iwCAR-T 2025 | Integrating autoimmune diseases into cellular therapy centers

David Miklos:

Hi, I’m David Miklos. I’m the Chief of BMT Cell Therapy at Stanford. And today at the iwCAR-T, we had a really dynamic and I think thought-provoking session on the application of cell therapy into autoimmune diseases. David Porter chaired the session and he started us off with some plenary, over-viewing comments. But then we had data today. We had the presentation of two investigator-initiated trials and two ongoing company-sponsored trials. I am joined by panelists. I’m going to ask them to introduce themselves and their institutions so that we can get this kicked off. 

Frederick Locke:

Thanks, David. I’m Fred Locke. I’m the chair in the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center in Tampa, Florida. 

Sarah Nikiforow:

I’m Dr Sarah Nikiforow. I am the Medical Director of the Cell Manipulation Core Facility at Dana-Farber Cancer Center in Boston and the Technical Director of our Immune Infector Cell Program. 

Lazaros Lekakis:

And I’m Lazaros Lekakis. I’m a Professor of Transplantation and Cell Therapy at the University of Miami. 

David Miklos:

Thank you, guys. Thanks for joining us today. I’m going to ask three questions that I’m going to ask each of you to think of kind of short answers. We had a session on this last year, and I want to ask you, what do you think the change in attitude, interest, and data is in a one-year period looking at cell therapy and autoimmunity? Significant? Lack of change? What do you think is going on? 

Frederick Locke:

I mean, to me, there’s increasing enthusiasm. I mean, I think particularly investors who are funding many of these clinical trials are seeing this as an avenue, a large patient population that could benefit from these cell therapies. And so now we’re into the aspects of operational details. How are we actually going to run these clinical trials? How are cell therapists going to interface with the disease experts? And where are these treatments going to be done if they are ultimately FDA approved? 

Sarah Nikiforow:

I would say the same thing. The company interest in this from companies that either were former CAR companies in the oncology space or are coming at this anew with novel concepts, designs, and even cell types, like NK cells, is very impressive since last year. I would also say that based on the physicians we work with, the enthusiasm is much more, right? So before there were case reports and people were saying, you know, a rheumatologist might approach a cell therapist and say, so what do you think about? But now it’s, “I’ve heard from four different companies. We have lots of lupus patients. Can you help us navigate how to decide what is the best approach?” And as Fred was saying, how do we get this started? Right? 

So after the scientific session today, we had a very vigorous panel discussion about how each of our institutions is planning to approach this. What’s feasible today? What’s feasible in the future? And I think we’ve got ongoing discussions on a daily basis between the cell therapy and the autoimmune groups that indicate the interest. 

And the last thing I’ll say is, I think a year ago we had case reports. Now we really do have data, right? We have 33 patients enrolled on your trial. So we are accumulating information about not just efficacy and safety, but how are these products and how should our biologic approach be different in autoimmune diseases and maybe amongst the different autoimmune diseases than cancer. So it is very exciting. 

Lazaros Lekakis:

So I see a big potential on this therapy for autoimmune diseases. There are many patients in the United States with severe autoimmune diseases, especially dyscleroderma, lupus polymyositis. The new cell therapies that are being tried now seem that they don’t have so much toxicity as we have seen before in lymphoma and leukemia. We didn’t have a grade 4 or grade 5 on the BMS trial. And to the best of my knowledge, the German study did not show any grade 4 or 5 toxicities. And the efficacy is overwhelming, meaning the German study that was published, Nature Medicine, New England Journal of Medicine, by Dr Satter. So all 15 patients went to corticosteroid free state. And apparently those patients need to be referred to as fast as possible and not when they develop a renal failure or when they have severe lung disease with being dependent on oxygen from ILD. Maybe in that case it’s too late. They need to be referred earlier. 

