ACR 2025 CAR-T Topic Panel Save

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Hello, everyone. Welcome to RheumNow's coverage of ACR twenty twenty five. In this session, we'll be reviewing abstracts and presentations on CAR T cell therapy and cellular depletion therapies. We've got a faculty who were out there scouring abstracts and presentations for insights and what was notable. We're going to review their favorites in this podcast and video cast.

I'm Jack Cush with RheumNow, I'll ask our faculty to introduce themselves. Akhil?

Thanks, Jack. I'm Akhil Sudh. I'm a rheumatologist at Washington University in St. Louis with an interest in lupus.

Yous.

Hello, My name is Yousuf. I'm a rheumatologist in Leeds.

Yes, Philip.

Hi, I'm Philip Mees. I'm a rheumatologist based in Seattle, Washington and director of rheumatology research at Providence Swedish Medical Center.

And Al. Hi, I'm Al Kim, adult rheumatologist also at Washington University School of Medicine. Also interested in lupus where I direct the lupus center. Excellent.

All right. So we're going to do a few rounds of discussion and presentation. Let's begin with Doctor. Sood.

Yeah, so I think during ACR twenty five, there's definitely a lot of abstracts on CAR T. I think we've definitely seen, since the landmark case series of ERLOG in 2024, we've seen an explosion in new CAR T therapies since then. And I think the AIR LOGAN study was a really robust study showing efficacy and safety, and abstract six sixty three took a different approach. It took an off the shelf approach with CAR T. So essentially what it was is compared to autologous CAR T extracting individuals on T cells, engineering them to target the C-nineteen T cells.

They're taking off the shelf approach, meaning they're extracting T cells from a bank of induced pluripotent stem cells and injuring them to target the CD19 B cells. And the advantage of this is that the CAR T is accessible and available. And for the patients, this is wonderful and that they have a much shorter hospitalization for monitoring. So this abstract six sixty three, the value of the safety and efficacy of off the shelf CAR T in patients with autoimmune diseases. And to date, they had patients with lupus that were enrolled and the inclusion criteria were those that had a high sex to be based on SLEDA and bile duct scores.

And the patients were allocated to two regimens. One regimen involved a limited lymphodepletion, meaning they didn't receive fludarabine, but they received cyclophosphamide only. And then the other group, which was two patients, had no lymphodepletion at all. And to date, they've had 10 patients enrolled in this ongoing phase one trial. And they found that in terms of efficacy at the six month mark, all the patients had improvements in their CLIA2 case for at six months.

But after that is when we kind of start to see things kind of vary at the nine month mark. One patient actually had a spike or a rebound in their sleep. I took a at the nine month follow-up. And then when it came to patient reported outcomes, all the patients had improvements in their fatigue, especially those that received a limited lymphodepletion. The patient who receive the lymphodepletion had an improvement in fatigue based on his passive fatigue at the three month mark.

So a little bit shorter time. And then when it came to the B cell depletion, it's kind of where we saw differences in terms of B cell repopulation, both for those with limited lymphodepletion versus no lymphodepletion. Those with limited lymphodepletion had a much longer time, up to three months, of repopulation of their CD19 B cells. But on the other hand, patients who did not receive lymphodepletion had a much shorter time of repopulation of these CD19 B cells as much as just a few days post infusion. And so what I thought was just really interesting was that this off the shelf is a really exciting approach.

It seems it could be a more patient centric approach, meaning it's readily available, accessible, and the T cells an even much shorter time for hospitalization for our patients. But I think there's still a lot of questions that need to be answered, especially longer term follow-up, looking at other autoimmune diseases, and even the question of lymphodepletion that they did tap into in this abstract.

Here are a number of different approaches to the cellular depletion, and we're looking for the advantages and disadvantages. The others wanted to comment here on what the advantages and disadvantages of this off the shelf approach is? Yves?

