This episode explores new preclinical research suggesting that a ketogenic diet may enhance CAR T cell therapy for lymphoma. Join our expert panel as they break down the science, the potential implications, and what’s coming next for a first-in-human clinical trial.

 

HealthTree Resources:

• Connect - Nutrition & Wellness Group
• Articles - Navigating Your Health
• Event - Dietary Guidelines for Cancer Prevention After Treatment

 

Let me know your thoughts on today's episode! Please share them in a comment or reach out anytime at hannah@healthtree.org. 

Hannah Loosle (00:12)
Hi everyone, welcome to today's episode of the Health Tree Podcast for Lymphoma, where we connect patients with lymphoma to the research and information they need to know about. If you've been with us before, welcome back. If this is your first time joining us, welcome. We're so happy to have you join our lymphoma community. My name is Hannah Loosle I'm your host and the Lymphoma Patient Engagement Manager here at the Health Tree Foundation.

The goal of this podcast is to make research and new information coming out about your cancer easy to understand and easily accessible. If you've ever found yourself overwhelmed by clinicaltrial.gov or a medical abstract, we are here to change that. Stick around until the end of the episode when I'll be back to share my final thoughts on today's interview as well as some additional resources you can dive into related to today's topic.

The topic of today's podcast is early stage research, exploring the science behind a keto diet and CAR T therapy in lymphoma, pulling from the abstract Ketogenic Diet Enhances CAR T Cell Anti-Tumor Function Via Beta Hydroxybutyrate. It has not yet been tested in humans and should not be taken as medical advice. We chose this topic for today's podcast because we want to make sure patients like you stay ahead of the curve on all research that may impact lymphoma treatment now and in the future. We are going to be joined in just a few minutes by Dr. Liu, Dr. Guru prasad, Dr. Ruella, and Dr. Levy, a team of researchers on the study I just mentioned. Before we bring them on, I want to give you all a little introduction.

Dr. Puneeth Guruprasad completed his PhD in 2024 and is now a medical student within the Perelman School of Medicine. He works in the Ruella Lab and mentors new members.

Dr. Maayan Levy is an assistant professor of pathology at Stanford University and an innovation investigator at the ARC Institute. Dr. Levy's scientific mission is to understand, develop, and apply the concept of metabotherapy, the use of metabolites to prevent and treat disease.

Shan Liu is a postdoctoral researcher in the Ruella lab at the University of Pennsylvania. Dr. Liu investigates how lifestyle factors affect the efficacy of CAR T cell therapies. Dr. Marco Ruella is an associate professor of medicine at the Perelman School of Medicine at the University of Pennsylvania.

Dr. Ruella treats patients affected by hematological cancers and specializes in immunotherapy approaches. His laboratory focuses on the mechanisms of relapse after CAR T cell therapy. and now without further ado, let's bring on our guests.

Hannah Loosle (02:39)
Welcome everyone. Thank you so much for joining us today. I'm really excited to dig into this research today, but I like to start by setting the scene for our audience. So let's start with the why behind your research. Can each of you briefly explain why you decided to do research in the cancer or nutrition space? Dr. Ruella, maybe we'll start with you.

 

Marco Ruella (02:59)
thank you for having us. And I'm very excited to be part of this podcast with my colleagues today. as a physician, especially as a physician scientist, I've always been interested in treating patients with hematological malignancies and in particular lymphoma. And being passionate and being interested in immunotherapies, I've always sort of tried to find solution that could increase the efficacy of the therapies that we have. And the reason why I sort of got into working into sort of nutrition and immunotherapy is really the collaboration with Dr. Maayan Levy. she has, she will explain, she's a long experience with looking into metabolism, looking into ketogenic diet for cancer. And when I heard about her work, I sort of thought that it would have been great to sort of apply her findings to the immunotherapies that we are developing for lymphoma and other hematological cancers, in particular, CAR T cell immunotherapy.

