Genetically modified T cells beat leukemia for the first time

Things weren’t looking good for Alyssa. The then 12-year-old girl was diagnosed with an aggressive form of blood cancer in 2021: acute lymphoblastic leukemia with T cells. This most common childhood cancer affects the immune system’s T-lymphocytes, which fight off viruses. Alyssa did not respond to conventional treatments, including chemotherapy and a bone marrow transplant. The doctors saw only the possibility of palliative treatment – that is, to ease Alyssa’s death.

But today the British teenager from Leicester is doing well. A pioneering treatment at Great Ormond Street Hospital for Children (GOSH) in London eradicated the disease; after 28 days, Alyssa’s cancer was in complete remission. This allowed her to have a second bone marrow transplant, which restored her immune system. This recovery is “quite remarkable,” noted a doctor at the hospital, but the results will need to be monitored and confirmed in the coming months.

Alyssa took part in a phase 1 clinical trial at GOSH in May last year, in which she received genetically modified immune cells from a healthy volunteer. According to a statement from GOSH, Alyssa is the first patient to receive base-edited T cells. The results were also presented at the American Society of Hematology (ASH) Congress.

Like the CRISPR/Cas method (“gene scissors”), which can selectively insert or cut genes into DNA, base editing is a gene technique. However, it doesn’t exchange whole genes, just individual bases in the DNA. The human genome is encoded in DNA in the four nucleotide bases adenine (A), guanine (G), cytosine (C) and thymine (T), which always connect in AT or GC pairs in the DNA double helix. A base editor can chemically convert a GC base pair into an AT pair or vice versa an AT pair into a GC pair by an enzyme.

Base editors contain a guide RNA (gRNA) that takes them to the target sequence in the genome they are supposed to change. Using a modified Cas9 enzyme, they cleaved the DNA strands without separating them. This has the advantage that base editing does not cause breaks in the DNA and is therefore associated with fewer undesirable effects than CRISPR/Cas. With these “gene scissors” it can happen that DNA building blocks are accidentally inserted or lost during the repair of the double-strand break.

Until now, base editing has been especially important in medicine, because many diseases can be traced back to point mutations in the genome, which are specifically targeted by this gene technology. Researchers at GOSH and University College London have been developing genome-edited T cells for the treatment of B-cell leukemia since 2015. The challenge with T cell leukemia, however, was that the T cells, which are supposed to recognize and destroy the cancer cells, killed each other during the manufacturing process. The basic editors therefore had to be adjusted first.

In Alyssa’s case, the researchers turned T lymphocytes from a donor into so-called chimeric antigen receptor T cells (CAR-T cells) so that they could recognize and destroy the cancer cells in Alyssa’s body. The T cells were modified in four steps:

“Base editing is currently the most advanced cell technology, paving the way for other new treatments and ultimately a brighter future for sick children,” said immunologist Waseem Qasim, a research leader and professor at University College London, in the hospital’s statement. Alyssa herself says that she participated in the clinical study not only for herself, but also for other children. And her mother Kiona added: “Hopefully this proves that the research is working and they can offer it to more children.”