ACR 2025 CAR-T Topic Podcasts Compilation 1 Save

This is an ACR 20 '25 podcast coming to you from Chicago. Hope you enjoy it.

Hi. My name is Aikhil Sood reporting for RheumNow. Imagine you have a patient with stubborn autoimmune disease. You cycle through multiple biologics and even tried next generation b cell depleters. Initially you see a positive response but within months the disease flares again.

You start to wonder why is the patient not responding? Is it possible that the answer may lie elsewhere such as the lymph node? Abstract 02/1995 from the Erlogen group looked exactly at that, how different B cell depleting therapies reshape the lymph node environment in autoimmune disease. They performed lymph node biopsies before and after treatment with various treatments including rituximab, obentuzumab, t cell engagers, and CD19 CAR T. Across twenty four patients with various autoimmune conditions, all patients had complete B cell depletion in the blood but what happened inside the lymph node told an entirely different story.

CAR T cells achieved complete B cell depletion in every patient and disrupted the lymphoid follicle architecture entirely. In contrast, protein based therapies reduced B cells but left the follicular structures intact. And here's the kicker, patients with complete follicular disruption after CAR T achieved stable drug free remission while those with residual follicles eventually needed retreatment. And the findings can reframe how we think about B cell depletion. It's not just about how many B cells are gone from the blood, what's hiding inside the tissues.

The lymphoid follicles may act as a reservoir for autoreactive B cells to repopulate after conventional therapies. And while findings from CAR T studies are exciting, mechanistic studies like this can explain why some patients relapse after B cell depletion. So next time your patient flares, the answer may lie in the lymph nodes. Thank you.

Greetings from Chicago. My name is Doctor. Al Kim, an adult rheumatologist at Washington University School of Medicine in St. Louis, Missouri. And welcome to RoomNow, the video series that provides updates for the American College of Rheumatology Convergence twenty twenty five Conference.

So I'm the faculty lead for the CAR T and T cell engager group. And the poster, the abstract I'm going to be selecting today is actually abstract number one entitled XM AB six fifty one, a CD19 by CD3 T cell engaging bispecific antibody for autoimmune disease. Now this is a preclinical poster. Typically we don't cover these but I think one of the issues with T cell engager data in the past such as compounds such as blinatumomab is that they haven't been as efficacious as we want them to be compared to CAR T cells and this may be due to the fact that they are not as potent. They don't deplete B cells out of tissues.

So again, this is a preclinical poster examining this compound XM AB five XmAb651. This is another three by 19 T cell engager and what they do is some ex vivo RA and lupus PBMC killing assays which it does very well. Then they actually moved into in vivo in non human primates and this is where it gets a little interesting. So not surprisingly after a single dose you get rapid depletion peripherally I. E.

In the blood of B cells. Now what they did was they actually looked in the bone marrow and lymph node and saw equally good depletion in those compartments. This is new and different. Georg Schetzgrupp and Erlagen had previously published that when using first generation T cell engagers like blinatumomab, you can't deplete out of the lymph node but this one can at least in a non human primate. This is going to be important because this can translate into more durable clinical responses.

You can restore potentially pre disease B cell compartments and homeostasis which appears to be required for that durability of response that we're seeing with the CAR T cells. Know so the advantages for T cell engagers compared to CAR T cells are quite numerous. No need for lymphodepleting chemotherapy, easier access, particularly if they can formulate a successful subcutaneous delivery approach. So if we can get these T cell engagers to be more effective without creating increased toxicity, this may be an interesting future for our patients instead of CAR T therapy.

Hi, my name is Akhil Sood reporting for RheumNow. When it

comes to cell therapies, the landmark study published by

the Erlang Group really set the stage. The case series showed a remarkable efficacy and safety of CAR T therapy across several autoimmune conditions. But there's a catch. The process is intense, it requires harvesting a patient's own T cells, engineering them to target CD19 B cells, and giving conditioning chemotherapy to make room for the CAR T cells. And this is followed by prolonged hospitalization to monitor side effects.

But not every patient has the time, resources, or ability to undergo that kind of intensive treatment, especially when you factor in time away from work or travel to a specialized site. So what if there's a faster, less labor intensive approach? That's exactly what abstract o six six three did. They looked at an off the shelf approach for CAR T. Instead of extracting T cells from each individual, a researcher is developing CAR T from a bank of pluripotent stem cells, essentially mass producing them for broader use.

And to make things even simpler, they're testing whether one of the conditioning drugs can be eliminated altogether. And so what do they find? Patients experienced fewer side effects with those less intensive regimen, and most showed improvement in these activity as measured by the Siliadide two ks, though a few did have some rebound in activity by the nine month mark. As for B cells, there's significant CD19 B cell depletion followed by repopulation of naive B cells. So the bottom line?