Maayan Levy (04:05)
Yeah, so maybe I'll continue from here that the broad research question that we wanted to understand as part of these studies, whether we can use lifestyle factors and particularly diet and specifically dietary metabolites to understand if they can improve the effectiveness of chimeric antigen receptor or CAR T cells the idea behind this research was not to design new CAR T cells, but to use lifestyle factors to enhance existing therapies.

 

Puneeth Guruprasad (04:38)
thank you for having us first of all. I think adjacent to Dr. Levy's point, when I did my PhD with Dr. Marco Ruella, over the course of five years, we tended to focus a lot on genetic factors and genetic manipulation of T cells to improve their function against cancer. I think that our approach is unique in that we're focusing on how the environment can affect the function of T cells and in particular diet as this major lifestyle factor. So it's a little bit different than the paradigm that has been followed for the past five to 10 years about manipulating the DNA itself of the T cells and rather focusing on how the extrinsic environment affects its function.

 

Shan Liu (05:23)
Thank you for inviting us. So from my PhD experience, I'm working with how environmental factor can contribute to the cancer development. So when I joined Dr. Levy's lab in 2023, she mentioned this project to me that we can, how can modulate the environment factor and how that can affect the immunotherapy. So I started working on that and I think it's exciting work that we can affect the immunotherapy by change the diet.

 

Hannah Loosle (06:01)
Thank you all so much for those answers. It definitely is an interesting and unique take to have that lifestyle changes can affect immunotherapy such as CAR T therapy. So I'm really excited to dig more into this research today. So we'll start with a high level overview. So can you give us a brief description of this study?

 

Marco Ruella (06:21)
Yeah, absolutely. We are very excited because at the University of Pennsylvania, have developed for the last 12 to 13 years chimeric antigen receptor T cell immunotherapies for patients with lymphoma and with other cancers. As a reminder, is a strategy, therapeutic strategy where the white blood cells, so these are the cells of the immune system of a patient, are taken out from the patient through a process called apheresis. They are modified, they are genetically engineered so that these T cells, which is a subset of the white blood cells, they can now recognize cancer cells. So once we infuse them back, they can circulate around the body, find the bad guys, the cancer cell, and kill them similarly to what they do when there is an infection. The T cells find the infected cells, like you have flu, for example, influenza, and they would kill the cells that are infected. And so this therapy called CAR T cell involves the manipulation of the immune system in the laboratory and then the infusion of these manipulated cells to make them able to recognize cancers.

And so this approach has been very successful, especially in the hematological malignancies, lymphoma and myeloma. And as a testament to that, we have five products approved, five CAR T cell products approved for lymphoma. They all target a protein called CD19 in lymphoma cells and two products for myeloma that they target BCMA. And so this was a great, great advancements for our patients in the last few years.

However, if we look at the long-term results, and we have done that, other groups have done that, we can see that we can really cure only about a third of the patients. And so these are the patients that would be otherwise with a very, very poor prognosis. So it's already a great result, but we want to improve on that. We want to bring that 30%, maybe to 50%, to 60%, to 70%. And so the rationale for all this project was, can we find a way to boost the function of this immunotherapy. And again, the work by Dr. Levy sort of inspired the approach in the sense that the modulation of the diet can actually change the metabolites, which means the nutrients that the T-cell can use to kill cancer cells in our body. And so the hypothesis was really, we test different diets and see which diet in, of course, in preclinical animal mouse model would improve the function against the tumor of the CAR T cell. And that led to the discovery that the ketogenic diet, and then Dr. Levy will tell us about what is a ketogenic diet, the ketogenic diet was really the best diet, at least in our model, to boost the function of CAR T cell against cancer. And we tested initially in lymphoma. Now we're doing some models of solid cancers and our other hematological malignancies.

 

Maayan Levy (09:38)
Yes, I would say that maybe the key finding in this study is that from the six different diets that we've tested, that Shan and Puneeth have tested, the ketogenic diets, which are the diets that are very rich in fat and low in carbohydrates, they significantly improved CAR T cell performance against different tumors. And like Dr. Ruella mentioned, we've tried it in different B-cell lymphomas also solid tumors such as pancreatic cancer, and we've used both mouse models and human cell studies. And we also found that this beneficial effect that was seen by using ketogenic diet was primarily due to one of these ketone bodies that is produced in our body after we consume ketogenic diet, which is called beta hydroxybutyrate or BHB. So it's a metabolite that is produced during ketosis.

