ACR 2025 CAR-T Topic Podcasts Compilation Save

This is an ACR twenty twenty five podcast coming to you from Chicago. Hope you enjoy it.

Hi. This is doctor Al Kim again from Washington University School of Medicine reporting for RheumNow. I'm the faculty head for the CAR T and T cell engagement group here that's been very busy reporting on numerous abstracts at the ACR Convergence twenty twenty five conference. I'm gonna be presenting data actually from four different abstracts that have finally given us high resolution molecular data to justify why deep depletion that CAR T cells have been able to demonstrate to date may be the reason why we have the extraordinary durable clinical response that we are in lupus patients treated with CD19 CAR T cells. So as a little bit of a background about B cells and why they're dysfunctional in lupus, remember when B cells grow up in the bone marrow, they develop there, they come out as naive naive B cells.

Now in uninfected people or people that don't have any recent vaccination, these B cells stay as naive B cells. If you're vaccinated or you get an infection, these B cells move to what's called the B cell follicle in lymph nodes where then they initiate germline center responses. Here, the B cells differentiate so that they are able to create high quality, high affinity antibodies which can be then be protective once you get re exposed to that particular pathogen. In lupus, this is completely hijacked. In the case of lupus, the B cells emerge out as naive B cells but they are never brought into the lymph node B cell follicle.

Instead, they are activated in what's called the extrafollicular pathway. And what this does is that it creates a unique population called double negative two B cells that are strongly associated with lupus pathogenicity. In fact, these B cells harbor almost all of the auto reactive B cell clones that you see in lupus patients. So as a result, the clones that you, that in terms of if you wanted to graph out all your B cell clones in a pie graph, these would occupy maybe 80 or 90% of them. And then when they eventually then grew up into antibody secreting cells such as plasmablast, they are making most of the autoantibodies in lupus patients.

So in these four separate abstracts, what we are seeing in the pre CAR T state is the very low naive B cell counts but very high double negative B cell and plasmablast populations, consistent with what we see in lupus patients that are flaring. Early on within weeks after getting CAR T cells up to six months, we see numerous changes in the B cell compartments. First, there's a strong reemergence of naive B cells with a substantial reduction in plasmablast and these double negative B cells. So that's great. On top of that though, the B cell repertoires in terms of the B cell receptor, they're not auto reactive.

They tend to homage, become very heterogenic and are equally represented amongst all the different B cells. Again, suggesting almost a pre disease state. Looking further out to twelve months, the Erlogen group here has shown that this remains durable. There is a population of these double negative B cells that do come back, but they're not the pathogenic ones. They're called DN1 cells.

They're not DN2 cells. And also there's evidence that these B cells are activated through the germinal center and not through the exofilicular pathway. I So think when we sum all of this complicated B cell biology up, basically what we're seeing is complete reconstitution of the B cell compartment after CAR T cell therapy. In this case, all CD 19. Some people have been calling this immune reset.

I'm not exactly sure how we're going to define that specific term but I think this is extraordinarily encouraging, something we've never really seen before in autoimmune diseases and it's something that we're going to be looking at long term, years down the line for lupus patients but also for other autoimmune diseases being treated by CD 19 CAR T cells.

Hi, this is Bella Mehta reporting for RheumNow from ACR twenty twenty five. We have Jeff Sparks with us who's from Brigham and Women's and he's the director of immuno oncology. And

autoimmunity. And

autoimmunity at Brigham and he there's a lot of talk at ACR about CAR T cells, so we thought we'd hear from the expert here. So tell me, what do you think about CAR T cells and what are the best abstracts or sessions you could recommend people to go to?

Well, as in previous meeting, there's a lot going on with CAR T, and I think the field is exploding. And, you know, cells, cellular biomarkers, cells as intervention, it's just really been incredible to see it grow. As we know, maybe a few years ago, we were really only talking about auto CAR T, talking about chemotherapy, long hospitalizations. And now this year, it's moving even more into off the shelf, which is Allo. Also doing in vivo CAR T, and then I think a lot more, interest in T cell engagers, both bispecific, even trispecific antibodies.

And the way I would term it is that at the moment, there's some early adopters that are really trying to test out the field. I think the rest of rheumatology is really trying to see where things fall into place. And are they going to have to get an oncologist on board, a pheresis unit, get familiar with chemotherapy? Or is it going to be something where you could do all this in vivo? But certainly it's been transforming the field.

Great. Great. So just for people to understand, when you say in vivo, how does it work?

Well, don't have all the time here, but basically lipid nanoparticle units are injected and basically give instructions for the engineering to actually occur within the body as opposed to having to extract cells carefully, engineer them ex vivo, you know, freezing them. So you can imagine that there's a lot of appeal to do this in vivo because you don't have to go through all those inefficiencies. However, of course, there's so many details. There's so many things to iron out that this is still very, very early days.

Okay. So, does it change the cost? And do you think that will open up, this technology to more patients?

Yeah. Cost and efficiency access are gonna be the big issues. And all of those we need a lot of work on as you probably know. Right now it's very expensive. It's a bit of a cherry pick patient that's able to be sick enough to qualify, but adherent enough and have all those resources involved in order to undergo these really complicated protocols.

And certainly, it's very expensive now. And there's so much enthusiasm here. I am I am cautiously optimistic that many of these inefficiencies can be, lessened.

Great. Great. Thank you. So is there any particular sessions that you would recommend people to go to? Or any particular drug is your which is the big one, do think?

I think, I'll highlight a few things. I think most rheumatologists understand that c d nineteen based therapies can really effectively deplete b cells and probably to a greater extent than our other, therapies such as rituximab and other related items. But this is really a platform where you can choose many different targets. You can also choose other types of cells, not just T effector cells that have all these side effects. There's some really innovative cars looking at NK cells, but also T regulatory cells.

And those are in particular, I'm really excited about. These recently run the Nobel Prize about Treg, and you wouldn't expect much toxicity in here. You're basically injecting a peacemaker that hones into where the, inflammation's going on. And in theory at least, there should not be a lot of the, you know, acute side effects that would that would be expected in other types of cells. So I'm not sure one really is standing out from the crowd, but to see the, depth and breadth.

And also we're moving on from case reports. Like, all the studies now are prospective, they're interventional, they're pre specified, and that we're now getting into dozens of patients. But certainly, we need to get into even more patients. We also need to think about at what point do we do a comparator group. So still early days, but it's incredible how much the fill is advanced in, you know, just a few years.

Thank you so much. This is, really, really helpful, and thank you, to Jeff Sparks, and, you'll see more coverage on CAR T, at RheumNow. Thank you. Bye.