A recent study has revealed that BHB supplementation can enhance the cancer-fighting activity of CAR-T cells.
The results, which were presented at the 66th American Society of Hematology (ASH) meeting and exposition, highlight the potential of the liver-produced metabolite in improving the efficacy of the targeted cancer therapy, which can be used to treat a range of blood cancers.
Researchers from the Perelman School of Medicine at the University of Pennsylvania have stated that — although the findings will have to be assessed further in clinical trials — BHB supplementation could offer as a cost-effective and efficacious support for those undergoing CAR-T cell therapy.
BHB as a fuel for CAR-T cells
CAR-T cell therapies have been around in their earliest form since 1993, with many advancements being made on their cancer-targeting capabilities in this time period.
The personalised immunotherapy is particularly useful as it can reprogramme a patient's immune cells to detect and kill cancer cells — offering patients with blood cancers new hope when other standard treatment options become exhausted.
Although CAR-T therapies have been proven to be highly effective in patients with diffuse-large B-cell lymphoma (DLBCL), scientists wanted to determine if there were any simple alterations a patient could make to their diet to improve the treatment's efficacy.
To test this, researchers at the UoP tested the impact of several diets on a CAR-T cell's capabilities; this included ketogenic, high-fibre, high-fat, high-cholesterol and high-protein.
Through this study, the mice that were fed a ketogenic diet responded better to CAR-T therapy, as the cells were able to exhibit better tumour control.
This was likely because of BHB — a metabolite produced in the liver that is commonly produced in association with a low carbohydrate, high fat diet — whcih was found in high levels in the ketogenic mice.
BHB supplements show great promise
Once the researchers had established that BHB may be associated with improved outcomes post-CAR-T cell therapy, they wanted to determine the impact of BHB supplementation on animal models of human DLBCL.
From this in vitro experiment, they noted that the cancer was completely obliterated in the vast majority of mice, while also finding that CAR-T cells were able to activate better when a model was given BHB supplements.
To confirm if this impact could be found in humans, the team at the UoP assessed blood samples from patients who had received CAR-T cell therapies — finding that those with higher levels of serum BHB experienced better CAR-T cell expansion.
Healthy patients taking a BHB supplement in the study experienced similar changes to their normal T-cells, suggesting that BHB may have some influence in immune cell functionality and metabolism.
The research builds on previous work from Levy’s team, which found that BHB strongly suppressed the growth of colorectal tumors in lab experiments.
Puneeth Guruprasad, medical student at the Perelman School of Medicine, and co-author of this study, commented: “Our theory is that CAR-T cells prefer BHB as a fuel source rather than standard sugars in our body, such as glucose,”
“So, increasing the levels of BHB in the body gives the CAR-T cells more power to take out the cancer cells.”
Moving forward
Following this discovery, Penn Medicine's Abramson Cancer Center is running a Phase I clinical trial to test the potential of BHB supplementatio in enhancing patient responses to CAR-T therapies.
“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-lead author Shan Liu, PhD, a postdoctoral fellow who presented the study at ASH.
“We took an outside-the-box approach to improve CAR T cell therapy, by targeting T cells through diet rather than further genetic engineering.
Scientific director of Penn Medicine’s Lymphoma Programme and assistant professor of Microbiology, and Maayan Levy, added: “We’re talking about an intervention that is relatively cheap and has low toxicity potential,”
“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.”