A simple nutritional supplement may offer a new approach to boosting CAR T cell function, researchers say. University of Pennsylvania Perelman School of Medicine and Penn Medicine’s Abramson Cancer Center. This approach needs to be evaluated in clinical trials, but early research was shared at today’s press conference. 66th American Society of Hematology (ASH) Annual Meeting and Exhibition (Summary 4), suggesting a potentially cost-effective strategy to improve CAR T cell function and cancer-fighting ability.
CAR-T cell therapy This is a personalized treatment approach pioneered at Penn Medicine that reprograms a patient’s own immune cells to kill cancer.
“Thousands of blood cancer patients have been successfully treated with CAR T-cell therapy, but it still doesn’t work for everyone,” said the co-lead authors. Dr. Xiang Liua postdoctoral researcher who presented research at ASH. “We took an unprecedented approach to improve CAR T-cell therapy by targeting T-cells through diet, rather than further genetic engineering.”
Liu co-led the study Dr. Puneeth Guruprasadreceived his PhD from the University of Pennsylvania and is currently a medical student at the Perelman School of Medicine. The first author worked under the guidance of the co-senior author Dr. Marco Lueraassistant professor of hematology-oncology, researcher in the Center for Cellular Immunotherapy, and scientific director of Penn Medicine’s Lymphoma Program. and Dr. Mayan Levyassistant professor of microbiology.
CAR T cells prefer BHB as a fuel source
First, the research team used a diffuse mouse model to show that several different diets, including a ketogenic diet, a high-fiber diet, a high-fat diet, a high-protein diet, a high-cholesterol diet, and a control diet, stimulated CAR T cells. The effect on the ability to fight tumors was tested. – Large B-cell lymphoma. They found that mice fed the ketogenic diet had improved tumor control and survival compared to all other diets. In subsequent studies, they found that high levels of beta-hydroxybutyrate (BHB), a metabolite produced by the liver in response to a ketogenic diet, was an important mediator of this effect.
The research will be based on Previous work by Levy’s teamlaboratory experiments found that BHB strongly inhibited colorectal tumor growth.
“Our theory is that CAR T cells prefer BHB as a fuel source rather than standard sugars in the body such as glucose,” Guruprasad said. “In other words, when BHB levels increase in the body, CAR T cells become more capable of eliminating cancer cells.”
Translational research in patient samples and healthy volunteers
Next, the researchers tested the combination of BHB supplements and CAR T-cell therapy in a laboratory model of human cancer (standard diet). The results showed complete disappearance of cancer in the majority of mice and enhanced proliferation and activation of CAR T cells. To see if BHB, which occurs naturally at different levels in our bodies, has similar effects in humans, the team evaluated blood samples from patients who had recently undergone CAR T-cell therapy and found that higher We found that BHB levels were associated with better CAR T cells in an expanded number of patients. They also looked at T cells from healthy volunteers who took BHB supplements and found similar changes in the way normal T cells produce energy after exposure to BHB.
While previous studies in several cancer types have examined the effects of dietary treatments, such as high-fiber diets, on the response to cancer immunotherapy, the mechanism behind the BHB effect in this study was This appears to be due to metabolic changes within the body. rather than through the gut microbiome, as is the case with high-fiber diets.
Next steps and potential impact
The theory that BHB supplementation may improve response to CAR T cell therapy is being tested in research laboratories. Phase I clinical trial at Penn Medicine’s Abramson Cancer Center.
“We’re talking about interventions that are relatively inexpensive and have a low potential for toxicity,” Levy said. “If the clinical trial data is positive, it will be interesting to think about how a very simple approach like this can be combined with diet and other more traditional approaches to increase anti-cancer efficacy. I’m looking forward to it.”
Clinical trials led by principal investigators Dr. Elise ChongThe assistant professor of hematology-oncology will soon begin enrolling patients with relapsed or refractory large B-cell lymphoma who are receiving commercially available anti-CD19 CAR T-cell therapy as part of their treatment.
“As a physician and scientist, I share patients’ excitement about the possibility of new strategies to better treat cancer. And we’re very excited to see it move into clinical trials,” Luera said. . “However, we would like to emphasize that this study is still preliminary at this time and we do not intend to recommend any diet or supplement to patients based on this study until we have definitive clinical evidence.” .”
This research was partially funded by the Penn-CHOP Microbiome Core.
Liu will present the findings at a plenary scientific session on Sunday, Dec. 8, at 2 p.m. PT in Hall B of the San Diego Convention Center.
Patients interested in clinical trials at Abramson Cancer Center can Search for open clinical trials here Or call 1-855-216-0098 to speak to a clinical trial navigator.