Yeah. This is really interesting because it does help that phase whether we can give therapy without doing lymphodepletion. And also an interesting thing is you can get it off the shelf from this pluripotent cell. I think we still need that longer term data about this, whether in the long run, whether there is a problem with the graft versus host disease or anything like that, certainly from the preliminary data that they, you know, reported, they couldn't see one. But it is really interesting.

It's like you're trying to go back, you know, from your ANA test, isn't it? You know, with your hand letter like cell come from one person and then you then multiply it many, many times. So, I think this is what happened when they're trying to do in this, you know, IPSC protein in the CAR T. Yeah.

Philip, you've done tons of trials. At this stage of the game, we have so many, so such a limitation on numbers of patients, what are we learning?

I think that the autologous CAR T programs are giving us the gold standard of what to expect. We certainly saw that in the results from the Erlangen studies. I think that as mentioned, the allogeneic approach is going to be more practical and feasible. You don't necessarily have to be in a major center and automatically partnered with your HemOnc colleagues with this off the shelf approach. But what we're missing is what's the right dose?

And how durable is it going to be in comparison to the what I call the more gold standard autologous approach.

Yeah, Doctor. Kim, any comments?

Yeah, so a couple of them. So I think you brings up an interesting point about the LDC issue, lymphodepleting chemo. You know, that one patient that they had in that fate study that it was that's been described, you know, didn't do so as well as everyone else. It's stuck in LLDAS. The CAR T cells didn't expand very well.

The B cells didn't really reconstitute the way it did with people who got LDC but generally speaking, I'm very high on allo largely because there's gonna be a cost savings, substantial cost savings associated with this because there's no individual drug manufacturing. Most of the costs come through hospitalization, which probably hopefully will drop.

Yeah. I like that as well. Alright. Doctor Youssef, why don't you go next?

So talking about deep tissue depletion. So I do want to bring an abstract 26,995. This abstract was awarded as the Emerging Investigator Excellence Award. And it was actually presented at the very last session of the ACR where a lot of people have actually flown home. So I found it really interesting.

So basically, these studies, again from Professor Shed's group, they tried to look at the depth of tissue depletion in a few treatments. Basically, they did a biopsy at least three to four patients per group on the lymph nodes for people who receive treatment, including rituximab, which is your old NTCD20 monoclonal antibody, and we have the newer humanized type two anti CD twenty monoclonal antibody obinutuzumab. They also compared blinatumomab, which was your bispecific T cell engages monoclonal antibodies, and also patients who received a CD nineteen autologous CAR T cell. So when they look into the lymph nodes depletion, what they found that only patients treated with the CD 19 CAR T cell consistently achieve deep tissue depletion. All other protein based depleters reduce but not complete as c d c d 19 CAR T cell.

And of all these protein based depletes. So the one that comes sort of slightly closer to CD 19 CAR T cell was opinituzumab. So yeah, so I think I find it really interesting that in not just the blood, actually, we do have some evidence that all this treatment actually leads to depletion, which is really an important key therapeutic target here.

So was this done for just a comparative analysis or was it done with the idea that maybe we would be using these therapies together or in place of one another?

No. I think it's more of the mechanistic study just to demonstrate that, you know, a lot of the study before just showing blood depletion. But then people will say, like, you know, what you know, did you also deplete in the tertiary lymphoid tissues? And that's what they wanted to show here. Yeah.

Mhmm.

Excellent. Any other comment?

I think I haven't used a slide that shows this degree of depletion and exactly that. It's a comparative way of looking at the total effect. And I think visually, it's a great teaching slide.

Excellent. All right, Philip, do you have?

So I really appreciated a review talk that was presented by John Merrill in a session called The New Rules of the Road, an update on CAR T mediated immune reset for SLE that was moderated by Sarah Sheik on Sunday at 01:00. Joan started by presenting a just published this month systematic review of CAR T results in lupus. There were a total of 16 studies, 13 targeting CD19 and three CD19 and BCMA. There were 12 of these that were autologous and four that were allogeneic. The total number of subjects was one hundred and forty five patients with lupus.

