Last updated on:January 1st, 2023
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B-cell acute lymphoblastic leukemia (B-ALL)
B-cell acute lymphoblastic leukemia (B-ALL) is a type of blood cancer caused by defects in the differentiation of B-lymphocytes (B-cells). These defects result in the uncontrolled proliferation of dysfunctional and malignant B-cell precursors. B-ALL is a common pediatric cancer type; there is a second peak in adults >age 60, with a less favorable prognosis.
B-cells are specialized in the production of antibodies to defend the organism against pathogens. These cells differentiate from hematopoietic stem cells in the bone marrow. Hematopoietic stem cells have permanent self-renewal capacity, which is progressively lost during their differentiation into B-cells. B-cell differentiation defects can cause the maintenance of the permanent self-renewal capacity of B-cell precursors and trigger B-ALL.
Genetic causes of B-ALL
Genetic aberrations including gene translocations (transfer of a gene to another chromosome) and other gene rearrangements can cause the uncontrolled proliferation of a subset of the B-cell precursor population. These aberrant cells can also exhibit alterations in gene expression and signaling pathways.
The role of bone marrow microenvironment in B-ALL
Production of blood cells is governed by the bone marrow microenvironment. This region is densely innervated, has excellent blood supply, and is rich in regulatory molecules. Due to their critical role in B-cell differentiation, cells from the bone marrow microenvironment can also contribute to the development of B-ALL. On the other hand, B-ALL development can also alter the bone marrow microenvironment. These alterations are thought to further promote B-ALL development and progression and induce treatment resistance.
Therapeutic approaches for B-ALL
Therapies for B-ALL have historically included chemotherapy, neutralization with exogenous antibodies, and transplantation of hematopoietic stem cells. These treatments are associated with significant cell toxicity and high relapse rates, urging the development of alternative therapeutic approaches.
Gene therapy approach for B-ALL
Gene therapy for B-ALL consists of genetically modifying T-lymphocytes (T-cells) from the patient, to make them capable of killing malignant B-cell precursors. The process starts with the collection of peripheral blood from the patient, from which T-cells are selected. In the lab, T-cells are infected with artificial viruses carrying a gene coding for an anti-CD19 chimeric antigen receptor. After genetic modification and proliferation, T-cells are returned to the bloodstream of the patient. In the patient, these T-cells produce and display on their surface a chimeric antigen receptor that recognizes the CD19 protein on the surface of B-cell precursors. This recognition process initiates a biochemical response leading to the destruction of malignant B-cell precursors.
Chimeric antigen receptor
The T-cell chimeric antigen receptor utilized in gene therapy against B-ALL consists of a fusion of a protein molecule binding CD19, a CD8-alpha transmembrane region, and the intracellular 4-1BB, CD28, and CD3-zeta molecules. These molecules have co-stimulatory and signaling functions, respectively, promoting T-cell fitness, expansion, and activity against B-cell precursors.
Two gene therapies for B-ALL are currently approved by the Food and Drug Administration (FDA) of the United States: tisagenlecleucel and brexucabtagene autoleucel. These were approved in 2017 and 2021 respectively and consist of T-cells obtained from the patient and further modified to kill malignant B-cell precursors. Tisagenlecleucel was also approved for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma. Brexucabtagene autoleucel was also approved for adults with relapsed or refractory mantle cell lymphoma.
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. This treatment is used for many different types of cancers including multiple myeloma, B-cell lymphoma, and follicular lymphoma.