Investigating CD19-Targeted CAR T Cells for Autoimmune Diseases: Fabian Mueller, MD

In this interview from the American Society of Hematology (ASH) Annual Meeting, Oncology Data Advisor speaks with Fabian Mueller, the Principal Investigator at the Laboratory of Molecular Immunotherapeutics (LMIT) at the University Hospital of Erlangen, in Germany, about his study which investigated CD19-targeted CAR T cells for refractory systemic autoimmune diseases.  

Oncology Data Advisor: First question I wanted to ask you is if you would like to go ahead and introduce yourself and your research interest?

Fabian Mueller, MD: Yes, absolutely. Pleasure to be with you today. Thank you very much for your invite. My name is Fabian Mueller. I’m a Researcher and a Doctor, by training, an MD, and I have been working on this particular research topic that we’re covering today.

Our main research is based on CD19 CAR T cells. This is a T cell that is modified with a so-called CAR, a chimeric antigen receptor, that targets on the outside based on an antibody fragment called CD19 on the surface of cells, and it’s located on a T cell. On the inside of this CAR, you have T-cell activating molecules. What happens is, once the CAR binds to the target, it actually activates the T cell that is carrying the CAR, and the T cell then fully executes what T cells usually do—most of the time, T cells need co-stimulation, which is already included in the CAR. So, whatever binds then induces this very strong T-cell signal, which in terms of cytotoxic T cells means killing, and in helper–T-cells means supporting the inflammation.

Very broadly speaking, there are obviously a lot of variants in there, but that’s the basic concept. So, what we are using is the CD19 CARs, which then target B cells, but normally we use them in B-cell malignancies, so ALL/CLL, acute or chronic lymphocytic leukemia, and non-Hodgkin’s lymphoma are the first that we have treated. We have also now other targets and other CARs—predominantly in multiple myeloma—but we use the CD19 CARs in hematologic malignancies and that’s where we have experience for a couple of years now in clinical application, five years probably. We repurposed those CD19 CARs for a lupus patient, so systemic lupus erythema. She had a lot of different treatments, like she went through all the different treatment options there are, even experimental treatment options, and her lupus progressed within two and a half years to a life-threatening situation where the heart was about to fail, the lungs were terrible, she had joint pain, she had serositis—a classical symptom of the lupus—skin changes, fever, and all the complement levels were low. It was a very, very active lupus.

Then we decided to use the CD19 CAR based on preclinical data and on a couple of findings that we know from lupus, because she had a life expectancy that was really short—a couple of weeks, two months—and she said she can’t do that anymore and she would try anything. So, we suggested her to do the CARs, which we by chance at the same time were allowed to produce at our facility. We have a manufacturing license at our university clinic at our Department of Hematology and Oncology, and then we joined with the Rheumatology Department who sent us that patient.

We treated her and it was quite impressive. We were very scared initially that the patient was going to have substantial side effects because you infuse hyperactivated T cells into a massively activated lupus that we didn’t know for sure was B-cell driven. It could have just as much been T-cell driven at the time. So, it was really just a, “Let’s see if it works,” but for the patient, really, a dangerous situation. She said she wanted to take a risk, so we thought we would go ahead and do it, and we were super lucky. The lupus was a massively active lupus; there are scores from zero to 25 and she had a 22, which is very high, and it was down to zero in activity within a month, which no other treatment achieves in lupus in that speed from such a severity down to zero.

Then we tried a couple of more lupus patients and achieved the same activity. We went on to a couple of other autoimmune diseases that are also thought to be B-cell–driven—systemic sclerosis, systemic myositis, and all of those patients that we have treated. I reported 15 patients at ASH, and all of those patients remain at remission and are treatment-free. It’s something that is unprecedented in the end because all of those are chronic diseases, and with just one shot of CD19 CARs plus lymphodepletion, short chemotherapy before that, we achieved substantial complete remissions and resolution of most of the symptoms.

Oncology Data Advisor: That’s fantastic. It’s honestly such an inspiring study. I wanted to ask, because you said your team was scared starting this, what was you and your team’s reaction to such a positive outcome for these patients?

Dr. Mueller: You have to think of it, it’s a very special type of CAR T. We produce that with a Miltenyi system, and what happens is that different from most of the commercial CARs, you put in fresh cells, and you take them fresh out of the machine and we infuse them in the evening, so between four and five in the evening. We infuse those CARs in the late afternoon and there were a couple of people having sleepless nights. So, it was really just the question, does it actually work? What was going to happen? We’re seeing this patient respond that quickly and doing so well. There’s a resolution of, for example, proteinuria, which all of us always thought that it’s a permanent damage of the kidneys that happens in the lupus, and it’s all just gone.

It’s something that nobody had ever believed is actually even possible. We thought if we achieve a stop of the symptoms without any reversal, that would already be a major achievement, but the fact that they just go back to normal lives is just something very impressive for us. So, it’s the combination in the end, it’s the depth and the speed of the remission that we achieve that is just super fascinating.

