SABCS 2025 | Intrathecal cDC1s induce adaptive immunity in leptomeningeal disease

Yeah, so the basic idea is the dendritic cells are kind of the Paul Revere of the immune system, so they alert the immune system that there’s proteins that shouldn’t be there or peptides, and the rest of the killing apparatus for the immune response should kill them and get them out of there. So what we did is, so there’s Brian Czerniecki, our institution has been working on dendritic cells for 30 years and he’s great. He’s done this in breast cancer in the rest of the body. And we are applying this to the problem of breast cancer when it goes to the spinal fluid, kind of like a bacterial meningitis, except it’s tumors. And before we talk about any results or anything, it’s leptomeningeal disease is a major problem. It’s pretty heartbreaking, actually. For some reason, which we don’t understand, it seems to affect young women. So many of the patients are, you know, 30 or 35 or 28 and have young kids. So it’s heartbreaking because of that. It also has a very short prognosis of maybe two or four months. And there’s not much that’s known about it. And the treatments aren’t very good. And let’s see, what was the other thing? Oh, yes. The third reason that it’s heartbreaking and a major challenge is that it almost, the typical situation is that a woman gets her cancer treatment and everything’s under control. It’s in the rest of her body, like the breast lumps are gone. Maybe they had metastasis to their liver or bone, everything’s okay, but then this problem in the brain pops up and that almost always happens and it’s heartbreaking for them because look, there’s virtually nothing in the rest of my body, what the heck is going on with my stuff in the spinal fluid, and it’s for reasons we don’t understand, it’s like a sanctuary site. So there’s something special where that space in the brain is protective or it evades the immune system or something. So yeah, so the phase one study isn’t done yet. It’s still in progress. I think we treated our probably 13th out of 15th patient three weeks ago. But the poster is about the patients in whom we could examine their spinal fluid and do single cell analysis on the spinal fluid, so we could see exactly what was going on and if we were getting the response that we thought we were. So if you work in test tubes and mice, you know, you can do stuff in the lab, but you have no idea what’s going to happen when you do it in people. So we just, we’re going to do all this when the trial is over, but we just want to look at the first six patients. So we had some idea and some reassurance we’re on the right track. So the big picture is that the patients are living a lot longer, sort of on average about a year and a half as opposed to four months, which is a long time. It’s still not good enough. And that’s a bit of a moving average because that includes patients that were only treated like a few weeks ago. So their survival kind of is short, not because they’re in trouble, but because we don’t have a lot of follow-up. So that was pretty impressive, actually. And many of the patients got better. And then when we looked at the immune cells, so I didn’t explain this, but it turns out the leptomeningeal disease is kind of an inflammatory immune-based disease, because I always thought it was just a bunch of tumor cells floating around in this watery spinal fluid, but I was completely wrong when we do the single cell analysis to look at each and it characterizes each individual cell, so if there’s 5,000 cells in there, we get this detailed, you know, 100 gene signature on each particular cell, but so most of the cells were immune cells, right? Which is weird. And there’s certainly cancer cells, but since they’re immune cells, we thought this immune approach would be useful. And just to make it easy or simple, we could, you know, turn on or enhance the good cells and kind of turn off the bad cells. So it turns out that we are reorganizing the immune microenvironment in a good way. So there’s more immune killing cells like CD4s and CD8s, for example. And there’s fewer cancer cells. That’s the other thing is we can look before and after treatment and say, oh, well, this woman had 500 tumor cells and now she has five or something, right? So that was, okay, that’s good, and so we did see what we expected, and then there’s a big increase in the B cells, which is an immune cell that makes antibodies, so we think that maybe the dendritic cells are not just turning on the tumor cell helping cells, the CD4s, as well as the tumor cell killing CD8s, but the B cells, and those are cells, the immune cells that make antibodies and hopefully provide long-lasting protection, you know, so we don’t know. So, and then we did find using this ELISA-based test, it’s a little qualitative, it’s not the exact answer, but it looks like we did find some evidence of antibodies being made against HER2 and HER3, so kind of is very suggestive that you know this approach looks really useful, so and it’s kind of reassuring to me because, of course, you stay awake at night and worry that maybe you’re doing the wrong thing, actually, right? So we’re moving on to finish that phase one. And I think we’re also lucky because we’re able to really interrogate the science, you know, in detail, so we can really understand this. And of course, we want patients to live forever, but we need to look at our data, figure out and figure out how to make it better and what the next step might be.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.