In terms of the mechanism, we found that this metabolite BHB was able to enhance CAR T cell function by doing a few things. First of all, it gave the CAR T cells more energy. So it fueled the cell's energy production cycle. It changed some of the gene expression, but it also supported the proliferation of the CAR T cells and the production of the of different cytokines that are very important for the function of these cells. So this was all done in animal models, but we've also started exploring the relevance of these findings to humans using a small study of healthy

 

Hannah Loosle (11:13)
Thank you for that wonderful overview of the study. I was wondering if we could dive a little bit more into the specifics of what the goals and objectives were of this study.

 

Puneeth Guruprasad (11:23)
Ruella described that one of the major concerns with CAR T-cell therapy now is the percentage to which we can treat patients and have those patients enter complete remission or a cure. And One of the major concerns that we had and one of the major objectives that we had was how can we modulate environmental factors, lifestyle factors, namely diet, which is a important lifestyle factor for every patient that comes through the door. How can we modulate something that is a daily activity for patients that could also enhance the long-term function of CAR T cells in order to get that remission rate potentially from the one third that Dr. Ruella said to a higher percentage like 60 or 70%. So one of the major goals of this project was to see rather than follow the paradigm of genetic modulation in CAR T cells, how can we use day to day kind of concept such as diet to influence the ongoing treatment that a patient is receiving in order to, with the long-term objective still being in order to kind of improve this overall complete remission rate of patients receiving CAR T therapy.

 

Hannah Loosle (12:47)
Perfect, thank you for that answer. And now let's move into some of the more specifics about the intervention and the findings from this study. several different diets were tested in this study. Can you walk us through which ones you looked at and why the ketogenic diets stood out compared to the others?

 

Shan Liu (13:07)
I can answer this question. as Dr. Levy already introduced briefly, we tested six different diet in three clinical diffuse large B-cell lymphoma of model. And those diet, they are representative of the common diet we're using. So for example, we're using a high fat diet, a high protein diet, a Western diet that mimic the fast food diet that enriched in fat, sugar, and cholesterol. And we also include high fiber diet, which we think is like good diet, and a ketogenic diet, which is very high fat and very low carbo hydrate diet, and a control balance diet with matched nutrition. So among all of these diets we found that ketogenic diet in combination of CAR T cell therapies produced the best tumor control in our preclinical models.

 

Hannah Loosle (14:11)
Perfect, thank you for that answer. And then I know Dr. Levy mentioned the molecule BHB a little bit, but can we dive into that molecule a little bit more and how it is helping CAR-T perform better?

 

Shan Liu (14:25)
So, BHB, as Dr. Levy mentioned, BHB is the main keto body our body can generate when we switch from burning carbs to burning fat, like diuretic fasting, intense exercise, or following a ketogenic diet. So, in the liver, fat is broke down into ketones, including beta-hydroxybutyrate, BHB, which is the primary and most abundant form of ketone bodies in our bodies. there's other forms of ketone bodies, including acetoacetate and acetone. So in our study, we saw that mice fed a ketogenic diet has much higher levels of BHB in their blood. And when we tested BHB directly, we find the BHB itself can mimic the effect of ketogenic diet to enhance the CAR T functions.

Hannah Loosle (15:21)
Thank you. And then what have you seen in this research so far. Are there any trends that are notable for patients or anything like that?