And I am interested on the data also of bispecific T-cell engagers. We’ll see what this will show, and other targets like BCMA targeting with CAR T-cells. Also, I’m interested in naked antibodies like inebilizumab that is already approved for neuromyelitis optica and has shown significant activity in myasthenia gravis and IgG4-related diseases. 

David Miklos:

Okay, so you’re seeing a lot of promise. You’re seeing some logistical difficulties in bringing it on board, you’re seeing a lot more interest in industry trials and how we get this done. Are you seeing benefits in patients? I mean I just want to say it out loud, like let’s talk about how amazing the individual patient experiences that have been presented so far are and what the possibility for a patient who otherwise is on lifelong immune suppression, debilitation, many people losing lung function, morbidity, mobility and then to suddenly see someone walking down the hallway that was wheelchair bound. Have you yourself seen this? 

Frederick Locke:

So I have not. And to be clear, I mean, there are these single cases or a few cases on these trials where this is happening. But we haven’t gotten to the point where we’re treating a bunch of patients on trials and we’re seeing that happen because we’re just launching the trials now. And so… but it’s very clear the benefit of this treatment for these patients who have severe and debilitating autoimmune diseases. And so really my next question after that is, okay, these are the severest of the severe autoimmune diseases. Actually, can we make this therapy safe enough and effective enough that you could even give it to patients with more mild disease, right? And interrupt the disease course because there are millions of patients with autoimmune diseases. And so from a sort of global perspective, how many patients will we actually reach? And it may be many more than we treat with cancer. We’ll see. 

Sarah Nikiforow:

I’m going to defer the majority of the patient experience on, but in the few patients we have seen and also at the discussion today was, how do you define success right? And I think that it’s very different than what the cell therapists to date who are typically oncologists are used to defining in terms of scans, metrics, resist criteria. I think that many of these are patient reported outcomes, the measurement schema are different in each individual disease. And then someone had brought up the parallel to graft versus host disease in the discussion today, in terms of being on fewer medications is actually a win, which is a very different way of assessing success. So I think there’s going to be symptomatic improvement, but even if, potentially, your symptoms are not that much better, but you’re on many, many fewer therapies and the burden of your care is less, that may be a definition of success, right? So I think that I can’t speak to this as much personally, but I think we need to think about how we define improvement in these studies. 

Lazaros Lekakis:

You mentioned the graft-versus-host disease, and Dr Miklos, of course, has a lot of experience, has launched therapies, new therapies in the area. I also see this one as a possible new target for CAR-T therapy or NK CAR. But I also heard what Fred said, that it’s better to bring it a little earlier to the treatment paradigm. Because those patients are treated with immunosuppression almost indefinitely. And the worst of the immunosuppressive therapies probably is the corticosteroids. It’s not too big for years on corticosteroids, but probably has more side effects than giving one course of CAR-T therapy. So I see a lot of potential for benefit in those places. 

Sarah Nikiforow:

Do you have any patient cases that you’d like to share? 

Lazaros Lekakis:

It’s still early. 

Sarah Nikiforow:

Okay. 

David Miklos:

Yeah, no, I think that at Stanford, we have two open investigator-initiated trials. The advantage, of course, is we can speak to the investigator-initiated data. We’re not in a non-disclosure setting. We’ve seen some dramatic clinical improvements in MS as well as today, what we talked about with the dermatomyositis. It is still early. 

You also, Sarah, I want to pick up on what you said. That is the objective measurements of success in this area. As you say, in cancer, we can objectify how much cancer. We can even count individual cells using next-generation sequencing. In this disease, it’ll be so important, I believe, so important to define what is an immune reset, an objective term, so that we can start to compare the efficacy and potency of the individual, well, CARs, but also modalities of autologous, allogeneic, or in vivo as to long-term expectations. Because right now, I think Fred described it as a car jam – there’s a lot of cars on the road, at least. And so this immune reset assay and an ability to really scientifically show that we have accomplished a meaningful and a potent and a durable response will also be important. 

