Nowadays, CAR-T cell therapy has completely changed the treatment of certain types of cancer. The longer these CAR-T cells survive in the patient’s body, the more effective their response to cancer becomes.
Recently, a research report titled “FOXO1 is a master regulator of memory programming in CAR T cells” was published in the journal Nature. Scientists from institutions such as Stanford University School of Medicine found through their research that a unique protein called FOXO1 can enhance the survival and function of CAR-T cells, indicating the potential for developing more efficient CAR-T cell therapies and potentially expanding their applications in the field of refractory cancer.
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T cells are a type of special immune cells that can recognize and kill pathogens to protect the host body. Cancer cells usually evade detection and attack by the host body’s immune system. However, CAR-T cell therapy recognizes and eliminates cancer cells by reprogramming the patient’s T cells, making it an effective therapy for certain types of lymphoma and leukemia.
Among patients receiving CAR-T cell therapy, less than half of them still maintain a state of recovery after one year of treatment. One important reason is that the survival time of CAR-T cells in the patient’s body is relatively short, which is insufficient to eliminate cancer. Previous studies have shown that patients who have been successfully treated with CAR-T cell therapy often have CAR-T cells with longer lifespans and stronger combat power in their bodies.
To explore what factors can prolong the survival of CAR-T cells, researchers have turned their attention to the biological principles of memory T cells. Memory T cells are a type of T cells that naturally exist in the body, aimed at maintaining their function and long-term existence. Among them, the FOXO1 protein has aroused strong interest among researchers because it can activate genes related to T-cell memory. Although previous studies have revealed the role of FOXO1 in mice, there is still insufficient research on human T cells, especially CAR-T cells.
Researcher Professor Evan Weber said, “By studying specific factors that drive T cell memory, such as FOXO1, we can better understand why CAR-T cells can persist and operate efficiently in some patients.” To further explore the specific role of FOXO1 in human CAR-T cells, the research team used CRISPR technology to remove FOXO1. The results showed that when FOXO1 was missing, human CAR-T cells lost their ability to form healthy memory cells and fight cancer in animal models, which strongly proves the importance of FOXO1 in regulating memory and anti-cancer activity. ”
Subsequently, researchers applied special methods to force CAR-T cells to overexpress FOXO1, thereby enabling the expression of memory genes in animal models and enhancing their ability to persist and resist cancer. On the contrary, when researchers overexpressed another memory-enhancing factor, the activity of CAR-T cells did not improve, revealing the unique role of FOXO1 in prolonging T cell lifespan.
Importantly, researchers have also found evidence that FOXO1 activity in patient samples may be associated with persistence and long-term disease control, revealing that FOXO1 may be involved in CAR-T cell responses in clinical practice.
Researcher Weber suggests that these findings may help improve the design of CAR-T cell therapies and promote wider patient benefits. At present, researchers are analyzing CAR-T cells in patients with special persistence through joint research, to identify other proteins such as FOXO1, and use them to improve the persistence and therapeutic effect of CAR-T cells in patients.
In summary, this study reveals that overexpression of FOXO1 can significantly enhance the anti-tumor activity of human CAR-T cells, and emphasizes the broad application prospects of memory reprogramming as an optimization of therapeutic T cell status.
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Reference
Doan, A.E., Mueller, K.P., Chen, A.Y. et al. FOXO1 is a master regulator of memory programming in CAR T cells. Nature (2024). doi：10.1038/s41586-024-07300-8