plasma or white blood cells. That remaining blood is then returned into an individual’s body. The collected cells are then genetically engineered to produce chimeric antigen receptors on their surface.
Chimeric antigen receptors are proteins that allow T cells to recognize an antigen on targeted tumor cells.
The process of growing cells in the lab reengineers CAR T cells until there are millions of them. The lab then freezes the cells and sends them to a hospital or center where the patient is being treated.
Once the CAR T cells arrive, they are infused into the patient receiving treatment. According to the Leukemia & Lymphoma Society, many patients are given a brief course of one or more chemotherapy agents prior to receiving an infusion of CAR T cells. The cells then multiply in number after being infused into a patient. These are considered ‘attacker’ cells that will recognize and kill cancerous cells that have the targeted antigen on their surface.
The goal of infusing CAR T cells is to guard against recurrence and bring about long-term remissions. The cells have the potential to remain in the body long after the infusion has been completed, according to the Leukemia & Lymphoma Society.
How a CAR T cell is made
A chimeric antigen receptor on a cell’s surface is composed of fragments – known as domains – of synthetic antibodies, according to the National Cancer Institute (NCI). Those domains can affect how well the receptor recognizes or binds to antigen on the tumor cell.
The receptors rely on stimulation signals from inside the cell to be effective, according to the NCI. Each CAR T cell has signaling and “co-stimulatory” domains inside the cell that signal the cell from the surface receptor. The different domains can affect the cells’ overall function, according to the NCI.
Advances in the engineering of CAR T cells have improved the cells’ ability to produce more T cells after infusion, leading to longer survival in the circulation.
Additionally, according to the NCI, advances have also shortened the time it takes to produce a batch of CAR T cells from several weeks to less than 7 days.
Side effects of CAR T cells
One primary concern with the widespread use of CAR T cells has been its toxicity profile.
CAR T-cell therapy – like other cancer treatments – may cause several worrisome, sometimes fatal, side effects, according to the NCI.
One of the most common side effects associated with CAR T-cell therapy is cytokine-release syndrome (CRS).
T cells release cytokines, which are chemical messengers that help to stimulate and direct immune responses. CRS occurs because the release of cytokines into the bloodstream is rapid, according to the NCI. This rapid and significant release may lead to high fevers and sharp drops in blood pressure.
Steroids and other standard supportive therapies can help manage CRS in both children and adults.
Another potential side effect of CAR T-cell therapy—an off-target effect—is a mass die off of B cells, known as B-cell aplasia. CD19 is also expressed on normal B cells, which are responsible for producing antibodies that kill pathogens. These normal B cells are also often killed by the infused CAR T cells. To compensate, many patients must receive immunoglobulin therapy, which provides them with the necessary antibodies to fight off infections.
Additionally, cerebral edema – or swelling in the brain – has been listed as a potential serious side effect.
Juno Therapeutics ceased development of an experimental CAR–modified T-cell therapy in March after three patients died of treatment-induced cerebral edema.
However, according to the NCI, leaders of other clinical trials analyzing the use of CAR T cells have reported no instances of cerebral edema.
Promising results
Early results from various CAR T-cell trials have generated impressive results and considerable promise in patients with blood cancers, according to the Leukemia & Lymphoma Society.
Multiple studies have shown durable responses in patients with acute lymphoblastic leukemia:
Anti–CD22 CAR T-cell therapy appeared active and safe for children and young adults with relapsed or refractory acute lymphoblastic leukemia.
KTE-C19 (axicabtagene ciloleucel, Kite Pharma) – an anti-CD19 CAR T cell – appeared safe for adults with high-burden relapsed or refractory acute lymphoblastic leukemia.
The combination of pembrolizumab and CAR T-cell therapy appeared safe and effective in a subset of patients with acute lymphoblastic leukemia who did not respond to CAR T-cell therapy or who relapsed due to poor CAR T-cell expansion and persistence.
Additionally, CAR T-cell therapy appears effective for patients with chronic lymphocytic leukemia. Anti-CD19 CAR T cells also demonstrated clinical benefit in patients with diffuse large B-cell lymphoma.
Additional information can be found on these websites:
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=771302
https://www.cancer.gov/about-cancer/treatment/research/car-t-cells
https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm
https://jhoonline.biomedcentral.com/articles/10.1186/s13045-017-0423-1