Sarah Nikiforow:

So, David, I just want to comment, because we talked about immune reset a lot, but the audience that we’re speaking to may not have. So I think it’s very important to realize that there was a lot of discussion about, do you need persistence of cells? Like in some oncology fields where CARs are used, we feel like you do. There was a lot of data presented about a quick expansion and disappearance, and persistence is no longer a definition of success, probably, in these diseases. We talked a little bit about do you need lympho depleting chemotherapy? Because what we believe biologically is the basis here in these primarily antibody B-cell driven diseases is, as you were talking about, immune reset, which we would be able to characterize by a shift back to naive B-cells that have not been educated, that have not had genetic and other modification switches that have directed them towards particular antigens. And then David Porter led off, and I think there were other speakers who showed that the CAR T-cells in the few patients who’ve been treated are achieving elimination of B-cells in areas that antibodies can’t get to, like rituxan, right? Like in the lymph nodes. So clearance of memory B-cells throughout the body is, in my mind, what we’re defining as immune reset. And then you’re saying, how do we define that so we can track it? But I just wanted to clarify, because it’s an interesting concept, that I don’t think has been applied in the CAR T-cell space for cancer. 

David Miklos:

And it’s a very targeted therapy, only attacking the CD19-expressing cells, unlike a steroid treatment or a metabolic treatment such as methotrexate. So, you know, here we are really perturbating and attacking one cell population, at least those cells that express CD19, and we’re having impacts, though, on T-cells and the other pathogenic mechanisms because immunity is a complex interaction of antigen driving both cellular T-cell and serologic B-cell responses together. So a lot to learn in that space. And really, all of us will benefit from some standardized assays and measurements of success in that tool. 

Lazaros Lekakis:

A crude measurement of success in terms of biomarkers or serologic markers is to have a B-cell naive regeneration and antibody regeneration, a normal immunoglobulin regeneration, and disappearance of the disease-specific autoantibodies. For example, in lupus DS, DNA or antiscleroderma-70, anti-RNA polymerase III antibodies, if they go away and you see an IgG level comes back to more than 400, and you see a good B-cell population more than two, three hundred, I think we are successful. 

David Miklos:

Yeah, ironically or coincidentally, I’m sitting here with directors of three cancer institutes and centers, and this is not cancer. And that was discussed at length today as well, taking advantage of lessons learned and deep cellular expertise at centers of excellence, and now trying to cross-pollinate and work with our disease experts. And I think all of us today decided that right now, this is best managed with a dyad approach of disease experts and cell therapists working together, either inter or intra institutionally. And that was a lot of discussion today, because that’s very challenging when the model up until now has been one PI, one contract holder, one person in charge, and now we really do need to build teams. And that dyad model, I think, is we kind of took a quick poll going across the panel today, and that seemed to be the most adopted situation. Comments to how you get it done that you’re learning about? 

Frederick Locke:

Well, you just got to do it, I think, which is easier said than done. It’s got to be a dyad, and for a cancer center at Moffitt, we focus on cancer. We have to go out and find those partners. We don’t have rheumatologists who treat these disorders, neurologists who treat these disorders within our cancer center. But we do want to disseminate the knowledge and we want to train these disease experts on how to be cell therapists and prepare for the likely outcome, hopeful that it will happen, that these are FDA-approved treatments for autoimmune diseases. So we’ve got to start to figure out how to connect these pieces together and make cell therapy more democratic so that more people can benefit from it. 

Sarah Nikiforow:

And Fred, you had said during that conversation, you’ve seen one cancer center, you’ve seen one cancer center, right? 

Frederick Locke:

They’re all different, yeah. 

Sarah Nikiforow:

So I think that the models that come up that have to be collaborative are going to be different at every institution, which I’ve got to say is going to drive any of our commercial sponsors nuts, right? Because they have to be flexible enough in their approach to accommodate some of this variability. But I think that the idea of, cell therapists need to own this in some manner, even if it’s mostly in terms of educating our colleagues and then figuring out, do we own this long term or do we set up some sort of parallel infrastructures where we consult with each other? And I think it looks very different here at the initiation than it will after any FDA approval. And we need to plan for now and think about what’s sustainable in the future in terms of our resources. 