 

Marco Ruella (15:31)
Well, I would say that the initial screening included different diets and then we focus on ketogenic because it seemed to be the best diet. again, ketogenic diet is based on fat and a little bit of protein and very limited carbohydrates. And that was mentioned that leads to enhancement of these metabolites called ketone bodies, like one of them is beta-hydroxybutyrate-BHB, right? And so from the, the focus on this work has been trying to use this metabolite, BHB, as a way to boost the CAR T cell And I would like to stress that, you know, BHB has been studied in medicine, and it is a known metabolite. As a matter of fact, there are supplements that you can buy in pharmacies or online that include BHB. And this is used to, you know, to boost productivity for exercise and so on. It's not an official drug, it's a supplement, but it's available. And we discovered that you can just use this metabolite and basically you get the same effect of the ketogenic diet. That was the first discovery. Second discovery was that we started to use this metabolite, this BHB, in multiple cancer models. So we use mouse tumors of lymphoma, then we use human tumors of lymphoma, and all of that using CAR T cells And we found that giving this BHB would enhance the function of the CAR T cells, as Dr. Levy mentioned, by sort of fueling their function. And basically getting an overall better anti-tumor effect. And this better anti-tumor effect was associated with an increased proliferation and an increased function of the CAR T cells inside the body of these mice. So this was done in the preclinical setting. Then another important finding was that we wrote a protocol for treating healthy volunteers with this supplement that you cannot by online of BHB. And so we gave this BHB to healthy volunteers and an hour and a half later, we measure the function of the T cell. So we measure the function of the immune system. And it turns out that even just after an hour and a half, we could see that the T cell, so these are the subset of the white blood cells of the immune system, the T cell were different. They were functioning in a different way as compared to before. So now we have started a trial in actual patient. This trial is open at the University of Pennsylvania. The PI is Dr. Elise Chong. And we are enrolling patients with lymphoma, any type of lymphoma that receive, who receive commercial CAR-19 therapy.

So these products such as Yescarta Breyanzi or Kymriah and we provide the supplement and the patient would take the supplement before receiving the CAR T-cell and during the first month. So right now we cannot recommend to patients quite yet to either adopt a ketogenic diet or taking the BHB supplement. However, the clinical trial is ongoing. And so we hope soon to be able to report the results and therefore having more data to either recommend or not recommend this combination. So these are really the main finding.

 

Maayan Levy (19:18)
Yeah. So basically we're trying to design this new approach to, to improve cancer immunotherapy through metabolic enhancement rather than genetic engineering of the cells. And we were trying, or at least started testing this in, in healthy volunteers, like Dr. Ruella mentioned, by asking volunteers to, take these oral supplements. And just by doing this, even though these are not patients, we saw an improvement of the metabolic function of T cells. So we think that there is indeed a potential for clinical translation that we will further explore in the near future.

 

Hannah Loosle (19:57)
That is super exciting that you're starting to test this in humans, which actually kind of leads into my next question, which is what are the next steps to move this research forward?

 

Marco Ruella (20:10)
I would say from one side, we want to test this in patients and we're already doing that in lymphoma. But at the same time, in the labs, Shan and Puneeth are working on testing whether BHB can be beneficial in pancreatic cancer, multiple myeloma and so on.

Dr. Levy already shown that BHB per se might have an effect directly on certain type of solid cancers by changing the way, basically blocking their progression. And so potentially we might be able in that setting to hit the tumor with a two-pronged approach, one directly against the tumor, the other one by boosting the CAR T cell. But the potential horizon is pretty broad because we can even test it with other types of T cell immunotherapies that are bi specific antibodies that are checkpoint inhibitors. And by the way, there are already some preclinical data that suggests that BHB can improve checkpoints. So I would say that from the clinical point of view, these are the key future direction. And then maybe Dr. Levy can discuss more on the more biological point of view, what are our key questions that we need to address about BHB and T-cell therapy.

 

Maayan Levy (21:29)
Yeah, I think that generally the way I see this research is that, or what excites me about this line of research is the fact that it bridges a fundamental gap in cancer treatment, which is the recognition that what patients do outside of the clinic can directly impact their therapy success. And for too long we focused primarily on engineering better treatments while overlooking the patient's own biology as a parameter that we can use in our favor to enhance the healing of the patients. it's a kind of discovery that makes you think why haven't we explored this sooner? Because it's such an easy and applicable approach that we can use hopefully against multiple types of cancers. We still have many, open questions such as how and what timing should we administer this specific metabolite and whether there are other metabolites that will have similar effects, if there are any toxic effects and side effects. But these are all questions that we should answer in humans directly. But at least the mouse data supports the beneficial effect and the attractiveness of this approach. So it's something I think kind of precious in cancer care. And it's a potentially powerful intervention that is accessible. It's relatively affordable. Like Dr. Ruella mentioned, this is a specific supplement that is available over the counter and it builds on a treatment that already works, which is the CAR T cells, rather than trying to design a completely new way to replace it. So we are trying to enhance an existing therapy while first understanding the biology behind it using mouse models.