Their baseline sleet eye score was 13. And then after a six month period, this decreased to 2.3 on average, and after twelve months decreased to 1.4. Seventy percent of the patients achieved DORIS remission. LLDAS was achieved by eighty nine percent and drug free remission by eighty four percent. These numbers correspond to what we're experiencing in our autologous as well as allogeneic trials that we're doing.

So it was interesting and reassuring to see that there's a consistent degree of result across multiple studies that are occurring. There were side effects that were detailed and CRS or cytokine release syndrome was seen in fifty six percent of the subjects. Ninety eight percent of these were grade one or two. And when I'm working with my HemOnc colleagues, who are more used to more severe CRS, or possibly I cans with their lymphoma or myeloma patients, they are impressed by the fact that we're seeing much less of this kind of side effect in our lupus population, as well as scleroderma myositis patients. And presumably, this is partly related to the lesser amount of B cell volume that's present in these patients.

There were four cases of ICANS, the neurologic toxicity, one each in grade one, two, three, and four. And when it gets up to three and four with this particular side effect, this is an important issue to really focus on. Seven point six percent of the patients develop serious infections, and there was one case of fatal pneumococcal meningitis. So in summary, on the one hand, we saw terrific efficacy that came close to what we saw in the original Erlangen studies. But there's also this set of side effects that we're seeing.

Al, what do you think?

Yeah, so this is such an important review that Ankenazi's group has done. You know, I think it does a couple things. First, it actually helps restore some faith in what we should see globally with these trials. As people have mentioned before, Georg's Erlogen study, the first one, the council study, 10 out of 10 hit doors. I'm not sure that is actually realistic.

And I think there are reasons for that. The rest of the experiences that people are having, including myself, Phil's, others, are more in line with what this review is and help set expectations.

So For the others, what would then be the side effect you're most concerned about going forward? We're not seeing yet what the FDA was worried about with all the oncology CAR Ts with now a black box warning for secondary malignancies and whatnot. That's good news, but still we're early in the process. What is the concerns that you as a group have, you've been studying this, what would you want to be most concerned about or worried about going forward? Akhil?

You're muted. I will come back to you, Joosh.

Yeah. So I think, well, for me, I still want a longer follow-up data even particularly in terms of efficacy because really, you know, what, you know, the CAR T cell principle, you know, trying to sell is this, you know, profound depletion, blood and tissues. And hopefully after that, be able to, you know, potentially immune reset patient to be in remission free on drugs. However, we have seen a few, although it's still a smaller number, cases of relapse after these therapies. So really, at what cost we are putting our patients in to go through all this potentially toxic medications.

And then at the other side, in a few years down the line, they will relapse and need potentially further treatments. Whereas we will also now have like a better monoclonal antibodies. For example, the obinutuzumab that can do almost as good. Yeah, so I think that's quite a question from my point of view.

Philip, not a lot of mention of serious infections and opportunistic infections. What was said about that in your session?

That they can occur and need to be monitored for. And when a patient presents with fever, is it CRS or is it, a brewing infection? So these patients need to be monitored, and looking for evidence of infection, partly because of the cytopenia and hypogammaglobulinemia that can sometimes occur. Just yesterday, I had one of our patients, we needed to give IVIG because of low immunoglobulins. I think it's, so these are real things we're going to need in services from our HemOnC colleagues to really get up to speed with how to look out for these and monitor for them.

It's way too early, I would say, before we can tell whether they're going to be CAR associated malignancies. And so that's why we're being asked to monitor patients for a total of fifteen years, after the

treatment. Okay. Doctor Kim, what do you have?

All right. A lot of the discussions in past ACRs and ULRs have been focusing on AON lupus with increasing myopathies, scleroderma and whatnot. But now we finally have some RA data that's out there. So it was abstract four seventy one looking at Kiverna's autologous CD19 product against in RA. So this is going to be ACPA positive, as one should imagine in these type of trials, and difficult to treat RA.

