Keto diet metabolite could fuel CAR-T cells to kill cancer

A simple dietary supplement could provide a new approach to boosting CAR T cell function, according to a study led by researchers at the Perelman School of Medicine at the University of Pennsylvania and the Abramson Cancer Center at Penn Medicine. Although the approach needs to be evaluated in clinical trials, early research, shared during a press briefing at the 66th American Society of Hematology (ASH) Annual Meeting and Exhibition, suggests a potentially Cost-effective to improve CAR T cell function and cancer-fighting capabilities.

CAR T cell therapy is a personalized treatment approach, developed by Penn Medicine, that reprograms patients’ own immune cells to kill their cancer.

“Thousands of patients with blood cancers have been successfully treated with CAR T cell therapy, but it still doesn’t work for everyone,” said co-senior author Shan Liu, Ph.D., a researcher. postdoctoral fellow who presented the study at ASH. .

“We took a novel approach to improve CAR T cell therapy, targeting T cells through diet rather than additional genetic engineering.”

Liu co-led the study with Puneeth Guruprasad, Ph.D., who received his Ph.D. at Penn and is now a medical student at the Perelman School of Medicine. The lead authors worked under the mentorship of co-senior authors Marco Ruella, MD, assistant professor of hematology-oncology, investigator in the Center for Cellular Immunotherapies and scientific director of the Lymphoma Program at Penn Medicine; and Maayan Levy, Ph.D., assistant professor of microbiology.

CAR T cells prefer BHB as a fuel source

First, the research team tested the effect of several different diets, including a ketogenic, high-fiber, high-fat, high-protein, high-cholesterol diet, and a control diet, on tumor-fighting abilities. CAR T cells using a mouse model of large B-cell lymphoma. They found improved tumor control and survival in mice fed a ketogenic diet compared to all other diets.

In subsequent studies, they found that higher levels of beta-hydroxybutyrate (BHB), a metabolite produced by the liver in response to a ketogenic diet, was a key mediator of this effect.

The research builds on previous work by Levy’s team, which found that BHB strongly suppressed the growth of colorectal tumors in laboratory experiments.

“Our theory is that CAR T cells prefer BHB as a fuel source rather than the standard sugars found in our bodies, like glucose,” Guruprasad said. “So increasing BHB levels in the body gives CAR T cells more power to eliminate cancer cells.”

Translational studies on patient samples and healthy volunteers

Next, the research team tested a BHB supplement combined with CAR T cell therapy in laboratory models of human cancer (with a standard diet); results showed complete obliteration of the cancer in the vast majority of mice and resulted in higher expansion and activation of CAR T cells.

To see if BHB, which occurs naturally at different levels in our bodies, had a similar effect in humans, the team evaluated blood samples from patients who had recently received CAR T cell therapy and found that Higher levels of BHB were associated with better rates of CAR T cell expansion in patients.

They also looked at T cells from healthy volunteers who took a BHB supplement and found similar changes in how normal T cells generated energy after BHB exposure.

Previous studies across multiple cancer types have examined the impact of dietary interventions, such as a high-fiber diet, on response to cancer immunotherapy. However, the mechanism behind the BHB effect in this study appears to come from metabolic changes in the blood rather than the gut microbiome, as in the case of a high-fiber diet.

Next steps and potential impact

The theory that BHB supplementation could improve response to CAR T cell therapy is being tested in a phase I clinical trial at Penn Medicine’s Abramson Cancer Center.

“We’re talking about a relatively inexpensive intervention with low potential for toxicity,” Levy said. “If the clinical trial data is confirmed, I look forward to thinking about how a fairly simple approach like this could be combined with dietary interventions, or other more traditional approaches, to enhance the anticancer effect.”

The clinical trial, led by principal investigator Elise Chong, MD, assistant professor of hematology-oncology, will soon begin enrolling patients with relapsed or refractory large B-cell lymphoma who are receiving anti-CAR T cell therapy. -CD19 commercially available as part of their treatment.

“As a physician and scientist, I share my patients’ enthusiasm for potential new strategies to better treat their cancer, and I am excited to see this research move from the laboratory to translational studies and now to a clinical trial,” Ruella said. .

“However, we would like to emphasize that at this stage the research is still preliminary and we are not making any dietary or supplement recommendations to patients based on this study until we have definitive clinical evidence.”