This off the shelf approach looks promising. While it may be effective, it's unclear whether non response in some of these patients may be driven by the limited conditioning chemotherapy or the off the shelf approach. So we're still early in terms of CAR T, there's ongoing enrollment and longer term follow-up that's needed. But this could be a major step toward making cellular therapies more accessible and convenient for our patients with autoimmune disease. This is Akhil Sud reporting for Mnow.

Thank you.

Hi, my name is Al Kim from Washington University School of Medicine in St. Louis, Missouri and welcome to day two of the ACR Convergence twenty twenty five meeting. We've been covering the cellular therapy and T cell engager abstracts here, which there are over several dozen. I thought I'd be covering a lot more of the clinical trial data, but what's been really striking in my eye has been a lot of the innovation, the preclinical work. And so I wanted to highlight one of these abstracts, it's abstract nine eighty one called GNTI three fifty, a CAR Treg therapy offering durable immune reset with improved safety in the B cell driven autoimmune disease.

The title is a little bit overstating since all of this work is preclinical but nevertheless this is actually a really interesting compound created by a biotech company called Genta Bio in collaboration with the University of And what this is is a CD19 CAR T cell that has been polarized upon after activation to also become a Treg. So this combines two really of the newer concepts in CAR T cells. The first is the killing of B cells vis a vis inter interaction with CD 19 but also then functionally creating a that CAR T cell to become a Treg and provide an immunosuppressive mu wherever that Treg is. So as I mentioned before, is all preclinical work. And so they start off with in vitro work demonstrating that yes, their CAR T cell can kill CD19 positive B cells.

That's not a problem. When you co culture JNTI three fifty with B cells, they upregulate their Treg markers and then they can suppress other T cells that are also within that culture again consistent with the product. On top of that, when you combine that with inflammatory conditions that can create a cytokine release syndrome, those conditions are attenuated. And I think this is the really interesting and important point of this compound, why you would want to combine Treg function with a killing function in the CAR T cell. The main direct effect that the company thinks is its advantage is that it will abrogate cytokine release syndrome issues because a lot of that is going to be coming from the dying B cells within that tissue.

So it will be interesting to see whether or not this actually pans out in humans. They do have in vivo data to suggest this is true so that they do see reduction in cytokines such as IL-six that are responsible for cytokine release syndrome in mice when it depletes B cells and then they show efficacy data in a mouse model of lupus, the SLE-one 123 mouse model strongly attenuated disease progression. So, you know, it's interesting, innovation is everywhere right now at ACR in terms of CAR T cells and T cell engagers And this is just one example. There are other companies that are trying to alter the signaling of the CAR construct in order to reduce cytokine release syndrome. Here, what they're doing in this particular example is going to give that CAR T cell an additional function.

You could argue this may be over engineering, right? There are other solutions to be able to get around cytokine release syndrome. And there's also additional questions long term. How long does the Treg actually last for after they differentiate into these Tregs following CD19 stimulation? And the other issue here too is what happens if these CAR T cells that are now Tregs go into irrelevant tissue?

Does it immunosuppress? A lot of questions that need to be answered in long term, either preclinical studies or in first in human studies. But again, innovation's everywhere here and this is just another example.

Hi, everyone. Professor Peter Nash reporting for RheumNow from HDR Convergence in Chicago in The US. And I thought we would summarize a dozen abstracts and the numbers will be given to you that are looking at CAR T therapy, the flavor of the month here for autoimmune rheumatic diseases. There was a lovely presentation by Anka Akenazi who summarized the information we have today. She talked about 16 studies of CAR T therapy up to one hundred and forty five lupus patients, but also patients with myositis, scleroderma and, a number of other autoimmune diseases, IG4 disease for example.

And these patients, the targets have been CD19 which takes out the plasma blast which makes lots of the autoantibodies we're interested in. Double stranded DNA, SSA, JO1, also targets like BCMA, which takes out the plasma cells. Now that's where STL70 comes from, but unfortunately if you take out the plasma cell, the downside is infection and that's something that has to be considered. 12 of them were autologous, where there's expansion of these T cells externally, the CAR Ts externally, then put into the patient. Four of them are allergenic, which is much more convenient because it's an off the shelf product with a fast turnaround.

There's a number now looking at in vivo expansion rather than expansion in the laboratory. The efficacy has been quite amazing. Seventy percent of these patients are in doris remission which is quite hard to get. Eighty nine percent in LLDAS which is also hard to get. Eighty four percent in drug free remission.