So phase one study, six people were enrolled. Primary outcome is going to be safety, obviously. They all received lymphodepleting chemo. So not surprisingly, six out of six people got transient cytopenia, fine. Six out of six people though did develop cytokine release syndrome, which is going to be higher than what Philip just talked about in terms of that meta analysis.

Four were grade one, two were grade two. But so this is a little bit higher than we expected. Now, terms of efficacy and PD type stuff. So interestingly, most people, almost all of them, drop their ACPAs to either very low or undetectable levels. All five out of six.

But only four out of the five hit ACR20, Right? Now granted, three out of those six haven't hit the sixteen week level time point yet, the four month. So maybe it's a little too early. But the other three, there's one that did not hit ACR20, and I believe they told me it was largely because of pain. It opens up a whole bunch of different questions.

For me, first of all, is this the right target? Should we be targeting something that's more antibody secreting? Although their ACPAs do drop a lot, so maybe 19 might be sufficient. B, are ACPAs pathogenic in these type of diseases, right? Maybe in terms of the inducing disease, but its removal once the disease has started, is that sufficient, right?

So I think that's the other beauty about these studies, right? Like we think very simplistic about how these model out. But the nuances that we're seeing in some of these very small studies are intriguing.

Yeah, I'm thinking as you're talking about this, clearly there's a biologic effect. Clearly the issue is, does that correlate with the clinical outcome you desire? We don't know about that lowering of seropositivity, but there was an abstract by Smolin's group two years ago about drugs that lower rheumatoid factor have better outcomes, better responses. I'm not sure I agree with that, but they have the data and I have an opinion, so I'm waiting for that paper to come out. But nonetheless, if we can do that here, maybe we can.

Tying together biologic responses and clinical responses for whatever disease is going to be important going forward. Let's go one more time around the horn with Akhil.

Yeah. Can you hear me? Yes. Oh, perfect. Yeah.

So, yeah. So the other abstract was abstract two thousand four and sixty five. This was looking at CD19 BCMA dual targeting CAR T in patients with refractory lupus. This was a single center investigator initiated trial. So essentially, they had 10 patients with refractory lupus, sliced score of 2K score ranging from eight to 20.

And in this one, all the patients received lymphodepletion, meaning cyclophosphamide plus fludarabine, and this was followed by a single dose of a rapidly engineered autologous CAR T, the CD nineteen BCMA CAR T, and was given at three dose levels. The primary outcome was looking at both the tolerability and the safety of CAR T, but they also evaluated the efficacy based on the SRI4 Doris criteria and renal response. And they found that by week twenty four, all 10 patients achieved an SRI4 response by week twenty four, and then five of the 10 patients met Doris remission criteria by week twenty four, six by week thirty six, and it continued until week forty '8. In terms of disease control remission, one patient did flare at week forty. Found that four of the patients actually experienced proteinuria.

And with that proteinuria, was a concern if there was a relapse of their lupus. But when they did a renal biopsy, they actually showed that there was resolution of acute inflammation and there was a decrease in immune complex deposition. So I thought it was really interesting. So overall, I thought and also one thing was that the safety profile was relatively safe. Six patients had grade one cytokine release syndrome, one patient had grade two, no reports of ICANS or higher grade CRS reported, with common side effects as previously alluded, including cytopenias and hypogalamicomponemia.

And so while overall these findings are exciting, I still think we still need ongoing enrollment as well as longer term follow-up with this trial.

Be it small 10 patient cohort, no infections, no major issues on immunoglobulins that you would worry about because BCMA is going to go after plasma cells and is clearly going to affect immunoglobulins and antibody production. The question is, is that going to be great or disastrous? There are a few of these CD19 BCMAs that are in play, so we maybe need to pull this data to know how safe this approach is. Any other comments on this?

Well, I think there's somewhere in between, Jack, where, yes, BCMA by ablating plasma cells, you're likely to lose your viral memory for mumps, measles, etcetera. But we can monitor that and we can also revaccinate. So this is something that we're building into the next program we're going to be working with where we do a dual CD19 and BCMA, where we absolutely caution the patients that we're going to need to revaccinate.