 

Hannah Loosle (23:22)
That's great. And it's super exciting that this is starting to be tested in some other types of cancers. And Dr. Levy, really like that you mentioned about how this, you know, following a certain diet is something that patients can do outside of the clinic to impact their success. That's so important for patients because when they get a lymphoma diagnosis or any cancer diagnosis and treatment and all of that is out of their control. So it's really nice to know that there potentially might be something they can do like diet that would be in their control. So it's great that this is starting to be researched to help enhance some of these treatments that are already existing.

 

Maayan Levy (24:03)
Yeah, and maybe we can take it even one step further and to say that it's not just the diet that we can use, but first of all, more broadly lifestyle interventions. But in this specific case, we're actually not focusing on the diet, but on the downstream metabolites, which we think is a much more feasible approach, asking patients to change their diet, specifically to a ketogenic diet that is a very hard, difficult diet to follow is challenging. So instead of this, we have identified in the lab the specific molecule that just by supplementing this molecule, beta hydroxybutyrate ketone body, we saw the same beneficial effect. So instead of changing the entire diet, we can just now supplement the downstream active molecule that will produce the same benefit. So it's an easier approach and something that we think will be more doable for patients.

 

Hannah Loosle (25:07)
That's great. Definitely important that it's something that's easy for patients to adopt. And you also mentioned before that it's affordable, which is also really important with everything with cancer can start to get really expensive. this is great. And then my next question is from everything that you've seen so far, what could these results potentially mean for patients down the road?

 

Marco Ruella (25:32)
Well, I would say that as we mentioned could be like, we don't necessarily have to change the treatment, but you know, we can take steps, to improve diet or to take supplements that are carefully evaluated in a rigorous way, to sort of improve the efficacy, but also the tolerability of the treatment. I would like to stress once again, because this podcast is directed mostly to patients that you should always disclose the type of supplements that you take when you go to your doctor. Herbal teas, the so called natural supplements or probiotics, prebiotics, you need to disclose all of those to your doctor because some of them, even if they are called natural, they might be natural, but everything is natural, right? So what I'm saying, they can have an effect on, of interaction with the treatment. So it's always important to double check with your doctor, everything you're taking. And again, I want to stress once again, that we don't recommend at this stage to make any changes beyond the fact that having a healthy diet is a good thing. Being active as much as compatible with the health condition is good. So try to be active, try to eat good food, not fried, not too fat and not processed. That's a general rule, it's okay. But we don't recommend at this stage to sort of take supplements or drastically change your diet because there are no data to support that in the clinic. Our work is mostly for pre clinic.

 

Hannah Loosle (27:12)
Great, thank you for that response. And then we did have a patient actually submit a question for this interview. So the question is, do you have any plans to test the keto diet along with other treatment options such as stem cell transplant?

 

Marco Ruella (27:28)
in the short term, we are focusing on T cell immunotherapies because we have seen a direct effect of ketone bodies in particular, BHB on the function of the T cell. So these cells of the immune system. But as mentioned, we can start with T cell, but then there are a lot of many different T cell immunotherapies that can be explored from bispecific to checkpoint inhibitors and so on. In particular in the setting of transplant, which it's a pretty complex therapy if we think about allogeneic stem cell transplant, I don't think there are data about ketogenic diet there as far as I know. There are data about how the diet can affect the microbiome and how differences in microbiome can affect the outcomes in terms of toxicity, for example, of allogeneic cell transplant, but there are not a lot of data of ketogenic diet and BHB usage in allogeneic stem cell transplant. So we are not currently doing it, but I don't exclude we will do it in the future. Keep in mind for allogeneic stem cell transplant, boosting the T cell might also potentially include increasing the risk of the so-called graft versus host disease, which is the T cell from the donor that attacked the healthy tissue of the recipient. I think that there need to be more studies before using ketogenic diet or BHB or other compounds in the setting of allogeneic stem cell transplantations. As far as I know, there are not many data there.

