iwCAR-T 2025 | Strategies to improve the efficacy and minimize the toxicity of CAR T-cell therapy

Elizabeth Budde

All right, hi, good morning. My name is Elizabeth Budde. I’m a hematologist from City of Hope, Duarte, California, and we have a great panel today. Let’s go down the road to do introduction. 

Mohammad Rashidian

Sure. I’m Mohamed Rashidian. I’m a faculty at Dana-Farber Cancer Institute at Harvard Medical School. Our lab focuses on protein engineering. We have an interest in T-cell immunology and developing protein-based therapeutics. 

Michael Jain

And I’m Michael Jain. I’m a physician who treats patients with CAR T-cell therapy at Moffitt Cancer Center in Tampa, Florida. 

Marco Ruella

Marco Ruella, I’m an assistant professor and physician scientist at the University of Pennsylvania. My group is interested in resistance and toxicity mechanism after CAR T-cell immunotherapy with a special focus in lymphoma. 

Elizabeth Budde

So we just had a pretty wonderful discussion on long-term toxicities and effects of CAR T-cells in patients. So I wonder whether we can, maybe, Mohammed, you can take the lead, and give just one minute summary about what you presented it. 

Mohammad Rashidian

Absolutely. So we, you know, one of the issues with cell therapy is that patients relapse. And for multiple myeloma, a lot of patients relapses with antigen positive relapses. And that means the major issue is the lack of activity and persistence for BCMA-CAR therapy. Somewhat similar for CD19, although we have CD19 loss, or the antigen loss, the epitope loss sometimes. But the majority of patients are still CD19 antigen positive. So enhancing activity and persistence of CAR T-cells is a major challenge. And what we tried to do is to make a protein so that the protein, which we named it CAR enhancer, these enhancer proteins basically have two arms. One of them is the antigen itself, which selectively target the CAR. And then it’s engineered to have a low affinity, almost dead IL-2 or IL-15 and so forth, so that the protein can be given to patients after they receive CAR-T therapy. And this way you would anticipate that the protein will selectively enhance activity and functionality of CAR T-cells, which in turn, you would anticipate this would result in better responses in patients. 

Michael Jain

So when patients have cancer, we all know kind of what they look like, which is often they are quite inflamed and can have things like cachexia, weight loss, and looking like they have active cancer. And the reason for this is that what cancer does is it sort of systemically reprograms the whole body to be quite inflamed for the purpose of suppressing our immune systems to prevent them from attacking the cancer. And CAR T-cell therapy is a very immune active cancer. And what we found is that patients who have high levels of this systemic inflammation actually have more toxicity from CAR T-cell therapy. And the CAR T-cell therapy does not cure as many patients in lymphoma. And so we wondered whether we could suppress this inflammation through various means. We started to try to use corticosteroids or an anti-cytokine drug called anakinra. But neither of those treatments seemed to improve the outcomes of the CAR T-cell therapy that we were using. So more recently, we started using a more potent anti-inflammatory that probably affects multiple of these inflammatory cytokines that patients are experiencing before and during CAR T-cell therapy, a JAK1 inhibitor called itacitinib. In our hands in this small study that we’ve done, we actually found that that has led to an improved rate of long-term remission and better outcomes than we would have expected for this patient population previously. 

Marco Ruella

And so similarly to what my colleague mentioned, we also try to focus on how to improve CAR T-cell therapy in our patients. And among the many projects that we’ve been doing about modifying the product, about combination, and so on. We tried to focus on something that we think is not really studied in the field, which is the effect of diet in CAR T-cell therapy. And so while we don’t have a good way to monitor diets in patients, at least retrospectively, we modeled that in mice. So we gave different diets to mice to understand which diet would be the best in pushing and boosting the anti-tumor effect of CAR T-cells. And so in this model, we saw that ketogenic diet was actually the diet that was giving the best effect in our animal models. And ketogenic diet is a diet where the core of the nutrients that are given to patients are fat and protein and with low carbohydrates and a little bit of fiber as well. But again, it’s a diet that leads to high level of these ketones in the serum. And it’s a diet that is actually used in some patients, for example, patients with epilepsy and other conditions. So it is a diet that is used in medicine. And we saw that we were able to identify what specific metabolites were able to do the effect of increasing CAR T-cell function. And so what we did then is we moved from the lab to the clinic and we started giving supplements to first healthy volunteers. And we saw that these BHB supplements were increasing the T-cell metabolism, the efficiency of the T-cell. And now we have a trial open where we’re giving this BHB beta-hydroxybutyrate, this ketone body supplement to patients receiving CAR T-cells. So I don’t think at this stage we recommend giving this supplement to patients. It’s early. We need to see the results. But we’re generating data that potentially can suggest that providing this sort of source of energy to our patient might lead to better results. 