I like that approach. Al?

Yeah, so, you know, it's interesting because I think we're starting to see some diversity in outcomes with BCMA targeting. You know, if you look at the engagers with blaclustamab, that is almost universally going to drive hypogammaglobinemia, and there are some drops in protective antibody tears presented at ACR. So CAR T versus engagers for BCMA is a really interesting question because yeah, you can revaccinate it. But in engagers, you're probably also gonna have to redose. So where does that leave you in terms of protective immunity?

I'm not sure. Of course, all of these were generated for multiple myeloma. Is this over engineering for autoimmune disease?

Good point. All right. Doctor. Youssef?

Yeah. Can I add that one as well? So based on this abstract, I did manage to have a discussion with the presenters. I mean, they were really busy with a lot of people coming to their stands. So I was particularly concerned, you know, regarding the risk of infection and also hyper gammagluminemia.

They did mention that they did see a few although they didn't put that in the poster and also and I think a few patients also had had treatment with IVIG as well. So I think we're trying to hit patients as hard as we can, but really at what cost and we have to find the balance between infection profile and also deep depletion to remove all the antibodies as well.

Yuz, what's your next one? A short one.

Yeah. So, I'll just move trying to move we talk about the cytokine release syndrome earlier. So, this is this is not CAR T. This is one of T cell engagers that this is like a a something that we can look forward to in the future. So I usually don't really want to discuss things that are not on the human studies yet, but I think this is something that I found out super sexy and super cool.

So the abstract is fifteen thirty five. So for this T cell engagers, the bispecific T cell engagers, so instead of engaging to the CD3, what they did is they engaged to pan gamma delta T cell receptor. So this is a release of Persexy. So they did a comparison using in vitro blood from patients treated with this compound, also compared with other BITE antibodies available, such as the blinatumomab and also mosanatumomab. What they found that the degree of the B cell depletion achieved in the bloods were comparable between these three.

However, from the safety profile, from the cytokine release syndrome perspective, they found that no issue with this pan gamma delta because you don't see So the interleukins, six, ten, interferon gamma, all completely reduced from this blockade. So I find it is really interesting. They're now progressing this to potentially interface one in the next few months. So it is something that we can watch out this mechanism of action.

Can we realistically expect there would be less or no cytokine release syndrome with T cell engagers or bites?

Yeah, so from the in vitro data, they showed absolutely just the level was absolutely suppressed from the engaging.

If that were true, that would be great. That's why we do the research. Okay, Philip.

So one of the side effect issues that has been emerging recently, highlighted by Melanie Hagen from the Erlangen Group is something called LICATS. And it stands for local immune effector cell associated toxicity syndrome. Say that rapidly. So this is a fascinating phenomenon and we have seen it in at least two of our patients where about ten days after cell therapy on average, you see a flare of arthritis, skin rash, kidney symptoms and signs like proteinuria. At first, when I saw this occur in our first patient, about that time, I thought, well, this must be their underlying disease flaring because of the rush out of their previous medications and before cell therapy had fully kicked in.

But Melanie has highlighted the point that the conditioning regimen is probably still having some effect to suppress the actual disease itself, the lupus, so it's probably not a flare of lupus. And so she has hypothesized that this represents a reaction to the dead B cells in the field of battle. So in the places where the patient had arthritis, where the patient had skin rash previously, where the patient had kidney involvement. And it was not associated with drops in complement or rising DNA antibody. And it was transient, just lasted on average about eleven days, and was easily treated with steroids and or tocilizumab.

So an interesting problem to be aware of and look for, but very manageable.

So how can you know that it's related to B cell death? What's the biomarker or the indication there?

So a couple of the points that I just made, I. E. That they're unlike the patient's previous low complement levels or high DNA antibody associated with their manifestations of disease, in this case, it was not. And the fact that it was, transient, easily treated. What I thought you were going to ask is how do you differentiate this, from, some other, issue arising, including differentiating it from infection or differentiating it from a flare of the disease.

