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Researchers Tap Into T Cells’ Natural Biology to Help Boost CAR T-Cell Therapy

Published on April 10, 2024 in Cornerstone Blog · Last updated 3 weeks 1 day ago
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By Nancy McCann

Artwork by Gerardo Sotillo
Artwork by Gerardo Sotillo. Like a lightbulb that burns out, CAR T cells that are designed to kill cancer often run out of steam due to exhaustion and poor persistence. Dr. Weber and his research team discovered that a transcription factor called FOXO1 is responsible for keeping the CAR T lightbulb brightly lit by activating genes which counteract exhaustion, promote persistence, and enhance CAR T-cell antitumor activity.

A team of researchers from Children’s Hospital of Philadelphia and Stanford Medicine discovered that the protein FOXO1 plays a key role in regulating the longevity and effectiveness of CAR T cells. These findings have major implications for cancer immunotherapy and especially for CAR T-cell therapy because persistence is an important aspect of patients’ response.

“What we have is an important piece of T cell biology that has been overlooked for a long time,” said Evan Weber, PhD, senior study author of the study published in Nature, and a cell and gene therapy researcher with the Center for Childhood Cancer Research and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics at CHOP. “Understanding what makes CAR T cells more likely to yield a durable response at a molecular level may help improve the design of CAR T-cell therapies and potentially benefit a wider range of patients.”

CAR T-cell therapy uses T cells genetically altered in a lab to locate and destroy cancer cells more effectively. This type of cancer immunotherapy treatment has revolutionized the field of oncology and led to FDA-approved treatments for certain types of lymphomas and leukemias; however, in some patients, the CAR T cells do not survive long enough to eradicate a patient’s cancer.

Dr. Weber and the research team explored the role of the transcription factor, FOXO1, in enhancing memory and antitumor function of CAR T cells. They discovered that tapping into the natural biology of memory T cells can help CAR T cells survive longer and kill both solid tumors and blood cancers.

“Our findings suggest that this protein is critically important for CAR T cells’ longevity, and that by manipulating FOXO1, we can engineer more effective and persistent CAR T cells to treat a wide variety of cancers,” Dr. Weber said.

The Role of FOXO1 in CAR T Cells

Evan W. Weber
Evan Weber, PhD

The researchers demonstrated that FOXO1 is mechanistically important for CAR T-cell memory and anti-tumor function by analyzing what happens when FOXO1 is absent from these cells. They found that when FOXO1 is taken away, they don’t secrete inflammatory cytokines like a healthy CAR T cell would. The T cells lose their ability to form a healthy memory cell, and they are ineffective at controlling tumors.

The research team also reported that enhancing FOXO1 activity drove CAR T cells to be more memory-like, more persistent, and retain anti-tumor activity both in vitro and in vivo. They used an overexpression approach that compared overexpression of FOXO1 with overexpression of a different transcription factor TCF1, which is generally accepted as the major memory-driving transcription factor both in murine models and humans.

“We were surprised that overexpressing TCF1 did not promote the memory phenotype or enhanced anti-tumor function that we hypothesized,” Dr. Weber said. “It was only FOXO1 that was able to drive this important memory phenotype. We performed in vitro studies and both liquid tumor models and solid tumor models to show that overexpression of FOXO1 can dramatically enhance CAR T anti-tumor activity and persistence in vivo.”

The researchers also looked at the genes that were downregulated in FOXO1 knockout cells and the genes that were upregulated in FOXO1 overexpressing CAR T cells. They discovered an overlap of approximately 40 genes, many of which were not classically implicated in T cell memory or persistence. 

Working with these 40 genes and performing correlative analyses on existing patient CAR T-cell data sets, they found that the 40 genes were highly predictive of how well a patient responded to CAR T-cell therapy. In patients who had low expression of these 40 genes, they almost always exhibited poor CAR T cells persistence and encountered treatment failure. But for patients with CAR T cells with higher expression of these 40 genes, many had long-term CAR T persistence in vivo and durable cure.

The research team is 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.