In recent years, cancer biologists have made impressive strides in the treatment of blood cancers, but there remains outstanding questions about why these treatments fail in some patients. One such cancer treatment involves the use of immune cells called T cells that normally fight infections by targeting pathogens like bacteria or viruses. These T cells can be removed from patients and engineered into CAR-T cells to target cancer instead of pathogens. However, when these cells are put back into patients to help fight their cancer, they sometimes become quickly “exhausted” and are unable to target cancer effectively. This results in minimal tumor reduction for the patient and a >50% overall relapse rate even after CAR-T cell therapy. 

Researchers from the Children’s Hospital of Philadelphia (CHOP) and Stanford Medicine set out to discover why some patients experience long-term CAR-T effectiveness and others do not. They focused on one protein called FOXO1, which had been previously reported to prevent T cell exhaustion. Doan et. al showed that removing FOXO1 from T cells resulted in less robust immune activity while increasing the level of FOXO1 resulted in more robust immune activity. They also used existing data to correlate higher levels of FOXO1 in their T cells with positive outcomes in actual patients who had received CAR-T cell therapy. Ongoing work by these authors includes data analysis of patients with extraordinary responses to CAR-T cell therapy to uncover other proteins that, similarly to FOXO1, could improve therapeutic outcomes.

The researchers speculate that developing a treatment that would increase the amount of FOXO1 to co-administer with CAR-T cell therapy could improve the efficacy of CAR-T therapy. Studies like these give hope that oncologists will soon have an expanded toolkit to improve the success rate of expensive and difficult cancer treatment options. 

This study was led by Alexander Doan with corresponding authors Crystal Mackall and Evan Weber at the Children’s Hospital of Philadelphia (CHOP) and Stanford Medicine.

Managing Correspondent: Olivia Lavidor

Press Article: Researchers identify protein that controls CAR T cell longevity (Medical Press)

Original Journal Article: FOXO1 is a master regulator of memory programming in CAR T cells (Nature)

Image Credit: Base image from Pixabay