And I think we just have to be aware of it. And if it persists and is associated with rising antibodies or low compliments, then we have to think it could be flare up disease.

My question though had to do with the fact that all these therapies are going to deplete. Then you assume depletion is associated with cell death. What is it biologically is different about these cells that leads to the syndrome?

I don't know the answer to that, Jack.

I'll make something up. I'll make something up. One couldn't hypothesize that tissue burden of B cells could be an answer. Right? We don't know that answer yet.

Right? That would be my hypothesis though.

Yeah. Interesting.

So so she said this was seen in seventy seven percent of their thirty nine patients. So it's not an an unlikely phenomenon.

Okay. All right. I'll wrap things up. Can I use it? Yeah, please.

I think this is really interesting, and it just brought me back to the old story of rituximab when I first started using it, when I first started doing my PhD a few years ago. So my groups, Professor Ed Vital and myself, when we used rituximab before, we did found that patient had this skin flare shortly after treatment with rituximab. And we did do some skin biopsy, which did show some active lupus. And some actually changed phenotype from acute cutaneous lupus before whenever we started treating it, and they changed into sub acute cutaneous lupus. And also some patients changed into CCLE as well, chronic cutaneous lupus.

So that was quite interesting, but that indicates sort of the disease flare in a post B cell lysis. We're also in this group. I did have a chat with the investigator as well. They said they did few skin biopsy and they said the biopsy wasn't abnormal in terms of active lesions. That's just an interesting phenomenon to be described as one.

By knocking out bees, your effect on T is going to be variable and how do we know this is not just a rebound effect of T cell compensatory activities and what that does to the disease? So It's a complex story that needs to be, I think. But I like that you're, A, you've given a name and hypothesis so people can work on this. Al.

Let's wrap this up. The older rheumatologists may remember when Jonathan Edwards first proposed this concept of restoring or resetting B cell autoimmunity with B cell depletion. And obviously, course, rituximab was the thing at the time. And that never got fully realized, maybe because it doesn't deplete well in lymph nodes where a lot of the immune responses start. So abstract 2,442 comes from Erlag.

And this is the largest study that I'm aware of and the longest study looking at B cell subsets only in the blood, but they did some really great work with spectral flow cytometry and single cell RNA seq. Bottom line for patients with lupus, they have really skewed B cells. They're very heavily double negative two memory B cell phenotypes. And they become plasmid blasts that are 95% of them are autoreactive. And then when you look at B cell receptors, the auto reactive B cell receptors dominate the scene.

In healthy people, it's complete opposite. Naive, no auto reactivity. The bottom line, twelve months after getting CAR T cells, they look like controls. And interestingly, of the B cells that do come back and they're activated, they're all activated through pathways that are not recognized to be autoimmune, I. E.

Extrafiliker pathways, but rather the traditional ways of being activated, germinal centers. So there's this durability in B cell biology in this resetting that could explain the durability of clinical response.

So that data is developed on the Schett Erlangen group?

Yeah, so this is multiple trials though, not just CASL, but also other ones.

Okay, well, that's great. And then what I like about this and what I hope is gonna happen in this field as an outsider watching is that there'll be a lot of cross talking, lot of cross learning because everybody's experience is gonna be small. And right now there's 40 plus agents that are in play by, actually it's much probably larger than that. And everyone's got an N of single digits. What is the largest trial and how far out are we going?

Al, do you following this, do you know?

The answer is yes, I don't know.

Good answer. But we are getting out there with numbers in a few cases, but often when we have high numbers, have no controls. I definitely think this is a big step forward for the field and what you guys have covered and reviewed here today. Obviously next year is going to be a real eye opener if this year wasn't. I want thank everyone for their efforts and great coverage of, cellular depletion at ACR.

Take care.

All right. Thanks.

Thanks, Jack.