Uncovering The Mystery of The Failure of CAR-T Cell Therapy! The Double-edged Sword Effect of IL-4 Protein

Chimeric antigen receptor T (CAR-T) cell therapy is a revolutionary immunotherapy, but its durable response is still limited, partly due to the exhaustion of CAR-T cells. Recently, in a research report titled "IL-4 drives exhaustion of CD8+ CART cells" published in the international journal Nature Communications, scientists from Mayo Clinic and other institutions revealed a new reason why CAR-T cell therapy fails in some patients, and proposed a new strategy combining antibodies and gene editing technology, which is expected to improve the effect of this breakthrough therapy.

CAR-T cell therapy is a regenerative immunotherapy in which researchers collect T cells from patients and genetically modify them in the lab to target proteins on tumors. These engineered T cells are then delivered back into the patient and act as a "living drug," harnessing the power of the patient's own immune system to recognize and destroy tumors. The therapy has shown remarkable results in certain blood cancers, but is only effective in about a third of patients.

One of the main reasons CAR-T cell therapy fails is T cell exhaustion. This occurs when CAR-T cells become weak and lose the ability to multiply, target, and destroy cancer cells. T cell exhaustion causes many patients to relapse within a year of receiving CAR-T cell therapy.

In search of a solution, the researchers analyzed CAR-T cells in patients treated with CAR-T cell therapy, comparing data from patients who had entered remission and those whose treatment had failed. They also studied the efficacy of CAR-T cell therapy against lymphoma, leukemia, and multiple myeloma in laboratory mice, comparing mice that responded well and those that did not respond.

The researchers found that levels of interleukin-4 (IL-4) protein were significantly increased in CAR-T cell depletion samples from humans and mice. IL-4 is a special protein that regulates inflammation and immunity, and usually activates the immune system to fight cancer. However, the study found that too much IL-4 protein can cause CAR-T cells to be overloaded and cause exhaustion.

To verify this finding, the researchers used CRISPR gene editing technology to remove the IL-4 protein from CAR-T cells. The results showed that after removing the IL-4 protein, the ability of CAR-T cells to recognize and kill cancer was significantly improved. In addition, the researchers also tested the effect of monoclonal antibodies blocking or neutralizing the IL-4 protein, and found that this could rejuvenate CAR-T cells and effectively block cancer.

Figure 1. A genome-wide CRISPR knockout screen identifies a role for the IL-4 pathway in the development of CART cell dysfunction resulting from chronic stimulation. (Stewart C M, et al., 2024)

This study provides new insights into the failure mechanism of CAR-T cell therapy and provides new directions for the development of improved therapies. Researcher Dr. Kenderian said, "This is a very exciting discovery that can provide new hope for overcoming the challenges of CAR-T cell therapy experienced by many patients. For the first time, we have described a molecular mechanism that causes patients to tolerate and fail CAR-T cell therapy, which may help scientists find new ways to improve the lifespan of CAR-T cell therapy."

In summary, this study identified the key role of IL-4 in inducing CAR-T cell exhaustion and identified a means to improve the therapeutic effect of CAR-T cell therapy. This discovery provides a solid foundation for future clinical trials and treatment strategies.

Reference

Stewart C M, et al. IL-4 drives exhaustion of CD8+ CART cells. Nature Communications, 2024, 15(1): 7921.