Maayan Levy, PhD, and Marco Ruella, MD, on How a Ketogenic Diet Enhances CAR T-Cell Antitumor Function Via Beta-Hydroxybutyrate (BHB)

Dr. Ruella: My name is Marco Ruella. I’m an assistant professor of medicine at the University of Pennsylvania and the scientific director of the lymphoma program. I’m here with Dr. Maayan Levy, also an assistant professor, microbiology at Penn. And we’re here to discuss our recent work on the role of ketogenic diet on CAR T-cell immunotherapy. We have seen definitely a revolution with CAR T-cell in the clinic, because now we have seven FDA-approved chimeric antigen receptors product for lymphoma, myeloma and leukemia. As much as we are excited about these results, we also recognize that the majority of patients actually unfortunately either do not respond or relapse to therapy. And so a lot of groups, including our group, has been really interested in understanding the mechanism of relapse. But most groups are looking into the function of T-cell by engineering them or looking at the tumor, and we took a different way. We wanted to see how lifestyle factors can affect the function of CAR T cells. Dr. Levy: Yeah, so there’s a real pressing need to develop new and feasible approaches to enhance the activity of CAR T cells. We’ve decided to take this approach of using one of the easiest things that we can modify, which is our diet. So we’ve previously shown that we can use diet to either prevent or even treat different kinds of cancers, primarily colorectal cancer. So together with Dr. Ruella, we decided to look at the effects of different diets on CAR T cells and whether we can combine CAR T cells together with different diets to enhance their activity. Dr. Ruella: I remember we were at a meeting at Penn at the Institute for Immunology and Maayan presented her wonderful day on ketogenic diet. And so after the talk, we met and we said, maybe we should test these diets in CAR T cells. And so that’s really what led to the study where we compared different diets. So high fat, high fiber, western diet with cholesterol, high protein, and ketogenic diet. We gave it to mice and we saw some incredible results, right? Dr. Levy: Yeah. So like Dr. Ruella said, we really screened different diets for their combinatorial effect with CAR T cells in different preclinical mouse models. So we gave mice, different groups of mice, these different diets. And then in combination with CAR T cells, we looked for their antitumor effects. And what we found is that among all the diets that we screened, there was one particular diet, which is the ketogenic diet, that really enhances the activity of CAR T cells. And ketogenic diets are these diets that are very rich in fat and low in carbohydrates and they’re called ketogenic because they induce the production of ketone bodies in our body, primarily beta hydroxybutyrate. This is one of the main ketone bodies. And in our study, what we found is that we don’t need the entire combination of the diet, which is, if we’re thinking about the feasibility to treat patients, then something like a ketogenic diet can be a bit challenging for patients to consume. We found that it was sufficient to provide these ketone bodies, this one metabolite, to see the same beneficial effect. So now we can combine beta hydroxybutyrate, this ketone body, together with CAR T cells to see a very impressive antitumor effect, an enhancement of CAR T cell activity. Dr. Ruella: So we call beta hydroxybutyrate BHB because it's obviously easier. So we gave BHB to mice with certain effects, but of course the next step was to see what happens in humans. And so the study continued by giving BHB as a supplement to healthy volunteers. And also in this model in actual human beings, we saw that BHB would enhance the metabolism of T cells. And so for us that was sort of the proof in humans that modulating this pathway can be actual beneficial. But of course the next step will be to get to patients. So from one point of view, we went back to our CAR T-cell patients with lymphoma treated with different levels of BHB based on the microbiota, based on the diet were naturally present. Each one of us is different, and we saw that higher levels of BHB in the serum that were correlated with higher expansion of the car. And now what we are doing in a prospective fashion, we are giving a BHB supplement to patient receiving commercial car 19. So these are lymphoma patient receiving FDA approved products that were giving BHB before and throughout the first month after third. And of course we will see the response, the safety and we'll do a lot of cool correlative studies, right? Dr. Levy: Yeah. At least in mouse studies, we found that BHB supplementation resulted in enhanced proliferation of CAR T-cells. So there are now more CAR T-cells and the CAR T-cells that are present in the tumor are more active, they secrete more cytokines. So we're trying to see if something similar can be observed in patients that receive this BHB supplement. Dr. Ruella: So I think that why we need to wait for the clinical data. So I don't think we are quite ready to recommend ketogenic diet for patient receiving CAR T-cell. I think the clinical trial will provide more information on that, but I think that the rational with the data that we've seen so far is pretty strong and really suggest that BHB fuels the T-cell function in a, that leads to a antitumor activity. I think one of the features of this work is sort of the synergy between two groups. Dr. Levy's group that is a group with expertise in metabolism, diet and microbiome. Our group more on the translational side, CAR T-cell hematological malignancies. Really I think that the synergistic merging of these skills really led to these results.