Michael Jain

You know, Marco, I was very interested in your diet-based results because we also ran a metabolomic study where we looked at 700 metabolites in patients who had CAR T-cell therapy. And I asked our statisticians to tell me, well, what is the metabolite or thing in the blood that goes up the highest after CAR T-cell therapy? And they told me it was adipic acid. And so, of course, like any scientist, you go down a rabbit hole trying to figure out what it is. And it turns out that because, you know, in our setting, the patients were admitted to the hospital at the time they received their CAR T-cell therapy. And adipic acid is a very high component of jello that we were basically able to measure through metabolomics the presence of hospital cafeteria jello in their blood. But, you know, so it’s sort of a funny thing. But, you know, what it tells us is that what we are eating very profoundly shows up in the blood of while we’re getting these therapies. And I think it’s really important. 

Marco Ruella

No, thank you. No, absolutely. I mean, we also did metabolics in more patients. We would see caffeic acid or stuff that they clearly coming from coffee or they’re coming from the lymphodepletion. We were able to identify the drugs that we gave them during lymphodepletion, so they are still present in the patient. So there is a lot of things that you can understand. 

Elizabeth Budde

Any effect that you found would affect the levels of IL-15, IL-7, IL-2? 

Marco Ruella

So in our experiment, given the ketogenic diet, what is increasing mostly interferon gamma, less so IL-7 and IL-15. But I don’t know, maybe with your CAR enhancer, you might say. 

Mohammad Rashidian

The protein, the CAR enhancer, selectively binds to CAR T-cells and provides the signaling, which is kind of a cross signaling between the CAR and IL-2. And that results in CAR T-cells getting activated. And they do produce interferon gamma and they do undergo very robust proliferation. So we do see cytokine production with them. 

Marco Ruella

Michael, I actually have a question for you, because I think we also had the trial with the itacitinib open at Penn. I don’t know. It probably was the one by Dr Frigault. And when they opened that, I mean, I did in 2016 laboratory work that show that JAK inhibition can actually modulate cytokine production by T-cell. We never published that, but was also decreasing CAR T-cell proliferation. So I was worried that by giving a JAK inhibitor, like itacitinib or ruxolitinib, for sure you reduce inflammation. But there is also the risk that you reduce CAR T-cell effector function, because you block the pathways that the T-cell have activated when cytokines stimulate them. So how do you sort of put together these two things, right? The effect directly on T-cells and the effect in the inflammatory milieu. 

Michael Jain

Yeah, so I think that there’s a couple of different scenarios where this could be a little bit different. And so one question, you know, that you’re asking there is like, which are the cells that are benefiting from the JAK-stat inhibition? It’s likely, you know, things like myeloderived suppressor cells or perhaps the T-regs that are dependent on these pathways to a greater extent than the effector cells. Marcela Maus also showed that in hematologic malignancies, the things like canonical cytokines like interferon gamma just tend to matter less. And so I wonder how much of the inside of a person, the actual antigen-driven CAR T-cell activation really needs that third signal compared to in other settings or other models, how much is actually required. And then another aspect of it though, so it’s hard when you do a clinical trial, we can’t dissect things in the same way as you do in animal models. But in fact, one subtle detail is that we’re only giving the drug once a day. And there’s quite a bit of evidence that if you sort of rest the CAR T-cells for a period of time, you may actually reinvigorate their function. So it may be the case that by giving the drug in that way, it’s sort of an on-off kinetics that is favorable overall to the CAR T-cell proliferation. So we wonder about all these things. We’re going to try and work that out in some of our collaborative work. 

Marco Ruella

What do you think is the way to get the final answer? Are you thinking about an end of my study? 

Michael Jain

So I think ideally it would be great to do a larger study, but I think that there’s more work to be done in terms of, I think, one of the nice things was discussed in the discussion is that one way to improve CAR T-cell therapy is, yes, to create novel engineering designs. But another way is to add things like dietary interventions or additional drugs that are already approved. And so I think of this as, look, if we can get a platform of, you know, like a JAK inhibitor that has little toxicity and has a good interaction, okay, what can we add to that to then, you know, raise the bar even further? And then once we kind of get to a place where we think, okay, this is the best combination of therapies that we’re at, then we can go and run the larger trial and be confident that we’re going to get a positive result. 

Elizabeth Budde

I also remember from a few years ago when people look at the JAK inhibitors that function on T-cells, it’s also a dose-dependent phenomenon. But a lower dose could be beneficial, but a higher dose, it suppresses proliferation so much that you don’t get the benefit anymore. 

Michael Jain

There is a literature in the checkpoint inhibitor literature of something called chronic interferon signaling. And there the idea is that having no cytokine signaling is you don’t get T-cell proliferation. But actually if you have excessive or too much, you end up upregulating all these checkpoints and other mechanisms of suppressing the T-cells. So there’s probably like a bit of a sweet spot where you need a certain amount of stimulation, but not too much and not too little. Now how much that matters for any particular CAR T-cell setting may vary. And so that’s why I think it’s an impure question we can really only answer by human trials. 

Elizabeth Budde

Well, thank you for watching this session. We have a great time discussing how to maximize the efficacy of CAR-T’s and at the same time, minimize the toxicity of CAR T-cell therapy. Thank you all.

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