Now the downside of safety, fifty six percent of these patients have CRS, but it's been relatively easily managed with paracetamol and subsequently tocilizumab. Only one has been grade three, none have been grade four compared to the oncology experience. Four patients have had ICANS. One grade three and one grade four, it's a neurotoxicity. Eleven out of one hundred and forty five have had severe infections and there's been one death from pneumococcal meningitis.

There has been no deaths as far as known from other issues and there's been one successful pregnancy, there's been a couple of recurrences that have allowed retreatment, so there's a number of long term follow ups with drug free admission after four to five years now in significant numbers of people. If you want, there's a very nice review in July's edition of seminars Arthritis and Rheumatism twenty twenty five by Nordmann and that summarizes the experience to date with CAR T. So what are the problems and the take home messages from my point of view? If you're going to have CAR T, you need to set up a center of excellence model where you can go to a academic center or a private center, it doesn't matter, but you need collaboration between Rheum, HemOnc, Nephrology who have stolen all our lupus patients, and the infectious diseases group who are set up to do this kind of treatment for the and there are a number of issues. One is finding the appropriate patient.

As I said, the nephrologists have stolen our lupus nephritis. We only see these patients when they have extra renal issues they want sorted out. Number two is the question of lymphodepletion. Lymphodepletion means eight days in hospital and we all know how difficult it is to get public beds and they would have to pay for private beds and they're neutropenic so they need HemOnc to collaborate and look after these patients for those eight days. Then you need access to filgastrum, you need access to tocilizumab, neither on simple easy label for these kinds of things.

And so there's a number of practical feasibility issues for the average Rheumatologist to do this kind of involved, treatment. So cost is the next issue. I'm sure it'll come down over time. The oncologists are used to using it for lymphoma and myeloma and I think those kinds of costs can will come down but they're very country dependent. In some countries half €1,000,000 in Germany.

In America, expensive. In Oz, we can do it much cheaper. QIMR quoted something like 40,000 US dollars to develop the CAR T, but they still weren't able to collaborate and do it for us. So there are a number of issues, excellent efficacy, if it's your daughter with lupus nephritis and bad prognostic features and the option is a life of low dose prednisone, mycophenolate or oxychloroquine, belimumab, in and out of hospital, issues of pregnancy and fertility, or, a therapy with upsides and downsides that are manageable, four to five years of drug free remission, I think it can be an

easy

sell. So complicated, I suspect it needs center of excellence model, appropriate patients will be the ones that will be the trick And now with T cell engagers coming along, which we'll discuss another time, there might be a more feasible alternative that the rheumatologist could do in his own office compared to what's involved with CAR T therapy. So I hope you found this discussion of interest and I look forward to the next one. Thank you.

Hi, my name is Akhil Sood reporting for RheumNow. Today I have the pleasure of speaking with Doctor. Melanie Hagen from Erlagen, discussing abstract fifteen thirty seven which describes a new reported adverse event in patients who received CAR T. Doctor. Hagen, could you tell us a little bit more about, LICATs?

Yeah, thank you for invitation. So LICAT stands for local immune cell affected toxicity syndrome, which means that we have observed a transient inflammation and worsening of symptoms of priorly affected organs in autoimmune disease were treated with CD19 CAR T cell therapy.

That's very interesting. And can you tell us about the onset of LICATs? When do you expect to see this adverse effect?

Yes, so we had a median of fourteen days. But referring to different organs, for example, patients with lupus nephritis showed an earlier onset of worsening of the creatinine or the proteinuria earlier than for example skin manifestations who occurred at about three weeks after treatment. So maybe there's also a difference in the ability from the CAR T cells to migrate into the tissue in a different speed in different organs.

That's very interesting. And, what would the management involve in, for LICATs?

Yeah. So we graded it, referring to the treatment and grade one for example was just the watch and wait approach, so we didn't do exactly nothing and just be patient and brave and see what happens. And grade two were the use of steroids, only short term. And grade three for example would be steroids and prolonged hospitalization. We only see that in three patients and we define grade four as ICU treatment, but there were no patients fortunately, who, were experiencing grade four LICATs.

So most of the time it's self limiting and it's very mild.

That's really reassuring to hear. And have you seen, similar, reports of LICATs in oncology?

Yeah, that's a pretty good question. So when we did all the observations and did the research and literature, it's interesting because for lymphoma patients there were big trials reporting after CD19 CAR T cell therapy and then doing the follow-up PET CT scan, they saw an increased uptake of the tracer in this lymphoma patient. They were really afraid that this is progression or this is a secondary malignancy. And then they did a lot of biopsies showing this is just inflammation or necrosis. And we have also performed biopsies showing that we see only inflammation and we had no signs of the disease, for example, in the skin.

