Evan Weber, PhD, on Improving CAR T-Cell Fitness

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The assistant professor of pediatrics at Children's Hospital of Philadelphia discussed the role of the FOXO1 gene in T-cell persistence and exhaustion.

“I think the big picture here is that up until this point, a lot of the focus in the CAR T-cell field has been on target identification and creating different CAR architectures to promote different types of signaling in T-cells. But I think what our work and many other labs’ work shows now is that the quality of the T-cell is really a strong predictor of how well these therapies actually do in patients.”

Over the past 5 to 10 years, chimeric antigen receptor T-cell (CAR-T) therapy has provided an important new treatment option for many patients with hematologic malignancies, and ongoing research holds the potential to apply this modality to a broader range of cancers, including solid tumors. Despite the successes seen so far with CAR-T therapies in clinical trials and in the real-world setting, the modality continues to have a number of limitations. One of these limitations is the phenomena of T-cell exhaustion, in which the CAR T-cells become less functional over time, and the limited persistence of CAR T-cells. It is thought that these phenomena may reduce the efficacy and durability of responses from CAR-T therapy, potentially leading patients to relapse. As such, methods to overcome T-cell exhaustion and enhance the persistence of CAR T-cells are a major area of focus for ongoing CAR-T research and development. Evan Weber, PhD, an assistant professor of pediatrics at Children's Hospital of Philadelphia, and his colleagues and have been researching the role of the FOXO1 gene in T-cell fitness and the potential of upregulating expression of this gene in order to improve the efficacy of CAR T-cells. Weber presented on this topic at the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting, held May 7 to 10, 2024, in Baltimore, MD.

In an interview with CGTLive® at the conference, Weber explained the background behind this research and the key findings obtained so far. He highlighted that overexpression of FOXO1, a transcription factor implicated in T-cell memory, in human T-cells allowed for improved clearance of leukemia and solid tumors in his lab’s mouse models. Weber also pointed out that manipulation of FOXO1 expression may also have broader applications in other forms of T-cell-based immunotherapy beyond CAR-T.

Click here to view more coverage of the 2024 ASGCT Annual Meeting.

REFERENCES
1. Weber E. Augmenting CAR T cell fitness through memory reprogramming. Presented at: ASGCT Annual Meeting 2024, May 7-10; Baltimore, Maryland.

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