← Blood, Sweat and Smears - A Machaon Diagnostics Podcast
Blood, Sweat and Smears - A Machaon Diagnostics Podcast
Scott Canna, MD returns to discuss the Cytokine Release Syndrome (12-test) Panel
00:35:14
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- [00:06]
A
Hello and welcome to Blood, Sweat and Smears, your Macheon Diagnostics podcast with tag team hosts including Our medical director, Dr. Brad Lewis, senior director Bjorn Stromses, that's me and other guest hosts. We hope you find these podcasts interesting and informative. Thank you for listening. And away we go.
- [00:26]
B
Welcome everyone. Back to Blood, Sweat and Smears, the hematology podcast that comes out of Matrion Diagnostics. I'm Brad Lewis. Once again I have the incredible pleasure today of talking with Scott Canna, who as many of you know, is the person I send people to when you want a really smart doctor to talk to. But Dr. Canna has been studying hyperinflammatory syndromes for almost 20 years, I believe began short vacation at the NIH where he was pulled into hyperinflammatory syndromes and has continued to this day. He's a clinician scientist running a laboratory that's studies hyperinflammatory syndromes, auto inflammatory syndromes and that sort of thing at CHOC Children's Hospital of Philadelphia. Today we wanted to talk about hyperinflammatory syndromes. Around the backbone of the new cytokine release syndrome panel that comes out of Machan Diagnostics we have a panel 24 hour turnaround with a number of cytokines that we'll be talking about as we go. And I'm going to try to get Dr. Candid to explain to me how to think about using that panel, when to order it and when I do order it, what do I do with all of those results? So question begins really with what kinds of scenarios would you think about using a cytokine release panel in?
- [01:38]
C
Fill in a couple things. One, thanks for having me on. This is obviously a topic I care a lot about and I like to share and learn a lot and sometimes teach a few things too. I'm really not that smart, but I'm very lucky to work with a whole bunch of very smart people who look at inflammation through lots of different clinical and scientific lenses through a multidisciplinary clinic. And so I am just one entry point for that sort of brain trust I very much lean on. You know, finally, I think the panel that we're talking about, it's sort of unique. It includes some of the tried and true classic things that people expect on their regular inflammatory cytokine panel like IL6 and IL10 and TNF and interferon gamma. It includes some things that people send usually as one offs, like 6, cl 9, il 18, which is sort of what my lab has been working on for a while and kind of dear to my heart. Soluble IL2 receptor, soluble CD25, soluble FAST ligand and the soluble Mac or membrane attack complex or soluble C5B9. So I think that to talk about like the panel and how people use it, to be honest, nobody uses this panel because it's, it's pretty new and so the components within it are used through a variety of different contexts. So I think that there's a couple nice things about this one. It includes a lot of the things that we order as one offs and sometimes we order one and forget to order another, which we had two. The turnaround time is pretty key. I'll take CXCL 9 for instance. The CXL 9 is a great interferon gamma disease activity biomarker. It's got a really nice broad dynamic range where it's like in the low hundreds in healthy people. And you know, we've seen values up into the hundreds of thousands and it's really dynamic over the course of probably, you know, hours. So that makes it a really good monitoring biomarker. Diagnostically it gets you a little bit involved part. But I think everybody's had a pretty elevated CXL9 at some point in their life with a bad virus or something.
- [03:56]
B
Is this something you would use for monitoring? In some sense we do, we use it pretty frequently.
- [04:01]
C
The problem is like we get the answer back three to five days after we send it when we know that that value can change overnight by orders of magnitude. You have to remember what things were like when you sent it to really interpret the value you get back. And the longer that is, the less useful it becomes. That's pretty true of pretty much everything that's on that panel. I would say Maybe, you know, IL18 is not super dynamic and soluble IL2 receptor also, you know, all of those are pretty dynamic. But over the course of like hours to days, ILAT and SOLID2 receptor may be a little more stable. You know, I also say that, you know, we've been running our an in house pro inflammatory cytokine panel that includes some, but not all of these things for a little bit. And every panel is a little bit different. You kind of have to get used to what the, you know, what does a certain level mean? Our in house panel is run on a certain platform that is a little bit of a hassle to run, but it's very sensitive. So an interferon gamma level of 50 for us is like, yeah, it's positive, but it's not, you know, Too concerning. But that same value if it had been run at a different Zen out where the sensitivity we kind of know from experience isn't as good. 50 can be quite a lot. So you kind of have to get some level of familiarity with how sensitive the assay that you're dealing with is. There are things still on your panel that are actually the only one on there that's pretty useless is IL1 beta. And that coming from a rheumatologist who throws IL1 blockade at lots of things, even if we don't know what you're treating, it's just not a great biomarker.