Oncology Data Advisor: Definitely, and what do you think this hypothetical cure could mean for the future of treatment?

Dr. Mueller: With that we are just super cautious. In some countries—Italy does this quite a bit—they do allogeneic (allo) transplant, so bone marrow transplant from a foreign person, human leukocyte antigen (HLA)–matched, and then you have rates of 80% of long-term cure of those that actually make it through the treatment and have achieved the remission. They have, I want to say at five years, 80% on remission. We have autologous (auto) transplant where we transplant the own bone marrow, which likely achieves a similarly strong reset. We haven’t compared side by side the B-cell compartment or the T-cell compartment, something that one should do. The autologous treatment achieves around 50% at five years. So, it’s really also a very strong treatment. We are just not in a long enough follow-up to compare it with that. What I feel confident in saying is that we likely are not going to be substantially worse than the autologous.

At this point, none of the lupus patients have relapsed, so it looks quite good. Systemic sclerosis has the same thing. The autologous transplant is really strong but it’s very toxic also. The systemic sclerosis patients really suffer from it. There are a lot of substantial side effects from the treatment, whereas with the CARs, you give it, they have a little bit of fever and that’s it. It’s extremely impressive how well tolerated it is. It’s really this entire combination that is fascinating. We are careful in saying they’re cured because there are alternate treatment options where we’ve learned that after two to three years there’s already a couple of relapses occurring.

Oncology Data Advisor: Definitely. Final question I want to ask is, for anyone that’s following this trial because it’s so exciting, what can we look forward to, if I’m allowed to ask, for the upcoming year?

Dr. Mueller: Oh yeah, that’s a very good question to ask. What is very important is that this was not a clinical trial that was—it’s very hard to translate it because there is nothing like this in the American system. It’s a little bit like a compassionate use but different. So, it’s not really something that I can name so that you actually understand what we are doing, but on a legal basis. In Germany it took us one and a half years to get the clinical study up and running, but now it is. We have started recruiting, and since July of this year we already have eight more patients treated, and it looks really good. Our number of patients is rapidly increasing. Phase 1 is pretty much the first eight patients, and we’ll see whether there are new security issues. If nothing happens, which so far it looks quite promising, we are going to extend it with another 16.

The plan is, now that with our previous five plus the eight, we have a solid panel of patients that we have treated with all three diseases, the plan is that we start reducing lymphodepletion. That’s something we are considering right now; extension with less chemotherapy to see whether we’re similarly active. That’s going to be the first step towards this critical question, “Do we need the lymphodepletion before?” It’s not answered, but we can at least say it works similarly well with less chemotherapy. There will be a crucial step to move forward, and that’s what we are working on and what I can disclose. I think those questions are, “Do we need the CARs? Are bispecific antibodies not doing the job just as much?” There is a first study going to start very quickly, and there are a couple of competitors in “Big Pharma” who have already started trials on lupus.

For us, it’s really crucial to see that other people with other CARs in maybe different genetic backgrounds, even so in different epidemiological fields, reproduce our data. That would be super good for us because that just shows that it’s not just happening here.

So, I think with the confirmation from all these different companies, which will come up very quickly now, there will be interim reports fast because for the companies, that is a very crucial thing to happen also. By ASH next year, there are going to be several reports on it. Actually, ACR, the American College of Rheumatology meeting that happens a month before ASH, so November next year, expects a couple of big things happening in the rheumatology field. In multiple sclerosis and other neurological diseases, that’s going to be a game changer also. The preliminary results had one case that was published just recently with CD19 CARs. So, I think there is a lot happening in the field now. New molecules, new diseases, think of it—you can name whatever phenomenon that is B cell you can think of. It’s just something that people discuss now. We just opened a huge box of new possibilities.

Oncology Data Advisor: Most definitely. This is so much to look forward to and I wanted to first thank you for your time today. I know this is such a busy time, but I also wanted to say thank you so much for your passion and you and your patients’ willingness to take the leap of faith. It’s definitely really exciting. So, we’ll definitely follow up with you next year around November and ASH and everything. Thank you so much, Dr. Muller.

Dr. Mueller: Thank you very much for your time. It’s always a pleasure. It’s important to talk about that stuff.

About Dr. Mueller

Fabian Mueller is the Principal Investigator at the LMIT and an Attending Physician in the Department of Hematology and Oncology at the University Hospital of Erlangen, in Germany. Dr. Mueller participates in and conducts research surrounding autoimmune diseases, such as lupus, as well as ALL, CLL, and non-Hodgkin lymphoma.

For More Information

Mueller F, Taubmann J, Voelkl S, et al (2023). CD19-targeted CAR-T cells in refractory systemic autoimmune diseases: a monocentric experience from the first fifteen patients. Presented at: 2023 American Society of Hematology Annual Meeting. Abstract 220. Available at: https://ash.confex.com/ash/2023/webprogram/Paper180547.html

Transcript edited for clarity. Any views expressed above are the speaker’s own and do not necessarily reflect those of Oncology Data Advisor. 

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