CAR-T cell therapy, when a cancer patient’s T cells are modified to recognize and kill cancer cells, is an FDA-approved treatment for certain types of lymphomas and leukemias. However, a central challenge is creating CAR-T cells that can survive long enough in patients to completely eradicate the cancer.

Cancer scientists at Stanford and the Children’s Hospital of Philadelphia (CHOP) identified a protein, FOXO1, that improves the survival and function of CAR-T cells, which may lead to more effective CAR-T cell therapies and could potentially expand its use in difficult-to-treat cancers. The findings were published online in Nature.

Senior study author Crystal Mackall, MD, says, “These findings offer new insight into a critical question around CAR-T cell therapy. This insight could lead to stronger CAR-T cells and the ability to help more patients.”

Mackall is the associate director of the Stanford Cancer Institute, Ernest and Amelia Gallo Family Professor of Pediatrics and Medicine at Stanford University, founding director of the Stanford Center for Cancer Cell Therapy, leader of the Cancer Immunotherapy Program, and director of the Stanford Parker Institute for Cancer Immunotherapy. 

To determine what helps CAR-T cells live longer, researchers wanted to understand the underlying biology behind memory T cells, which are a type of natural T cell whose purpose is to persist and retain function. FOXO1, which activates genes associated with T cell memory, has previously been studied in mice but remains under-researched in human T cells or 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 senior study author Evan Weber, PhD, assistant professor of pediatrics at the University of Pennsylvania Perelman School of Medicine and cell and gene therapy researcher within the CHOP Center for Childhood Cancer Research (CCCR) and the Center for Cellular and Molecular Therapeutics (CCMT).

The researchers found that in the absence of FOXO1, human CAR-T cells lose their ability to form a healthy memory cell or protect against cancer in an animal model, supporting the notion that FOXO1 controls memory and antitumor activity.

CAR-T cells that overexpressed FOXO1 had activated memory genes and an enhanced ability to persist and fight cancer in animal models. This effect was not seen when a different memory-promoting factor was overexpressed, which suggests that FOXO1 plays a unique role in promoting T cell longevity.

Researchers also found evidence that FOXO1 activity in patient samples correlates with persistence and long-term disease control, implicating FOXO1 in clinical CAR-T cell responses.

Mackall says, “We look forward to validating these findings in patients and will continue to explore potential pathways that could lead to creating CAR-T cells capable of achieving durable responses in more patients with different types of cancer.”

April 2024
Image: Gerardo Sotillo