- [05:48]
B
Would you ever use an IL1 beta as a way of deciding that it was time to use an IL1L1 blocker?
- [05:55]
C
No. We have a little joke locally that there's a Snoop Dogg song called Drop It Like It's Hot. And so Snoop is not an immunologist. And so whenever we get that temptation to block it because it's high now, people have it in their head to hear Drop it like it's Hot. So don't be like Snoop. Snoop can interpret cytokine panels. There are occasionally times where you block it and it's high. So IL6 levels in cytokine release syndrome after CAR T cell therapy, interferon gamma levels often, but not always in certain forms of hlh, but they may not be the highest thing. And a lot of times you can look at a panel and oh my gosh, IL10 is really high. We should block that. And biologically, I almost never makes sense to do so. It's really more like kind of reading tea leaves or interpreting multiple things that operate on different sort of vectors of physiology at the same time and putting that pattern recognition together to give you kind of an output. And maybe someday with an adequate training data set, AI will tell us these, the patterns. And this is, this is what we're going to use, but we're really not there yet, in part for the reason that I mentioned that, like, different panels measure things differently. So you can't just extrapolate from the literature, because gamma level of 50 from one panel is a very different thing than another panel. And so you can't just plug all those data into an algorithm and figure it all out. Unless you lose a whole bunch of power by squishing down all the quantitation
- [07:27]
B
just to play games with this IL1 notion. So you have somebody after car T therapy or some other immune effector cell therapy, and you treated them with the tocilizumab and steroids and they're not getting better. Would you ever, at that point look to see if the IL one was still high and have that push you to make the next jump? Do you ever go to Anakinra in that setting?
- [07:48]
C
We often go to Anakinra in that setting for cytokine release syndrome. It's not first line, but there's lots of times where it's not crs, but we don't know exactly what it is. And we're giving the patient Anakinra because, you know, we want to try and move the needle a little bit on their inflammation, maybe keep them out of the icu. But we don't know if this is infection. We don't know if there's a malignancy, and we don't want to complicate that diagnostic workup. So blocking IL1 has a lot of advantages, but we don't really use IL1 beta as a biomarker for that. You know, diseases that respond absolutely marvelously to IL1 blockade often have totally normal IL1 beta levels. And yeah, you can go into literature and you can find that, yeah, NOMID patients have slightly higher IL1 levels than controls, but it's a pretty small delta. And clinically it's just not a great biomarker. Our best biomarker of IL1 activity is blocking it and does the patient get better? But, you know, that's not the case. For lots of the other things that are on that, you know, that panel, that list. We tend not to reach for gamma neutralization in someone that it doesn't have a decent signature for excessive interferon gamma activity, whether it's gamma itself. CxCl9 soluble L2 receptor We use as maybe pretty lousy but decent surrogate of systemic T cell activation. I think we increasingly are trying to figure out the contexts and levels where the soluble C5B9 may be a right indicator for complement inhibition. Certainly that's a test that was initially developed to help identify patients with HUS and then to track how well you were doing with drugs like eclizumab. But we've been really surprised. There have been HLH patients that we didn't think were that Sick, where the C5B9 levels were higher than we ever expected above the upper limit of detection. And others who similarly seemed almost as sick, but it wasn't nearly as elevated. And there's certainly case reports of going after that axis as a way of trying to limit immunopathology.
- [09:57]
B
That's what I was just going to Ask you if that would make you do that. We've certainly had patients where they were hlh, but they didn't seem to be getting better. And it turns out their soluble Mac is very high. And the question is, should we be blocking clearly that it marks complement activation. It's kind of like the interleukin. One question. So you got it. It's elevated. Should we be blocking it since we can.
- [10:18]
C
Yeah, I don't think we have enough data on that yet. Like I mentioned, there's a lot of patients where it's above the limit of detection who actually respond really nicely without intervening on that axis. So I think answering that question involves integrating risk and benefit of whatever drug you're using and how diagnostically sure you are of what you're dealing with and, you know, what's available. I think what you hit on, though, I think is maybe one of the things that I'd like to leave your audience with, which is that we want more from our biomarkers than it's reasonable to expect from them. Right. We want them to tell us exactly what the diagnosis is and what to treat and how to monitor. And, you know, each of them do those things better or worse based on the characteristics of the test. But mostly these are biomarkers that indicate a certain kind of physiologic process that goes along with certain diagnoses. But they're. They're rarely diagnostic. You know, I think that in general, inflammatory biomarkers, there's sort of a crisis of specificity. We want them. We want procalcitonin to tell me it's bacterial infection, except that it's sky high in Kawasaki disease and MIS C and certain vasculitis. Right. Where we don't think there's necessary bacterial infection. You know, we want interferon gamma levels to be diagnostic of hlh, and they're up in lots of other contexts. The. Maybe the exception to that is ILA teen where, you know, levels above a certain threshold and again, depends where you're getting it measured, but most places have sort of caught on, and that threshold is kind of 20 to 40,000, depending on how much else is going on with the patient, are pretty diagnostic for a relatively small number of disorders. Still's disease, including systemic GIA being probably the most common. But there's a few monogenic diseases where we've seen it really high, and you just almost never see an IL18 of 80,000 in someone with lymphoma. I think once we have kind of gotten to that, we've had a couple EBV HLH patients where the IL18 was way high and they didn't go on to necessarily clearly have Stills disease. But about half of Still's disease patients are monophasic anyway. So it gets a little hairy. And again, I think we measure it and it kind of puts us in a sort of physiologic ballpark of, of what kind of things are going on. But in terms of diagnostic specificity, you know, really high L18 levels are probably among everything that's on there, the most specific.