Lazaros Lekakis:

Yeah, we cannot do it alone. We need the rheumatologist or the neurologist to be part of the team. For example, let’s say I treat with a scleroderma patient and develops ICANS or CRS and I give steroids and then we go to renal crisis, scleroderma renal crisis. Do I know how to treat renal crisis? When was the last time? I don’t remember. I know only to give ACE inhibitors, nothing else. So then the rheumatologist needs to come in. And there are a lot of logistical problems. They are very busy clinicians as well, and they have clinic four times a week. But we need to… Who will give the cellular therapy? We will give it. We have the experience. They cannot do it, at least at this point. We do the apheresis, we know how to treat the complications, but we need their help and of course their referrals early, not when they are dependent on oxygen because I get referrals like that. 

David Miklos:

So we’re going to have one more question here. I want you to think about it while I speak. Why cell therapy? Why is cell therapy poised? This is the iwCAR-T, other mechanisms have been used, but what’s the advantage going to be in cell? 

I want to speak back to how this all came about in Europe with Georg Schett and with Miltenyi, Stefan Miltenyi providing the reagents and the ability to do this really at his cost. There were not clinical companies, they were not sponsored by big pharma involved in this. This was an experiment that was done at one hospital on patients that were not even on a clinical trial. It was an attempt to demonstrate benefit in limited numbers of patients that lit the imagination really of the world and demonstrated success. Now the questions with clinical trials of what is the actual efficacy, the real rates, the side effects and to be more objective on this. 

So in Europe they did this kind of on-site distributed manufacturing using reagents that were not as restricted. In America we’re seeing a lot of this being done by companies, pharma, biotech, but I want to make the plug again that we many, well all three, four centers sitting here, have GMP laboratories that should be able to do this and be able to do more of the learning and small investigator-initiated trials to more rapidly test individual questions, science, do we need lymphodepletion, what’s the correct target, should we redose, what are the opportunities here in a more rapid manner? I want to make that plea that we don’t just depend on sponsored research. We want to work with our companies because they are very good at putting together labels and making these things FDA approved. We’re very bad at FDA approvals, but we’re very good at first-in-human translational research and correlative science. And the correlative science will drive the insights and you have to have the patients on hand. 

Lazaros Lekakis:

David, you know what is the problem? That here we have too much regulation, too much defensive medicine, cover my back behavior, and we are afraid to do those things. And maybe you at Stanford, you’re able to do it, but in smaller institutions, including the University of Miami, no one wants to take responsibility to do that. 

Frederick Locke:

So I would add to that. I mean, I think, David, you’re right. We have cell therapy facilities, and we can work on these sort of scientific questions in probably a more efficient and effective way, rather than a company that from day one is thinking about FDA approval, right? And what’s the patient population? And how much money are we, you know, what’s the return on this investment gonna be? That being said, it still costs money to run the trial. So we may be able to run it more efficiently or with more focus, but we still need the money. And that leaves sort of minimal sources to pay for this kind of research,, because the NIH isn’t paying for these large, or these large expenses, even though they may be small trials, it costs a lot to run a cell therapy trial. So we need more, I think, industry partnership with academia to kind of seed fund these ideas, to do the translational work. And probably these are things that can be done by big pharma, but also could be done by smaller companies that need help in their developmental phase at a lower cost. So I think we need new approaches and new paradigms and to be open to that. 

