Identifying a key target for improving CAR-T cell longevity
Researchers at the Children’s Hospital of Philadelphia (CHOP) and Stanford Medicine (both PA, USA) have recently identified FOXO1 protein as a key regulator of CAR-T-cell longevity – an important factor in their ability to fight cancer.
Despite the expanding use of CAR-T therapy, over 50% of patients who receive the therapy experience relapse within a year. The therapeutic benefit of CAR-T cells is partially hindered by their limited longevity in vivo. Once infused into the patient, the engineered cells often don’t survive for long enough to entirely eliminate the cancer, rendering patients vulnerable to relapse. The length of CAR-T cell survival can vary among different people and this is thought to be a key factor contributing to disparities in treatment efficacy among patient groups.
Researchers at CHOP and Stanford aimed to investigate the factors that could contribute to prolonged CAR-T cell survival. Their focus centered on unraveling the biological mechanisms governing memory T cells, a subset of natural T cells whose purpose is to persist and maintain functionality over time. The protein of interest in this particular study was FOXO1 – a promotor that activates genes involved in T-cell memory. While previous studies in mice have explored FOXO1, its significance in human T cells and CAR-T cells remains relatively unexplored.
The researchers used CRISPR to switch off FOXO1 in human CAR-T cells. Consequently, these cells lost the ability to form memory cells and were ineffective at fighting cancer in a mouse model. The group engineered a different set of CAR-T cells to overexpress FOXO1. This switched on the genes associated with memory cell formation and boosted these cells’ longevity and cancer-fighting abilities in mice models.
The study also analyzed CAR-T cells from patient samples. They found that patients with higher natural FOXO1 levels generally benefitted from greater CAR-T cell longevity and longer-term disease control, affirming the idea that FOXO1 is an important factor in determining treatment persistence and efficacy.
“These findings may help improve the design of CAR-T cell therapies and potentially benefit a wider range of patients,” explained Evan Weber, senior author of the study. “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.”
The authors are hopeful that their results could pave the way for more widespread use of CAR-T therapy in hard-to-treat cancers.
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