We could not see immunocomplexes that were specific for lupus because someone were afraid that these are relapses and not only a new adverse event that is self limited.

That's really interesting. And should we be worried about this new reported adverse event in CAR T?

No. Totally not. As I mentioned, it's only mild, we can treat it, very easily, even with doing nothing or just a short term course of steroids. On the other hand it's very important to report it because we don't want to use unnecessary immunosuppressions in these patients because if you say okay, it's a relapse and I want to treat that, I think that would be, it's not necessary. And I think that's a key point of the whole, like its description.

And we should report it in all the ongoing trials and, yeah, state it like a new side effect.

Absolutely. And what would be some of the labs or parameters that we should use for monitoring of in the trials?

The labs. Yes. You mean if there was any correlation?

Some more in terms of the disease activity monitoring of

Ah, like cats. Yeah. That's a good question. So for example, in the lupus patients who then showed new or transient worsening of manifestations, we couldn't see any serological marker for that. Instead, they already were seroconverted and had normal complement levels,

and

they didn't see, we couldn't observe any increase of inflammation markers. So that's definitely also the difference between LICATs and a systemic inflammation like CRS.

Oh, that's really interesting. You know, thank you so much for sharing and discussing your, abstract highlighting this new adverse effect that's been reported in CAR T and, you know, discussing the management and manifestations. This is Akhil Sud reporting for RheumNow. Thank you.

Thank you.

Hey, everyone. This is Jeff Sparks from Brigham Women's Hospital in Boston, Massachusetts, and we are here at Chicago for day two of the twenty twenty five ACR Convergence Annual Meeting. Today, I'm gonna be talking about new paradigms for the treatment of rheumatoid arthritis. Obviously, we have a lot of great treatments for RA, but a lot of our patients are still suffering. And there haven't been a lot of advances over the past decade.

Certainly, lot of other diseases have benefited from this, but I think RA has languished a bit. But luckily, there's three trials I wanted to talk about here that are really paradigm shifting, at least potential to be paradigm shifting for rheumatoid arthritis. The first I'll talk about is RESETRA, which is an implantable left vagus nerve stimulation. So, obviously, this is very different from any other treatment that's ever been approved for rheumatoid arthritis before. This involves a surgical procedure, overall relatively minor, but certainly, different to refer your patient to a neurosurgeon to have this implantable device.

And this periodically stimulates the left vagus nerve, which has been shown to decrease inflammatory markers. So there were two abstracts that were interesting from this RESET RA study. The first abstract, sixteen seventy five, reported the primary results. And the primary outcome was an ACR twenty at month three, And this was randomized to basically turn the device on or to have a sham where basically the the procedure was implanted but not turned on. So in 1675, that the ACR twenty was hit at around forty percent of patients compared to less than twenty percent of those with the sham intervention, and this was statistically significant.

And this showed that this neuroimmunomodulation could be helpful and efficacious to treat RA, and many of these had failed several biologics. I think a particularly interesting part of this is that there continued to be improvement in month three where all patients crossed over into the active arm, and it seemed like this was overall pretty well tolerated. There were some patients who had some hoarseness and dysphonia, but overall not thought to be too severe. A corollary subgroup analysis of this was twenty six fourteen, and this was looking at, basically, radiologic progression, looking at MRI scores. And this is not something I necessarily expected that a neuroimmunomodulator would actually, decrease the progression of structural damage in rheumatoid arthritis.

And overall, there was a trend towards statistical significant and the intention to treat analysis. However, in the subgroup analysis where they restricted it to people who are at high risk of developing or worsening ROSENS, particularly if radiographic features at baseline, it was statistically significant. So this is a real proof of concept that this could be a very different therapy to offer our patients. The next study I'll briefly highlight is the Rinnoir study at l b 19, a late breaker. This is a phase two b study looking at rosinilimab.

This is a study that depletes pathogenic T cells. In one of my previous videos, we talked about T peripheral helper cells, T follicular helper cells, which seem to be present in higher numbers, particularly in people at risk for rheumatoid arthritis and those that are seropositive. So this study randomized people to rozanolimab versus placebo, and this also hit its primary outcome of hitting an ACR twenty, and, also had differences in ACR seventy as well as many other secondary outcomes and was also very safe and well tolerated. And I think that, should lead this towards, maybe perhaps a phase three study that would really needed to be established efficacy and safety. The last study is l b 23 that I'll highlight, and this is a CAR T study.

