Last updated on:December 1st, 2022
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Non-Hodgkin's lymphoma (NHL) is a group of cancers caused by uncontrolled proliferation of lymphocytes. Its most common type (about 85%) is B-cell lymphoma. There are several subtypes of B-cell lymphoma, all caused by uncontrolled proliferation of B-cells (B lymphocytes). B-cell lymphoma is conventionally treated through chemotherapy, radiotherapy, and immunotherapy.
Despite the different types of treatments available, B-cell lymphomas still have high rates of relapse and low survival rates following relapse. This grave outcome demands the development of new treatment approaches.
Immunotherapy is the utilization of patient immune cells to combat cancer. One of its types is adoptive immunotherapy, in which immune cells are collected from the patient and multiplied in the laboratory (i.e., ex vivo). Before being returned to the patient, these cells can be genetically modified to add new immune functions with anti-cancer effects.
T-cell chimeric antigen receptor
The T-cell chimeric antigen receptor is a transmembrane fusion protein with an extracellular region binding the target antigen. CD19, a protein located on the surface of human B-cells, is one of the most targeted antigens. It is a convenient recognition element for these cells—particularly when they are abundant due to uncontrolled proliferation. The T-cell chimeric antigen receptor also contains an intracellular co-stimulatory region (CD28 or 4-1BB), which enhances the function of an additional intracellular protein region, CD3-zeta. Upon binding of the extracellular region to CD19, CD3-zeta triggers intracellular T-cell responses, causing cytotoxicity against B-cells. When present on the surface of T-cells, this chimeric antigen receptor is a powerful molecular tool to combat proliferating B-cells.
Chimeric antigen receptor T-cell (CAR-T) therapy
Chimeric antigen receptor T-cell (CAR-T) therapy is a specific type of adoptive immunotherapy. Briefly, T cells are obtained from patient blood and ex vivo genetically modified to produce a chimeric antigen receptor. Genetic modification is achieved through infection with an artificial virus, modified to not replicate, containing genetic material coding for the chimeric receptor. This receptor will be produced by infected T-cells and displayed on their surface. This treatment is usually administered intravenously. After patient delivery, T-cells containing the chimeric antigen receptor will have an enhanced capacity to recognize and kill B-cells.
Adverse side effects grading
In clinical trials, adverse side effects are usually graded on a scale from 1 (not bothersome) to 5 (fatal). Grade 3 adverse effects are severe, can affect the patient's autonomy, and require medical care.
There are four CAR-T therapies against B-cell lymphomas currently approved by the Food and Drug Administration (FDA) of the United States: axicabtagene ciloleucel, tisagenlecleucel, brexucabtagene autoleucel, and lisocabtagene maraleucel. In general, they are approved for utilization for progressive disease despite at least two lines of systemic therapy.