CAR T cell therapy has transformed the treatment of certain types of cancer, and the longer these cells remain in a patient’s body, the more they can fight off cancer. Researchers have discovered that a protein called FOXO1 can enhance the survival and function of CAR T cells. This finding may lead to more potent CAR T cell therapies and possibly broaden its application to treat challenging cancers.A recent study by researchers at Children’s Hospital of Philadelphia (CHOP) and Stanford Medicine has discovered that a protein known as FOXO1 enhances the survival and function of CAR T cells. This could potentially lead to more effective CAR T cell therapies and broaden its application in treating challenging cancers. The findings were released today in the journal Nature.
T cells are a type of immune cell that identify and eliminate pathogens to protect the body. Cancer can often evade the immune system, but with CAR T cell therapy, a patient’s own T cells can be reprogrammed to recognize and attack the cancer.Researchers have made significant progress in developing CAR T cell therapy to treat certain types of lymphomas and leukemias. However, less than half of patients who undergo this therapy remain cancer-free after a year. One of the reasons for this is that CAR T cells often do not survive long enough in the body to completely eliminate the cancer. Previous studies have shown that patients who are successfully treated with CAR T cell therapy have cells that live longer and are more effective at fighting cancer. In order to understand how to prolong the lifespan of CAR T cells, researchers sought to investigate the biological mechanisms involved.T cells, known as memory T cells, are a type of natural T cell that are designed to last and maintain their function. A particular protein called FOXO1, which activates genes linked to T cell memory, has been researched in mice but not extensively studied in human T cells or CAR T cells. According to Evan Weber, PhD, an Assistant Professor of Pediatrics at the University of Pennsylvania Perelman School of Medicine and cell and gene therapy researcher, “Studying factors like FOXO1 that contribute to memory in T cells can help us better understand why CAR T cells persist and function more effectively in some patients than in others.”
The role of FOXO1 in human CAR T cells was investigated by researchers at the CHOP Center for Childhood Cancer Research (CCCR) and the Center for Cellular and Molecular Therapeutics (CCMT). Using CRISPR, the researchers deleted FOXO1 and discovered that without FOXO1, human CAR T cells lost their ability to form healthy memory cells or protect against cancer in animal models. This supports the idea that FOXO1 is responsible for controlling memory and antitumor activity in CAR T cells.
Additionally, the researchers forced CAR T cells to overexpress FOXO1, which activated memory genes and improved their ability to persist and fight cancer in an animal model.imal models. When researchers increased the expression of a different memory-promoting factor, there was no enhancement in CAR T cell activity. This suggests that FOXO1 has a unique role in promoting T cell longevity.
Additionally, the researchers discovered that FOXO1 activity in patient samples is linked to persistence and long-term disease control. This implies that FOXO1 is involved in clinical CAR T cell responses.
“These findings could potentially improve the design of CAR T cell therapies and benefit a broader range of patients,” Weber stated. “We are currently working with labs at CHOP to analyze CAR T cells from patients.”
Researchers are working diligently to find other proteins, such as FOXO1, that could be used to enhance the effectiveness and durability of cancer treatments.
This study received support from several organizations, including the National Cancer Institute, the National Human Genome Research Institute, the Parker Institute for Cancer Immunotherapy, the V Foundation for Cancer Research, the Society for Immunotherapy of Cancer, Stand Up 2 Cancer, St. Baldrick’s, the Virginia and D.K. Ludwig Fund for Cancer Research, and others.