However, it's a different kind of CAR T study because the T cell that they use is a Treg. And because this cell is, relatively, a peacemaker, if you will, this one doesn't actually need chemotherapy. It isn't expected to have much side effects. And it's also, targeted against citrullinated antigens that are specifically implicated in RA pathogenesis as opposed to CD 19 that many of the other CARs. So this is a a different kind of CAR T trial.

And this is very early study, just phase one, and there did seem to be some transient benefit. I'll say that compared to the c d nineteen, this was not as efficacious. However, this is a dose finding study, and perhaps a higher dose might be needed for more lasting effects. But, again, I think this illustrates how CAR T could be used in many different ways besides just a c d nineteen CAR T effector cell. So these are just, three examples of some potential paradigm shifting studies within rheumatoid arthritis.

To highlight, we're talking about neuroimmunomodulation with an implantable device. We're talking about depleting pathogenic T cells, and we're also talking about actually using CAR T regs as a anti inflammatory in a CAR T environment. So, again, thank you for your attention, and hopefully, you're learning a lot at ACR twenty five, and I'll look forward for more reports. Thank you.

Hello. My name is doctor Philip Meese. I'm the director of rheumatology research, at Providence Swedish Medical Center in Seattle, and I conduct rheumatology practice in Seattle as well. Over the past two years I've been the PI for a variety of CAR T cell therapy trials in combination with our hematology oncology division at my institution, and it's been quite a ride. So I've been taking on many of the cell therapy trials that have been conducted in autoimmune disease ever since the initial report from Erlang in Germany from Bjork Schetz group showed how effective CAR T cell therapy can be in lupus.

One of the sessions here at the ACR meeting was a overall review of CAR T cell therapy and a wonderful update from Joan Merrill. And she highlighted a meta analysis that was authored by Nordman Gomez in seminars in arthritis rheumatism and what he did was review 16 studies, 13 targeting CD19 and three targeting CD19 and BCMA. There were 12 autologous CAR T trials and four allogeneic ones, and for a total of one hundred and forty five subjects with lupus that were treated. Some summary from that included the fact that at baseline, these patients had very active disease with an average CDI score of 13, and with treatment this decreased to 2.3 after six months and 1.4 after twelve months. It does show that it takes a little bit of time, you don't get immediate results, but ultimately very, very significant improvement in overall disease activity scores.

With doris remission seen in seventy percent of patients, LDAS in eighty nine percent of patients, and drug free remission in eighty four percent of patients. Highly effective, and this mirrors our own experience working in clinical trials with lupus patients, where the longest out that we have is a one year patient who is drug free and having essentially no signs of lupus. Occasional rash, mouth sore, but really doing very well. Side effect wise, there are some very specific things that have been seen, something called cytokine release syndrome or CRS. In this meta analysis, that was seen in slightly over half of the patients, usually grade one or two.

This would be, for example, fever or slight change in blood pressure, but overall very well tolerated. In our center treated either with Tylenol or Tocilizumab. In these reports there were four cases of ICANS. ICANS is what is called immune effector cell associated neurotoxicity syndrome, which can be confusion, for example, or word finding problems, and usually quite responsive to either steroids and or other treatments, and we're rarely seen either grade one, two, or three most often. And then seven percent of patients developed serious infections and there was one case report of fatal pneumococcal meningitis.

So there are potential side effects. In addition to the CRS and ICANS that I mentioned a moment ago, there can be cytopenias, hypogammaglobulinemia, and downwind reported in the cancer treatment literature. Very, very rare risk of CAR related cancers. A new toxicity that has been reported is an interesting one, known as LICATS, or Local Immune Effector Cell Associated Toxicity Syndrome. What is happening with this condition is that the patient may report a flare of some of their basic lupus symptoms, such as skin rash or arthritis or proteinuria that occurs somewhere around three to four weeks after cell infusion.

And this tends to be transient, pretty easily treated with steroids or tocilizumab. It seems to be associated with an area where B cells have been ablated and this may be a reaction to the B cells that are dead there in that particular tissue. Again, this is transient and tends to be relatively benign. We don't think that this represents a flare in their basic lupus activity. So what I liked about this overall presentation was how much it mirrored our own experience, in terms of the degree of effectiveness that can be seen, many, many patients with Doris remission, but also some of the side effect profile.

There are a number of us who are conducting these trials that are now gaining the experience that the hematology oncology physicians have gained in their years of using this type of therapy. So I think that clearly we're going to be moving into an era where this type of therapy can become available for other refractory lupus patients. It is expensive, pretty arduous, and there are going to be some possibly more practical off the shelf allogeneic therapies coming along and T cell engagers. We'll save that for another video to have a more in-depth discussion about those newer approaches. Thank you very much.