Maayan Levy (28:59)
Yeah, I agree with Marco. I don't think we can generalize this currently with the data that we have in hand to other existing therapies.

 

Hannah Loosle (29:08)
Thank you for answering that question. And then for my last question for this interview, I just would love to have each of you answer this one. So what excites you the most about this research and what is the most important thing you want patients to take away from this discussion today?

 

Shan Liu (29:25)
For me, think the most exciting part is seeing what we're doing daily in the lab can eventually help patients. Like Dr. Ruella introduced, we have small clinical trials ongoing. So that made me feel very excited and make me feel like what we're doing is very meaningful.

 

Puneeth Guruprasad (29:50)
I agree. And I think that just like Dr. Ruella and Dr. Levy said, this is a really unique opportunity for patients to take agency of their own treatment and their own care. And I think while we cannot make a recommendation about the role of ketogenic diet or beta hydroxybutyrate, we can definitively say that living a healthy lifestyle is always a good thing. And I think that in the future, kind of hammering this point home will continue to benefit patients, whether we implement beta-hydroxybutyrate in the clinic or not.

 

Maayan Levy (30:25)
Yeah, just the fact we have the tools in our hand to translate some of the basic research findings that we found in the lab to the clinic and really influence and hopefully improve patients' life is for me the most exciting.

 

Marco Ruella (30:44)
Yeah, I would like to echo what the rest of the team has said. What is very exciting to me every day is to see that working synergistically between our groups, we can bring new ideas to the clinic pretty rapidly. We started this project probably about two years ago and we already have a healthy volunteer trial and a patient trial. So we want to continue to improve the outcomes of our patients by potentially in the future, even thinking about how we can define other metabolites that can improve the function of the CAR T cell and the T cell immunotherapy. So this idea about being quick in translating discoveries in the lab to the clinic, I think from my point of view is most exciting part of this story.

 

Hannah Loosle (31:29)
Thank you all for those answers. This research is definitely very exciting. And I know I said that was the last question, but I actually thought of something else I wanted to ask really quick. So it's been mentioned that there's some healthy volunteer trials going on related to this and some patient trials and things like that. So I was wondering if patients are interested in joining a clinical trial at the University of Pennsylvania, how can they find more information about that?

 

Marco Ruella (31:55)
Well, sort of the platform to look for trials is clinicaltrials.gov. so by going online and writing clinicaltrials.gov, you can find all the trials that are available in the world. if you put the BHB and CAR T cells, you will see that the study from the University of Pennsylvania will would pop out and that's a way to find it and then there are the contact information there or in the University of Pennsylvania website to be in touch with the treating team that can help you out to get involved and to get potentially enrolled. And you know, I'm happy if anyone interested, just email me and I can help.

 

Hannah Loosle (32:42)
Perfect. Thank you so much. And thank you all so much for joining us today and sharing the incredible work you're doing in the lymphoma and nutrition space. This has been so informative.

Maayan Levy (32:54)
Thank you. Thanks for having us.

Marco Ruella (32:55)
Thank you for having us.

 

Hannah Loosle (32:58)
I loved this interview! It was really interesting to hear about this research and how it may enhance existing treatments such as CAR T therapy for lymphoma. I loved the discussion about how this would be a more affordable option for patients looking to improve treatment outcomes. I'm super excited to hear more about this research as it progresses and as more in-human trials happen. If you want to keep learning about nutrition and lifestyle choices, we have some additional resources you can look at on our website. I'll link them in the episode description so you can check them out for Lymphoma. I you learned something new. Let me know if you have any thoughts on today's episode. Share them with me in a comment or send them to me in an email. You can find my email in the episode description. Join us again next time to learn more about lymphoma research and what it means for you.