Leukemia is a blood-borne cancer that originates from the bone marrow. It involves the production of abnormal white blood cells (WBCs) from the bone marrow and lymphatic tissues. Recently, GLOBOCAN showed a prevalence of 471,519 cases worldwide. Subtypes are; acute myeloblastic leukemia (AML), chronic myelocytic leukemia (CML), acute lymphoblastic leukemia (ALL), and Chronic lymphocytic leukemia (CLL). ALL occurs commonly in children. Risk factors include; genetic abnormalities, exposure to radiation, viral infections, smoking, chemotherapy, and familial factors. Treatment and prognosis depend on factors like age, molecular findings, and the type of leukemia. Treatment options for this disease include chemotherapy, radiotherapy, and bone marrow transplant.
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Leukemia. Credit: Manu Sharma
Leukemia cells were not detectable
Recently, a group of scientists at UCL have developed a new treatment option for ALL. This involves the administration of T cells that have been configured using modern gene editing techniques to children with the disease, causing a regression. The technique involves T-cell base editing using cytidine deamination guided by clustered regularly interspaced short palindromic repeats (CRISPR) which creates premature stop codons rendering the malignant cells inactive and ceasing replication.
The experiment involved 10 children between the ages of 6 months and 16 years with relapsed significant CD7+ T-cell cancer seen in the bone marrow. They received Fludarabine, alemtuzumab, and cyclophosphamide to institute lymphodepletion and immunosuppression. The T-cells were gotten from healthy volunteers via apheresis. Then, they based-edited the cells by removing existing receptors making them donor-universal. Next, the CD7 and CD55 T-cell markers were removed to prevent self-destruction and destruction by drugs. Finally, a Chimeric Antigen Receptor (CAR) was added to enable the recognition of CD7 T-cell receptors in the leukemia cells. This eventually destroyed the malignant cells by the based-edited T-cells.
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One of the patients, a 12-year-old girl had stem cell transplantation, 4 weeks after there was still evidence of little residual illness, and four months later, there was evidence of morphologic recurrence with CD7 expression on 100% of blasts. During the study, she was given the treatment cells, and 4 weeks after the leukemia cells were not detectable. She underwent a follow-up bone marrow transplant and is alive and well.
Clinical significance
Findings are consistent with allogeneic CAR T cells having antileukemic properties, properties that are adequate to secure remission and complete clearance of T-cell ALL. These findings could also be applied to other genetic conditions like sickle cell anemia.
Conclusion
With the advent of genetic engineering, many diseases previously thought to be incurable could be cured over the next two decades. Evidence has shown that base editing as a therapeutic strategy could be the solution for leukemia in the years to come.
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References
Chiesa, R., Georgiadis, C., Syed, F., Zhan, H., Etuk, A., Gkazi, S. A., Preece, R., Ottaviano, G., Braybrook, T., Chu, J., Kubat, A., Adams, S., … & Base-Edited CAR T Group. (2023). Base-Edited CAR7 T Cells for Relapsed T-Cell Acute Lymphoblastic Leukemia. New England Journal of Medicine. https://doi.org/10.1056/NEJMoa2300709
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