Sarah Nikiforow:

So I’ll piggyback on what Fred said and then answer your original question that you asked us to think about. So it actually came up when we were talking about solid tumors, right, and the applications of cell therapy in solid tumors yesterday that there is so much we don’t know. Phase I trials need to be pretty nimble to be able to follow, oh, this looks like it’s promising, right? Or build in multiple parameters. And that’s not something that typically a large pharmaceutical company-sponsored trial is designed to do. And could we come up with different paradigms, different ways of structuring collaboration in the Phase I setting, especially at larger institutions that do have manufacturing capability, who can sometimes manufacture for less and pivot in their manufacturing. So I think that just like in the solid tumors, any new burgeoning cell therapy disease entity, we need to have new models. 

In terms of why cells for autoimmune disease, part of what I was thinking of, because I guess I hadn’t really thought of that question before. But if you look at the patients, and David Porter laid this out quite nicely, and it was a fascinating review of myasthenia gravis over the years, right, since the 1900s. In terms of we maintain people right now in those settings on incredibly toxic therapies that impede their quality of life, right? So that part of the promise of cell therapy, and autoimmune autologous transplant, stem cell transplant was mentioned, but either a CAR or an auto transplant to be able to do that immune reset, again, no one can claim cure at this point in time, I’m not even attempting to. But if that’s something that really is a one-time deal that can have lasting effects, I think that would be transformative, right? So all of the cool immunology aside, the risk-benefit ratio that patients and physicians are willing to take, those are big questions. But the idea that you have a one-time therapy that has a lasting impact, I think is huge in autoimmune disease.

David Miklos:

I’m going to wrap it up with a thought as well. Well, gentlemen, I offered you the opportunity, So please. 

Frederick Locke:

Well, I spoke about it. I think, you know, it’s a great conversation. 

Lazaros Lekakis:

Let me tell you something. From the time that you put it on the paper, an investigator-initiated concept, to run a cell to until the first person you treat on a Phase I cellular therapy in your institution, how long it takes? 

David Miklos:

Us? Yeah. It’s easier for us to do investigator-initiated trials than sponsored studies. And that’s because we literally invest institutional funds. And we get going on the science and you say, that seems like it’s an unfair advantage. That’s what a university is supposed to do. 

Frederick Locke:

Every institution, cancer center, medical school is going to have different pain points when it comes to running clinical trials. So, you know, that’s a hurdle, and we’re always trying to improve that. But I think those are surmountable issues, yeah. 

David Miklos:

I want to give a big picture real quick, okay? I want to be indebted and grateful to the NIH. I want to remind everybody that all this has only been made possible because of the Human Genome Project of the 1990s. I was a geneticist as a graduate student in 1988, and there was one gene that had been sequenced, and that was hemoglobin back in 1972 using RNA and rocket fuel hydralazine by Bernie Forger, Ed Benz, and Sherman. 

Lazaros Lekakis:

He was my professor at Yale. 

David Miklos:

There you go. And he was a professor at Yale. And then 18 years passed before we started moving forward with Sanger sequencing, and then we moved into an investment of half of the NIH budget through the 1990s. And Francis Collins did a fabulous job of leading that forward. And then since 2000, now that we have this map and genes, we have seen a huge expansion. We have deep sequencing with companies like ABI, Illumina. We have Cirrus. We have PCR. And so now, what are the things that I’ve heard mentioned that are most remarkable? 

An mRNA vaccine that saved us from COVID. CAR-T, I’ve heard about it many times. Gene therapy repair or augmentation of sickle cell disease that is actually available now to patients around the world. A drug as well for obesity and for metabolic management of diabetes that nobody ever imagined. These are the scientific changes. And I think cell and gene therapy is poised right now to just explosively bring us to new therapies and benefits for people. I want to be deeply grateful to the organization and the investment that the government has placed into training, funding, and organizing scientific research. The Human Genome Project did not happen by chance. It was organized. 

Frederick Locke:

What a fantastic way to go out. I 100% agree. 

Sarah Nikiforow:

Thank you, David. 

Lazaros Lekakis:

Thank you. 

David Miklos:

Thanks for joining us, guys. Let’s enjoy the rest of the meeting – iwCAR-T!

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