This gene therapy destroys cancer cells in the most aggressive leukemias

This pioneering gene therapy (BE-CAR7) uses immune cells with an advanced version of CRISPR technology, called base editing, to treat previously incurable T-cell leukemias and help patients achieve remission, providing new hope for families affected by this aggressive cancer. Base editing allows individual letters of DNA to be modified precisely in living cells.

In 2022, researchers from GOSH and UCL administered the world’s first treatment using core editing to a 13-year-old girl from Leicester, Alyssa Tapley.

Since then, eight other children and two adults have received this treatment.

The results of the clinical trial are published in “The New England Journal of Medicine” and were presented at the 67th Annual Meeting of the American Society of Hematology.

Alyssa is already 16 years old. Following a diagnosis of T-cell leukemia in 2021 and not responding to standard therapies, he was offered to participate in the trial.

BE-CAR7 therapy achieved deep remissions in 82% of patients, enabling stem cell transplants without active disease. 64% still do not suffer from leukemia and some have been without treatment or signs of relapse for three years. Side effects were as expected and manageable (low blood counts, cytokine release syndrome, and rash), while the greatest risks came from viral infections during immune system recovery.

CAR-T cell immunotherapy has recently been developed to treat several types of hematologic cancers. This therapy modifies T cells of the immune system to express chimeric antigen receptors (CARs) that recognize and attack specific cancer cells. However, developing this therapy for T-cell leukemia, which arises from abnormal T cells, has been challenging.

genetic code

BE-CAR7 cells are engineered using base editing, a next-generation technique that does not cut DNA, reducing the risk of chromosomal damage. Using CRISPR guidance systems, individual letters of the genetic code are altered to modify T cells. These complex changes have generated storable banks of “universal” CAR-T cells capable of localizing and attacking T-cell leukemia.

These cellsuniversal» were made from white blood cells from healthy donors in a clean room at Great Ormond Street Hospital, using an automated process using custom RNA, mRNA and a lentiviral vector, developed by the research team.

The process modifies the donated T lymphocytes to make them universal and resistant: their natural receptors are eliminated to avoid compatibility problems, as well as the CD7 marks (to prevent them from attacking each other) and CD52 (so that they are not destroyed by immunosuppressive treatment). Finally, a CAR receptor directed to CD7 is added using a deactivated virusallowing them to recognize and destroy leukemia cells.

By giving the patient the base-edited CAR-T cells, they rapidly destroy all T cells, including leukemia cells. If the leukemia is eradicated in four weeks, the immune system is rebuilt thanks to a bone marrow transplant over several months.

CAR-T

“We have shown promising results with precision gene editing in children with aggressive cancer and this larger group confirms the impact of the treatment,” says Waseem Qasim, study leader and professor of cell and gene therapy at UCL, as well as a consultant immunologist at GOSH. “We have shown that base-modified “universal” CAR-T cells can destroy highly resistant CD7+ leukemias.

He acknowledged that “many teams participated and, while we celebrate the successes, we are aware that some children did not have the expected outcome. “These are intense treatments and families value the importance of learning from each experience.”

Rob Chiesa, researcher and bone marrow transplant consultant at GOSH, emphasizes that “although the majority of children respond well to standard treatments, 20% do not. For them, this research represents hope for a better prognosis against this aggressive leukemia.”