CUL5 Gene Modification May Promote the Growth of T Cells and Improve the Success Rate of Cancer Therapy

Chimeric antigen receptor (CAR) T cell therapy is a promising cancer treatment, but how to enhance its efficacy has always been a mystery. Recently, in a research report titled "Cullin-5 deficiency promotes chimeric antigen receptor T cell effector functions potentially via the modulation of JAK/STAT signaling pathway" published in the international journal Nature Communications, researchers from Nagoya University and other institutions in Japan have discovered a way to improve the effectiveness of this potential cancer therapy. By modifying a specific gene, the ability of immune cells to fight cancer can be enhanced for a long time, which may reduce the chance of cancer recurrence.

Researchers pointed out that reducing the activity of the CUL5 gene can enhance the anti-cancer effect of CAR-T cells, thereby improving the treatment effect of patients with a variety of aggressive cancers (such as leukemia, lymphoma and multiple myeloma). CAR-T cell therapy is an innovative treatment for advanced cancer. Scientists genetically modify the patient's own immune T cells in the laboratory and add chimeric antigen receptors (CARs) to enable these cells to target and eliminate cancer cells. In this study, the researchers focused on CARs that target the CD19 protein on the surface of B cells, because B cells are a special type of immune cell that becomes cancerous in diseases such as leukemia.

Although clinicians have successfully used this therapy to treat many patients, many still experience cancer recurrence due to the hostile environment created by the cancerous cells. When CAR-T cells are repeatedly exposed to cancer cells, they lose the ability to divide and effectively attack tumors.

To find a solution to this problem, the researchers used CRISPR screening technology to identify genes that can improve the effectiveness of CAR-T cell therapy. CRISPR allows scientists to turn off single genes in cells and observe which genes are critical for specific functions. The results showed that the CUL5 gene is involved in the breakdown process of certain proteins in cells. When CUL5 is inactive, the JAK-STAT signaling pathway becomes more persistent. This pathway sends signals to encourage T cells to grow and multiply, so that they can better deal with cancer.

Figure 1. CUL5 is involved in Janus kinase 3 (JAK3) degradation in response to interleukin (IL)-2 signaling-mediate activation. (Adachi Y, et al., 2024)

The researchers found that turning off the function of the CUL5 gene improved the growth and lifespan of CAR-T cells, even after repeated exposure to cancer cells. When they tested the modified CAR-T cells in mice with B-cell lymphoma, they found that these modified CAR-T cells were more effective than ordinary CAR-T cells in shrinking tumors and preventing cancer recurrence.

Traditionally, making these CUL5-deficient cells requires a process called electroporation, which uses electrical pulses to introduce changes into cells. But this method damages cells and is not suitable for large-scale application. To this end, the researchers developed a new method to partially reduce the activity of CUL5 by using viruses to transport genetic material into CAR-T cells. Because T lymphocytes were not affected by electroporation, they remained healthy after transfection.

This research finding points to a new way to improve the effectiveness of cancer therapy and enhances the possibility of CAR-T cell therapy to treat blood cancers such as lymphoma and leukemia. The improved CAR-T cells can not only better fight tumors, but also remain active in the body for a long time, thereby reducing the risk of cancer recurrence. Currently, researchers are exploring whether the same gene modification approach can be used to treat other types of cancer, especially solid tumors, although it remains challenging to treat these tumors with current methods.

In summary, this study shows that targeting CUL5 in the ubiquitin system may enhance the effector function of CAR-T cells, thereby improving the effectiveness of immunotherapy. This breakthrough provides new hope for future cancer treatment.