Findings from a series of studies conducted in mice, human tissues, and healthy volunteers suggest that a ketogenic diet may enhance the effectiveness of chimeric antigen receptor (CAR) T-cell therapy. The results point to β-hydroxybutyrate (BHB), a substance produced when a ketogenic diet is consumed, as a driver of increased CAR T-cell function against cancer. Results were presented by Shan Liu, PhD, during the Plenary Session at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 4).
“Our research found that a ketogenic diet can enhance CAR T-cell function, and we further found that BHB, one of the important metabolites produced in response to a ketogenic diet, plays a major role in mediating this effect,” said Dr. Liu, a postdoctoral researcher at the Perelman School of Medicine, University of Pennsylvania, Philadelphia. “Given that about two-thirds of patients who undergo CAR-T therapy either do not see a response or eventually relapse, a dietary intervention that could be implemented relatively easily along with CAR-T therapy would be very attractive.”
This study is reportedly the first to examine how specific dietary interventions modulate the antitumor effect of CAR T-cell immunotherapy.
BHB and CAR T-Cell Function
Researchers first tested several different types of diets including high-fiber, high-fat, high-protein, and ketogenic diets in mice with B-cell lymphoma, and they found that mice fed a ketogenic diet showed the best tumor control and overall survival after CAR T-cell therapy. They then found that BHB was the key metabolite enriched following ketogenic diet feeding and that mice fed a normal diet but given BHB supplementation showed improved CAR T-cell expansion and better tumor control than mice not given BHB supplementation.
Additional studies suggested that BHB increases CAR T-cell function by providing a more efficient source of energy compared with glucose, the typical fuel source for most cells. When the researchers used T cells from patients with lymphoma to manufacture CAR T cells, they found that BHB added to cell culture medium increased T-cell expansion and function of mitochondria. In addition, the team retrospectively analyzed the BHB levels in blood samples from 17 patients who received CAR T-cell treatment for large B-cell lymphoma and found that higher BHB levels were correlated with greater CAR T-cell expansion.
To assess the potential impacts of taking BHB supplements, the researchers recruited healthy volunteers and analyzed their T-cell function before and after consuming a BHB supplement. The results suggested that BHB enhances the function of T-cell mitochondria, further bolstering the hypothesis that BHB enhances T-cell activity through its effects on energy processing.
The research was largely conducted in the laboratory and in mice and did not involve interventions with any patients undergoing CAR T-cell therapy. Therefore, researchers caution that further studies will be required to determine the clinical significance of the findings. “At this point, we do not recommend adopting a ketogenic diet or taking BHB supplements during CAR-T therapy,” said Dr. Liu. The research team will soon start a clinical trial in patients with lymphoma receiving CAR T-cell therapy to study the effect of BHB supplementation in the clinic.
Disclosure: Dr. Liu reported no conflicts of interest. For full disclosures of the study authors, visit ash.confex.com.
