These days, lymphomas, leukemias, and other kinds of cancers can be effectively treated using chimeric antigen receptor T cell (CAR T) therapies. Now, new research from scientists at Children’s Hospital of Philadelphia (CHOP) and Stanford University School of Medicine helps explain why these therapies work and why they get better the longer the cells are in the body. Full details of the findings were published in Nature in a paper titled, “FOXO1 is a master regulator of memory programming in CAR T cells.”

Fewer than 50% of patients who are treated with CAR T therapies remain cured after one year. One of the reasons for this is that CAR T cells often don’t survive long enough in patients to completely eradicate their cancer. However, other studies showed that patients who were cured by CAR T therapy had cells that were more durable and able to fight the cancer longer. Results from the Nature study indicate that longer lasting cells benefit from a protein called FOXO1, which improves the survival and function of CAR T cells.

“By studying factors that drive memory in T cells, like FOXO1, we can enhance our understanding of why CAR T cells persist and work more effectively in some patients compared to others,” said Evan Weber, PhD, an assistant professor of pediatrics at the University of Pennsylvania Perelman School of Medicine and senior author on the study. 

FOXO1 is a protein that activates genes associated with T cell memory. It has previously been studied in mice but remains under-researched in human T cells or CAR T cells. To learn more about its role in human CAR T cells, the researchers used CRISPR to delete FOXO1. They found that in its absence, human CAR T cells lost their ability to form healthy memory cells or to protect against cancer in animal models.

Conversely, when researchers forced CAR T cells to overexpress FOXO1, they observed that memory genes were turned and that the T cells have an enhanced ability to persist and fight cancer. In contrast, when the researchers overexpressed a different memory-promoting factor, there was no improvement in CAR T cell activity, suggesting that FOXO1’s role is unique. The researchers also found evidence that FOXO1 activity in patient samples correlates with persistence and long-term disease control, thereby implicating FOXO1 in clinical CAR T cell responses.

“These findings may help improve the design of CAR T cell therapies and potentially benefit a wider range of patients,” Weber said. “We are now collaborating with labs at CHOP to analyze CAR T cells from patients with exceptional persistence to identify other proteins like FOXO1 that could be leveraged to improve durability and therapeutic efficacy.”

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