The first patient suffering from incurable T-cell cancer, namely Alyssa of 13, has been treated with base-edited T-cells gene therapy by the scientists in the UK. This trial was led by doctors and scientists at the University College, London, and Great Ormond Street Hospital (GOSH). She is the first reported patient in the world to have received this treatment at the GOSH for Children, for T-cell acute lymphoblastic leukaemia (T-ALL). The Bone Marrow Transplant (BMT) unit at GOSH received from a healthy donor genetically modified chimeric antigen receptor (CAR) T-cells, which were edited using a new base-editing technology to allow them to hunt down and kill the cancerous T-cells without attacking each other.
About Acute T-Cell Lymphoblastic Leukaemia
Acute T-cell lymphoblastic leukaemia is a form of blood cancer. T-cells are a class of white blood cells which are equipped to hunt and neutralise threats to the body. In this disease, these T-cells turn against the body and end up destroying healthy cells that normally help with immunity. The disease is rapid and progressive and is usually treated using chemotherapy and radiation therapy.
About Base Editing
The genetic code of a person is several permutations of four bases, namely—adenine (A), guanine (G), cytosine (C), and thymine (T). Sequences of these bases, similar to the letters in the alphabet, spell out genes that are instructions to produce the wide array of proteins necessary for the functioning of the body. In the case mentioned above, T-cells had become cancerous because of a misarrangement in the sequence of bases. To correct the error, a healthier immune system is necessary. There is a new technique which allows genes to be altered and errors can be fixed. The most popular among such other techniques has been the clustered regularly interspaced short palindromic repeats (CRISPR) or CRISPR–associated protein 9 (CRISPR-Cas9).
Though a nascent technology, base editing is reportedly far more effective in treating blood disorders, caused by so-called single-point mutations. Blood disorders may also be caused when a change in a single base pair causes terminal or incurable disease.
The CRISPR-Cas9 system consists of an enzyme that acts like a pair of molecular scissors and can snip two DNA strands at a specific location and modify gene function. With this technique, a piece of DNA at a precise location can be cut. Then, a guide RNA is used to insert a changed genetic code at the sites of the incision. The cutting is done by enzymes like Cas9, guided by pre-designed RNA sequences, which ensure that the targeted section of the genome is edited out. The CRISPR-Cas9 system is believed to be the fast, most versatile system to effect such gene editing.
Creating Donor T-Cells
To create these cells, healthy donor T-cells, arranged by the Anthony Nolan registry, were subjected to four separate ‘edits’ in the lab, before being armed to attack other T-cells. The steps of edit included (1) changing the donor T-cells so that they are not attacked by the patient’s own immune system; (2) removing a ‘flag’ called CD7 on the modified T-cells in order to avoid mutual attack before they could be used as a treatment; (3) removing a second ‘flag’ called CD52 to make the edited cells invisible to some of the strong drugs given to the patient during the treatment process; and (4) adding a CAR, which recognises the CD7 T-cell receptor on leukemic T-cells. The cells are now armed against CD7, and would recognise and fight leukaemia of T-cells.
These edits were achieved by ‘base editing’ through chemically converting single nucleotide bases (letters of the DNA code), which form a sequence that provides instruction for a specific protein.
David Liu, of the Broad Institute, Massachusetts, has improvised on the CRISPR-Cas9 system to be able to directly change certain bases: thus, a C could be changed into a G, and T into an A.
Performance of Base Editing Therapy
The patient was diagnosed with T-cell leukaemia in May 2021 and was treated in various hospitals with standard therapies, such as chemotherapy and bone marrow transplant. However, the doctors were unable to get the cancer under control and into remission. An experimental treatment of the patient for T-cell leukaemia showed some results.
After 28 days, the patient was in remission and received a second bone marrow transplant for the restoration of immune system. It was observed through follow-ups that the cancer did not resurface and the patient had been recovering. However, whether the treatment is reliable and has entirely fixed the immune system of the patient, is yet to be completely established.
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