Summary: New research from the Perelman School of Medicine at the University of Pennsylvania indicates that a ketogenic diet or supplementation with its key metabolite, beta-hydroxybutyrate (BHB), can enhance CAR T cell therapy in preclinical models of lymphoma. In mice, a ketogenic diet improved tumor control and survival by promoting CAR T cell expansion and activity. Laboratory studies and analyses of human samples showed that CAR T cells preferentially use BHB over glucose as an energy source, and higher BHB levels correlated with stronger CAR T responses. These findings have prompted a Phase I clinical trial to test BHB supplementation alongside CAR T therapy in patients with large B‑cell lymphoma.
This approach could offer a low-cost, low-toxicity adjunct to existing CAR T cell treatments if clinical trials confirm the preclinical results. The research was presented at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract 4).
Key Facts:
- Ketogenic boost: Mice on a ketogenic diet showed better tumor control and longer survival after CAR T cell therapy compared with mice on other diets.
- BHB preference: CAR T cells use beta-hydroxybutyrate (BHB), produced during ketosis, as an effective metabolic fuel, often outperforming glucose for their energy needs.
- Clinical testing underway: A Phase I clinical trial is being launched to evaluate BHB supplementation in people receiving anti‑CD19 CAR T cell therapy for relapsed or refractory large B‑cell lymphoma.
Institution: University of Pennsylvania
Researchers from Penn Medicine’s Abramson Cancer Center and the Perelman School of Medicine explored whether modifying host metabolism could strengthen CAR T cell therapy, instead of further genetic manipulation of the cells. The team tested multiple diets — including ketogenic, high-fiber, high-fat, high-protein, high-cholesterol, and a standard control diet — in a mouse model of diffuse large B‑cell lymphoma. The ketogenic diet produced the most pronounced improvement in tumor control and survival.
CAR T cells prefer BHB as a metabolic fuel
Follow-up experiments identified beta-hydroxybutyrate (BHB), a ketone body produced by the liver during ketosis, as a key mediator of the diet’s beneficial effect. In laboratory studies, supplementation with BHB combined with CAR T cell therapy resulted in near-complete tumor eradication in most treated mice and promoted greater CAR T cell expansion and activation. Prior work from the same laboratory group had shown BHB can suppress growth of colorectal tumors in vitro, supporting a broader role for this metabolite in anti‑tumor immunity.
The investigators propose that CAR T cells can efficiently oxidize BHB, gaining a metabolic advantage over relying solely on glucose. By increasing circulating BHB, either through diet or supplements, CAR T cells appear better equipped to proliferate and kill malignant cells.
Translational data in human samples and healthy volunteers
To evaluate relevance for humans, the team analyzed blood samples from patients who recently received CAR T cell therapy. Higher endogenous BHB levels were associated with improved CAR T cell expansion in those patients. In a separate small study, healthy volunteers who received a BHB supplement showed shifts in T cell metabolism consistent with the changes observed in preclinical models.
Unlike some dietary interventions that act indirectly through the gut microbiome, the mechanism in these experiments appears to be driven primarily by systemic metabolic changes—higher circulating BHB that directly fuels T cell function.
Next steps and potential impact
Based on the preclinical and translational evidence, Penn Medicine has initiated a Phase I clinical trial to test whether BHB supplementation can safely and effectively enhance response to commercially available anti‑CD19 CAR T cell therapy in patients with relapsed or refractory large B‑cell lymphoma. The trial is designed to assess safety, feasibility, and signals of improved CAR T expansion and anti‑tumor activity.
Investigators emphasize that the intervention could be relatively inexpensive and carry low toxicity compared with other experimental strategies. If clinical outcomes mirror the laboratory findings, combining metabolic interventions such as ketogenic diets or BHB supplementation with established CAR T approaches may become an accessible way to boost efficacy for more patients.
The research team cautions that findings remain preliminary and that no clinical dietary or supplement recommendations should be made for patients until trial results are available.
Funding: The study received partial support from the Penn‑CHOP Microbiome Core.
About this research
Author: Meagan Raeke
Source: University of Pennsylvania
Contact: Meagan Raeke – University of Pennsylvania
Image credit: Neuroscience News
Original research presentation: Findings were presented at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition.