Researchers at Penn Medicine's Abramson Cancer Center have discovered that a ketogenic diet and its primary metabolite, β-hydroxybutyrate (BHB), can significantly enhance the efficacy of CAR T-cell therapy in treating diffuse large B-cell lymphoma. The study, presented at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, suggests that BHB supplementation could offer a cost-effective approach to improve CAR T-cell function and cancer-fighting abilities. This research is particularly relevant as relapse rates following CAR T-cell therapy can be as high as 40%, highlighting the need for novel strategies to boost treatment outcomes. A Phase I clinical trial is now underway to test this approach.
Ketogenic Diet and CAR T-Cell Function
The research team, led by Shan Liu, PhD, and Puneeth Guruprasad, PhD, investigated the impact of various diets on CAR T-cell therapy using a mouse model of diffuse large B-cell lymphoma. They compared ketogenic, high-fiber, high-fat, high-protein, and high-cholesterol diets against a control diet. The ketogenic diet demonstrated superior tumor control and survival rates compared to all other diets. Subsequent studies revealed that BHB, a metabolite produced by the liver during ketogenesis, was a key mediator of this effect.
"We found that among all the dietary interventions, mice which were infused with CAR T-cells and were fed the ketogenic diet, experienced the greatest improvement in tumor control," said Liu during the ASH presentation.
Mechanism of Action: BHB as a Fuel Source
The study revealed that CAR T-cells preferentially utilize BHB as an energy source, particularly within the metabolically demanding tumor microenvironment. Isotope tracing showed that CAR T-cells metabolize BHB into citric acid cycle intermediates, bypassing glycolysis and supporting oxidative phosphorylation. This process enhances oxygen consumption, energy production, and cytokine secretion, all critical for CAR T-cell functionality.
Epigenetic analyses further indicated that BHB increases histone acetylation in CAR T-cells by boosting Acetyl-coenzyme A (acetyl-CoA) availability. This, in turn, opens chromatin regions associated with effector and memory genes (FOXO1, TCF7, GZMB), amplifying CAR T-cell expansion and persistence. The deletion of BDH1, a key enzyme in BHB metabolism, reduced the functional benefits of BHB, confirming its role in metabolic modulation.
Clinical Relevance and Ongoing Trial
To assess the clinical relevance of these findings, the researchers analyzed blood samples from patients who had undergone CAR T-cell therapy. They observed a positive correlation between BHB levels and CAR T-cell expansion. Additionally, a small interventional study with healthy volunteers showed that oral BHB supplementation enhanced T-cell respiratory capacity and energy production.
"We retrospectively analyzed the serum from a patient with B-cell lymphoma taken 7 days post–CAR T infusion, and we found that BHB serum concentration possibly correlated with CART19 peripheral expansion, possibly suggesting that natural variability and BHB level can influence the CAR T-cell proliferation in the patient," Liu said.
These encouraging results have led to a Phase I clinical trial at Penn Medicine, led by Elise A. Chong, MD, evaluating BHB supplementation in patients with non-Hodgkin lymphoma receiving CAR T-cell therapy. The trial aims to assess the feasibility of BHB supplementation and its impact on the patients' immune system.
"We're talking about an intervention that is relatively cheap and has low toxicity potential," Levy said. "If the clinical trial data pans out, I'm excited to think about how a fairly simple approach like this could be combined with dietary interventions or other, more traditional approaches, to enhance the anti-cancer effect."
