Almost every patient with a cancer diagnosis has asked me, “How should I change my diet?” Yesterday’s Plenary Scientific Session, Ketogenic Diet Enhances CAR-T Cell Antitumor Function Via β-Hydroxybutyrate, provided new insight into how we might more definitively answer this question. In advance of his plenary presentation, Marco Ruella, MD, a prominent physician-scientist at the University of Pennsylvania, described the fascinating journey from initial hypothesis to paradigm-shifting discovery in unraveling how diet can influence the efficacy of chimeric antigen receptor T-cell (CAR-T) therapy.
“It all started with a chance meeting,” Dr. Ruella said, noting that Mayaan Levy, PhD, a microbiologist researching the impact of diet on cancer progression, presented her findings at an immunology symposium he attended. “I was immediately intrigued by her work. We decided to collaborate and explore whether dietary factors could influence CAR-T cell therapy outcomes.”
Their joint research hypothesized that various diets could impact the efficacy of CAR T cells in cancer treatment. Immunocompetent mice were implanted with diffuse large B-cell lymphoma (DLBCL) tumors and fed various diets, including high-fiber, high-fat, and ketogenic. Murine anti-CD19 CAR T cells were subsequently infused. The endpoints focused on tumor control and overall survival based on the various diets. “As an Italian, I was rooting for the Mediterranean high-fiber diet,” Dr. Ruella joked. But the findings were indeed quite surprising. It was the keto diet that led to significantly better CAR T cell outcomes.
The ‘Beta’ Breakthrough
The Ruella/Levy team discovered that the superior tumor control and enhanced CAR-T proliferation in the “ketogenic” mice was mechanistically linked to beta-hydroxybutyrate (BHB), a key ketone body produced during ketogenic dieting. “The results were striking,” said Dr. Ruella. “BHB seemed to optimize T-cell metabolism, enhancing oxidative phosphorylation and boosting their cancer-fighting capabilities.” The beneficial effects of BHB extended beyond CAR-T19-treated DLBCL murine models. Oral BHB was also administered to pancreatic cancer xenografts treated with anti-mesothelin CAR-T, as well as to acute lymphoblastic leukemia xenografts that received CAR-T19, resulting in enhanced CAR T cell expansion and improved tumor control across all models.
To validate these findings, Drs. Ruella and Levy extended their research to previously collected samples of patients with DLBCL who had received CD19 CAR T cells in clinical trials. They discovered that patients with higher BHB levels demonstrated improved CAR T cell expansion and function. Moving rapidly from bench to bedside, the researchers have now launched an interventional trial to study BHB supplementation in cancer patients receiving CAR-T therapy. When asked if patients should just go on a ketogenic diet instead, Dr. Ruella pointed to the potential complexities in applying dietary interventions broadly. “Placing patients on a ketogenic diet isn’t simple,” he said. “Compliance would be low, given its restrictive nature.” Instead, BHB supplementation is a much more feasible alternative.
What Fuels This Particular Cancer Biologist?
I asked Dr. Ruella if he’s ever tried a ketogenic diet before. “Never!” he chuckled. “I’ve always thought we’re meant to eat mostly vegetables, fruits, and the occasional meat — like the primates we are.” His reflections on dietary habits underscore a broader point about human health and diet’s role in well-being. When asked which high-fat keto food he would hope for if stranded on a “ketogenic island,” Dr. Ruella immediately chose avocados over the options of endless bacon or cheese. “Definitely avocados!” he said. “They’re healthier. And let’s face it — the cheese available wouldn’t be good Italian cheese!”
Future Focus and Joint Efforts
The research of Drs. Ruella and Levy exemplifies translational science at its best — innovatively taking a hypothesis from preclinical models to clinical trial. Dr. Ruella doesn’t fail to emphasize that the success of this research arises from a strong cross-disciplinary partnership. “Our collaboration with Dr. Levy’s team has been truly collegial and enriching,” he said. “It’s the very definition of synergy — melding cancer biology with metabolism expertise. This work is about collaboration, discovery, and, most importantly, improving outcomes for those battling cancer.” Drs. Ruella and Levy are also unwavering champions of their junior faculty, graciously entrusting the honor of presenting this groundbreaking plenary work to their postdoctoral fellow, Shan Liu. If you missed the plenary session, make sure to catch it on demand on the #ASH24 online platform!
