The treatment of several cancers has been completely transformed by CAR T cell therapy, and the longer the CAR T cells remain in the patient’s body, the more successfully they combat cancer. Researchers at Children’s Hospital of Philadelphia (CHOP) and Stanford Medicine have now discovered that a protein named FOXO1 enhances the survival and functionality of CAR T cells. This finding could expand the use of CAR T cell therapies for cancers that are challenging to treat and result in more effective treatments.
The findings were published in the journal Nature.
T cells are an immune cell type that protects the host by identifying and eliminating infections. Although cancer frequently outwits the body’s defences, CAR T cell therapy allows a patient’s T cells to be reprogrammed to identify and eliminate these cancer cells. This has resulted in FDA-approved therapies for certain lymphomas and leukaemia.
After a year, less than half of the patients who undergo CAR T cell treatment are still healed. The fact that CAR T cells frequently do not live long enough in patients to fully eliminate their malignancy is one of the causes of this. Previous studies have shown that CAR T cell treatment patients frequently have CAR T cells that survive longer and are more effective in fighting malignant cells.
Memory T cells are a subset of normal T cells whose goal is to endure. Researchers wanted to study the biology underpinning memory T cells to find out what makes CAR T cells live longer. One interesting protein, FOXO1, has been examined in mice before, but nothing is known about how it affects human or CAR T cells. It activates genes linked to T-cell memory.
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.
Evan Weber, PhD
The researchers in this study employed CRISPR to remove FOXO1 to get additional insight into the function of FOXO1 in human CAR T cells. They discovered that in an animal model, human CAR T cells lacking FOXO1 are unable to create healthy memory cells or prevent cancer, providing evidence that FOXO1 regulates memory and antitumor activity.
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Subsequently, scientists employed techniques to compel CAR T cells to overexpress FOXO1, activating memory genes and improving their capacity to endure and combat malignancy in rodent models. However, there was no increase in CAR T cell activity when the researchers overexpressed another memory-promoting factor, indicating that FOXO1 has a more special function in prolonging T cell life.
Furthermore, and this is significant, the researchers discovered evidence linking patient samples’ FOXO1 activity to persistence and long-term illness management, therefore linking FOXO1 to clinical CAR T cell responses.
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These findings may help improve the design of CAR T cell therapies and potentially benefit a wider range of patients.
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
Evan Weber
Source: CHOP News
Journal Reference: Doan, Alexander E., et al. “FOXO1 Is a Master Regulator of Memory Programming in CAR T Cells.” Nature, 2024, pp. 1-8, https://doi.org/10.1038/s41586-024-07300-8.
