Gene modification could improve cancer treatment's success rate

Researchers have identified a method to enhance the effectiveness of a promising cancer treatment. They found that modifying a specific gene improves the ability of immune cells to combat cancer for an extended period, potentially reducing the chance of cancer recurring. The finding that reduced CUL5 gene activity increases CAR-T cell anticancer effects could improve treatment for patients with aggressive cancers such as leukemia, lymphoma, and multiple myeloma. The study was published in Nature Communications by a group led by Yoshitaka Adachi, Seitaro Terakura, and Professor Hitoshi Kiyoi of Nagoya University's Graduate School of Medicine in Japan.  

CAR-T cell therapy is an advanced cancer treatment in which the patient's own immune cells (T cells) are genetically modified in a laboratory. A "chimeric antigen receptor" (CAR) is given to these cells, enabling them to target and eliminate cancer cells. The researchers focused on a CAR that targeted the CD19 protein found in B cells, a type of immune cell that can become cancerous in diseases such as leukemia. 

Although clinicians have successfully used this therapy for treatment, many patients experience cancer relapse caused by the hostile environment created by cancerous cells. After repeated encounters with cancer cells, CAR-T cells lose their ability to divide and effectively attack the tumor. 

Altering genes to improve efficacy 

The research team used a method called CRISPR screening to identify potential genes that could improve CAR-T cell therapy. CRISPR allows scientists to turn off individual genes in cells to see which are important for a specific function.  

The gene of interest, CUL5, is involved in the breakdown of certain proteins inside cells. When this gene is inactive, a cell signaling pathway, known as the JAK-STAT signaling pathway, becomes more sustained. This pathway sends signals that encourage T cells to grow and multiply, making them better at fighting cancer.  

The researchers discovered that turning off the CUL5 gene improves CAR-T cell growth and longevity, even after repeated exposure to cancer cells. When the team tested their modified CAR-T cells in mice with B-cell lymphoma, the most common cancer in humans, they found that they were much more effective in shrinking tumors and keeping cancer from coming back than regular CAR-T cells.  

A new way to create targeted cells 

Traditionally, creating these CUL5-deficient cells requires a process called electroporation, which uses electrical pulses to introduce changes into cells.  However, this method can damage cells and is not practical for treating large numbers of patients.  

The Nagoya University researchers developed a new way to partially reduce CUL5 activity by using a virus to deliver genetic material to CAR-T cells. “We achieved the CAR-transfection and shCUL5 transduction at once by virus transfection,” Terakura said. “As the T lymphocytes were not subjected to electroporation, they remained healthy after transfection.” 

This discovery points to a way to make cancer treatment more effective. It may become possible to increase the efficacy of CAR-T cell therapy in treating blood cancers such as lymphoma and leukemia. The modified CAR-T cells not only fight tumors better but could also stay active in the body longer, reducing the chances the cancer will come back.  

The research team is now investigating whether this same gene-modification approach could help treat other cancers, especially solid tumors like those found in organs, which have been particularly challenging to treat with current methods. 

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