Gene-Edited Cell Therapy Offers Hope for Aggressive Leukemia

A groundbreaking latest treatment utilizing base-edited immune cells is demonstrating promising results for patients battling T-cell acute lymphoblastic leukemia (T-ALL), a rare and aggressive blood cancer. Developed by scientists at University College London (UCL) and Great Ormond Street Hospital (GOSH), this innovative therapy, known as BE-CAR7, offers a potential lifeline for individuals who have exhausted standard treatment options.

Understanding T-ALL and the Challenges of Treatment

T-cell acute lymphoblastic leukemia is a fast-moving blood cancer that originates in the bone marrow. While most children with T-ALL respond well to conventional treatments like chemotherapy, approximately 20% do not [1]. For these patients, finding effective therapies is a critical unmet require.

Traditional CAR T-cell therapy, where a patient’s T-cells are modified to target cancer cells, has shown success in some blood cancers. Yet, developing CAR T-cell therapies for T-ALL has been particularly challenging. The engineered T-cells can inadvertently attack each other, hindering the treatment’s effectiveness [3].

How BE-CAR7 Works: A New Approach to Gene Editing

BE-CAR7 utilizes a next-generation genome editing technique called base-editing, an advanced form of CRISPR technology. Unlike traditional CRISPR, base-editing doesn’t cut DNA, reducing the risk of chromosomal damage [1]. Instead, it precisely changes single letters of DNA code within living cells.

This allows for the creation of “universal” CAR T-cells derived from the white blood cells of healthy donors. These cells are genetically modified through several key steps:

• Existing receptors are removed, allowing the cells to be stored and used for multiple patients without the need for matching.
• The CD7 marker, which identifies cells as T-cells, is removed to prevent “friendly fire” where the engineered cells attack each other.
• The CD52 marker is removed to prevent the engineered cells from being eliminated by immunosuppressant antibodies.
• A Chimeric Antigen Receptor (CAR) is added, enabling the cells to recognize and attack CD7-positive leukemia cells.

Promising Clinical Trial Results

The first-in-human clinical trial of BE-CAR7 began in 2022, with Alyssa Tapley, then 13 years vintage, becoming the first patient to receive the treatment [1]. Since then, the treatment has been administered to a total of eleven patients – nine children and two adults – at GOSH and King’s College Hospital (KCH) [2].

Early results, published in the New England Journal of Medicine, are highly encouraging:

• 82% of patients achieved very deep remission after receiving BE-CAR7, allowing them to proceed to stem cell transplant without detectable disease.
• 64% of patients remain free of leukemia, with the longest remission lasting three years.
• Side effects, such as low blood counts, cytokine release syndrome and rashes, were manageable, with the highest risks associated with viral infections during immune system rebuilding.

Looking Ahead: Expanding Access and Continued Research

GOSH Charity has committed £2.3 million to fund an extension of the clinical trial, providing access to BE-CAR7 for an additional 10 children with relapsed or drug-resistant T-ALL [2]. This funding will also support the collection of long-term safety and effectiveness data.

Professor Waseem Qasim, who led the research, emphasized the importance of learning from each patient’s experience, even those where outcomes were not as hoped [1]. The research team continues to operate from the Zayed Centre for Research into Rare Disease in Children, a partnership between UCL and GOSH.

Alyssa Tapley, now 16, whose life was saved by the treatment, expressed her gratitude and her aspiration to become a research scientist, contributing to future breakthroughs [4].