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A novel approach involving a simple dietary supplement could potentially improve the effectiveness of CAR T cell therapy, a groundbreaking cancer treatment, according to new research from the University of Pennsylvania’s Perelman School of Medicine and Abramson Cancer Center. The study, presented at the 66th Annual American Society of Hematology (ASH) Meeting, suggests that a ketogenic diet may boost CAR T cell function, providing a cost-effective strategy to enhance cancer treatment outcomes.
CAR T cell therapy, a personalized treatment developed at Penn Medicine, involves reprogramming a patient’s own immune cells to target and kill cancer cells. While it has led to successful outcomes for many patients with blood cancers, it does not work for everyone. The new study, led by Shan Liu, Ph.D., a postdoctoral fellow, and Puneeth Guruprasad, Ph.D., now a medical student at Penn, takes an innovative approach by exploring how diet, rather than further genetic engineering, can optimize CAR T cell therapy.
“We wanted to improve CAR T cell therapy by targeting T cells through diet rather than additional genetic manipulation,” said Liu, emphasizing the potential for this approach to increase the therapy’s effectiveness.
Ketogenic Diet and CAR T Cells: A Promising Link
The researchers first tested the effects of various diets—such as ketogenic, high-fiber, high-fat, and high-protein—on CAR T cell function in a mouse model of lymphoma. They found that the ketogenic diet significantly enhanced tumor control and survival compared to other diets.
Further investigation revealed that beta-hydroxybutyrate (BHB), a metabolite produced by the liver in response to a ketogenic diet, played a crucial role in improving CAR T cell function. BHB appeared to be a preferred fuel source for CAR T cells over glucose, potentially giving them the extra energy needed to fight cancer more effectively.
“By increasing BHB levels in the body, we believe we are empowering CAR T cells to become more effective in eliminating cancer cells,” said Guruprasad, co-lead author of the study.
This research builds on previous studies by Maayan Levy, Ph.D., which demonstrated that BHB could inhibit colorectal tumor growth. The findings suggest that BHB could be a powerful tool in enhancing immune cell function in cancer treatment.
Translational Research: From Mice to Humans
In subsequent experiments, the team combined BHB supplementation with CAR T cell therapy in mouse models of human cancer. The results were promising, showing near-complete cancer eradication in most cases and increased activation and expansion of CAR T cells. Further analysis of blood samples from patients who had recently undergone CAR T therapy revealed that higher BHB levels were linked to better CAR T cell expansion and activation.
The researchers also tested the effect of BHB supplementation on normal T cells from healthy volunteers, which showed similar metabolic changes, further supporting the hypothesis that BHB boosts T cell function.
While other studies have investigated the impact of dietary interventions—such as high-fiber diets—on cancer immunotherapy, this study suggests that BHB’s effects may be mediated through metabolic changes rather than gut microbiome alterations.
Looking Ahead: Clinical Trials and Future Potential
The promising results of this study have led to a Phase I clinical trial at Penn Medicine’s Abramson Cancer Center, where researchers are now testing BHB supplementation in patients with relapsed or refractory large B-cell lymphoma undergoing CAR T cell therapy. The trial, led by Elise Chong, MD, will assess whether BHB supplementation can improve the response to this treatment.
“This intervention is relatively inexpensive and has low toxicity, which makes it an exciting potential addition to cancer therapy,” said Maayan Levy, Ph.D., a senior author of the study. “If clinical trials confirm these results, this simple dietary approach could be combined with existing treatments to enhance cancer-fighting abilities.”
While the research is still in its early stages, experts caution that patients should not make dietary changes or start supplementation without clinical evidence. “We want to emphasize that the research is preliminary, and we are not making any recommendations until we have definitive clinical results,” said Marco Ruella, MD, one of the senior authors of the study.
With the potential to enhance CAR T cell therapy in a low-cost, low-risk manner, this approach offers hope for future advancements in cancer treatment.
