A new dawn is breaking in the field of hematologic malignancies, as the first product based on chimeric antigen receptor (CAR) T cells was scrutinized today by a panel of experts and unanimously recommended for approval at the FDA for pediatric and young adult patients (age 3-25 years) with relapsed or refractory acute lymphoblastic leukemia (ALL).
Blood is collected from the patient, and then autologous T cells are separated out and genetically engineered. The process involves inserting a CAR that targets CD19, an antigen expressed on B cells and tumors derived from B cells. These CAR T cells are then infused back into the patient, who has undergone chemotherapy, and in the body the product homes in on B-cell leukemic cells and destroys them. The main action happens mostly about 2 weeks after those CAR-T cells have been re-infused. Some have termed this form of therapy as the “ living drug”
Autologous CAR-T cell therapy first shot into headlines about 4-5 years ago when it was thought about in CLL patients. Then several other studies were done essentially confirming that the concept is correct but there are serious toxicities.
https://www.ncbi.nlm.nih.gov/pubmed/28029927 ( gliobastoma)
The technology is complicated and initially when tried in CLL led to multiple toxicities of various organs including CNS, cardiac, renal and mostly requiring ICU admissions from acute cytokine release syndrome. This happens due to high levels of IL-6, a cytokine that is secreted by T cells and macrophages in response to inflammation. Etanercept and tocilizumab have been used to block the IL-6 activity to treat such side effects.
Acute renal injury following CAR T-cell infusion is multifactorial and almost always reversible. Reduced renal perfusion is often the most important cause of renal injury. Reduced renal perfusion can be caused by cytokine-mediated vasodilation, decreased cardiac output, or intravascular dehydration due to insensible losses from high fevers. Tumor lysis syndrome and drug effect from medications such as antibiotics are other possible causes of renal injury. Electrolyte disturbances, such as hyponatremia, hypokalemia, and hypophosphatemia are not uncommon but have been reported. A recent article in Blood summarizes all toxicities.
Now the therapy has returned and we may see this in many centers. We must be aware of the cytokine release storm that it can cause leading to AKI in that setting. There might be more in the pipeline of similar products such as the one that just got approved for ALL.
Figure source: http://www.lymphomation.org/programing-t-cells.htm
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