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Ketogenic Diet May Boost Efficacy of CAR-T Cancer Therapies


The results of this study demonstrate that BHB derived from the ketogenic diet can be provided as a dietary intervention to enhance CAR-T function in multiple cancer models. The results of this study will be translated into a first-in-human clinical trial of BHB supplementation during CART19 treatment for relapsed or refractory B-cell lymphoma.


Chimeric antigen receptor T-cell (CAR-T) therapy is a promising approach in the treatment of several types of cancer.


However, the success of this therapy can be influenced by several resistance mechanisms, including lifestyle factors such as diet.


Studies indicate that dietary-derived metabolites can modulate T-cell function by influencing metabolic, epigenetic, and transcriptional processes.


This study investigates how different diets can affect the efficacy of CAR T cells in fighting cancer.

To explore this question, researchers at the University of Pennsylvania implanted diffuse large B-cell lymphoma (DLBCL) tumors into immune-compromised mice and fed them five different diets:


1- ketogenic


2- high-fiber


3- high-fat


4- high-protein


5- Western (high-cholesterol)


6- a control diet


Following tumor implantation, the mice were injected with anti-CD19 CAR T cells (CART19).


The results showed that mice on the ketogenic diet had better tumor control and longer survival compared to the other groups.


This effect was attributed to β-hydroxybutyrate (BHB), a metabolite produced during ketosis, which was at significantly higher levels in these mice.


The hypothesis was that BHB could serve as a more efficient energy source than glucose for active CAR T cells. With a more efficient energy source, they could act more powerfully and quickly to fight tumors.


To test this, scientists gave BHB to mice with tumors, along with a CAR T-cell treatment.

The mice that received BHB had much better control over their tumors, meaning that the tumors grew much more slowly.


In addition, the number of CAR T cells in the mice's bodies increased, and there was also an increase in substances (cytokines) that help the immune system fight cancer.


This positive effect has also been seen in other types of cancer, such as pancreatic cancer and leukemia. When the scientists looked more closely, they found that the CAR T cells were using BHB to generate more energy.


They integrated BHB more efficiently than glucose into the energy-producing process within the cells (the citric acid cycle). This energy-generating process became more efficient, causing the CAR T cells to consume more oxygen and increase their tumor-fighting activity.


In addition, the study also showed that BHB helped to "unlock" important genes within the CAR T cells. These genes are responsible for helping T cells maintain their function and memory, that is, to continue fighting the tumor for longer.

This happens because BHB increases the production of a substance called Acetyl-CoA, which helps modify histones (proteins that "control" DNA inside cells), making T cells more effective in their function.


The scientists wanted to understand whether the findings made in mice also applied to humans.


To do this, they analyzed the serum of patients who were being treated with CART19 therapy (CAR T cells), and noticed that there was a positive correlation between the levels of BHB in the patients' blood and the increase in the number of CAR T cells in the body.


In other words, when BHB levels were higher, CAR T cells multiplied more, which is a good sign that the treatment could be more effective.

Additionally, the researchers tested whether adding BHB during the lab-made CAR T-cell manufacturing process (when cells are taken from patients and modified to attack cancer) helped the cells multiply more. And sure enough, when BHB was added, the CAR T-cells grew much faster.


These results suggest that BHB could be a useful strategy for improving the effectiveness of CAR-T treatment. So the scientists are planning a clinical trial (a study in patients) to test whether giving BHB to patients while they are undergoing CART19 treatment can help fight B-cell lymphoma, especially in harder-to-treat cases, such as those that have relapsed or are resistant to treatment.



READ MORE:


Ketogenic Diet Enhances CAR T Cell Antitumor Function Via β-Hydroxybutyrate

Shan Liu, Puneeth Guruprasad, Kecheng Han, Luca Paruzzo, Alexander Shestov, Andre Kelly, Kevin R. Amses, Amichay Afriat, Bhoomi Madhu, Lev Litichevskiy, Ezra Dubowitz, Neil Tangal, Alana McSween, Melody Tan, Alberto Carturan, Andrew Lee, Yunlin Zhang, Giulia Gabrielli, Raymone Pajarillo, Ruchi P. Patel, Marco Ruella

Blood, Volume 144, Supplement 1, 5 November 2024, Page 4

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