- [13:06]
B
So we kind of talked about. You talked about the panel nicely. Can I push you a little bit to talk about specific therapeutic situations and whether that changes things or how. How that changes things for you? Yeah, I mean the most common ones are for you. We get a lot of them are CAR T therapy.
- [13:21]
C
Yeah, well, yeah, I mean, I think. Oh gosh. So when talking about CAR T therapy and cytokine release syndrome and ICANS and ichs, it's a mess. And so there's been a lot of cytokines measured. Those patients tend to be really, really high. Nevertheless, the criteria for cytokine release syndrome have nothing to do. The only thing that's sort of directly related to inflammation, those criteria is fever. The rest is sort of shock and respiratory failure, which you can have in a patient who has really high levels and you can have for other reasons in patient levels aren't so high. So there's that part of it. The ICANS patients again that's a very mixed bag and correlates with pre existing CNS insults and the immune effector cell HLH like syndrome patients tend to look like really inflamed HLH patients where the ferritins and 100,000 sometimes and all the other things, the Cellul 2 receptor are really, really high. So I don't know that. There's a lot of clear cut hinge points within CRS and post CAR T cell therapy that tell you this is what you need to go after. I think that IL6 is still the right target up front and then after that I think the data are trickling in. Certainly lots of people have used Anakinra and it seems to help quite a bit. Interfering gamma blockade in certain contexts has been reported to be pretty beneficial, but then also reports of it not really helping very much in things like ichs. So we're still trying to wrap our heads around context in which, you know, you might want to block it when it's really high. But if it doesn't work does that tell you something else? So some of the simpler hinge points. So I'll go back to IL18, you know, new diagnosis, patient you suspect of having still disease. Before we could measure IL18, we're going to put these patients on steroids and some other stuff. And so we would usually get a bone marrow biopsy and often like a pan scan to sort of. Even if we didn't really think there was infection, many of these patients are a bit cytopenic because they're kind of mas like. And now if we can get the ILA team back in time, we say, okay, well, I didn't really think this was a leukemia or lymphoma or anything like that to begin with. Now I have an ILAT team that tells me that's even far less likely. So we're just not going to do bone marrow biopsy and a pan scan. We're going to initiate therapy, we're going to feel good about it, and we're going to send the patient home probably a bit sooner than we otherwise would have.
- [15:54]
B
You're primarily pediatric. I don't know how often you see adults, but in adults I would think harder about lymphoma in that kind of a setting. Work as well in.
- [16:04]
C
Don't know. I mean, we've had a heck of a time getting our adult colleagues to send it. There are some newer Stills disease data showing that it is still a very specific biomarker. We still don't know how to sort of draw a fixed line around what Stills disease is. And it may be a certain kind of inflammatory response that certain people could have in response to things like infection or lymphoma. So I don't know that they're necessarily mutually exclusive. So if you're. You're concerned about malignancy, you should always keep checking for malignancy. And like I said, we've had, I think I can only think of one patient where, you know, had an ILA 18 of like, I think 70,000 or so. But a lot of things didn't fit. Sometimes we'll get. We'll send these S100 proteins, which is another sort of Stills disease biomarker. And this patient's S100 proteins are actually normal, which is really kind of weird for having an IL that high. And an ended up having a very sort of hard to diagnose still B cell lymphoma, but had to took a couple of biopsies to get it. So, you know, nothing's perfect. But I think 18 gets you most of the way there for a small number of diagnoses, certain patterns have definitely triggered us one way or another. We've had, we had an HLH patient who had a classic HLH cytokine panel with high gamma, high IL10, not so much IL6 or TNF and then started treatment and watched those things improve and then spiked another fever and cytopenias worsened and it wasn't really clear is this the HLH sort of flaring back or is this complication? Got another cytokine panel. Gamma was normal. IL10 was kind of where it had been. IL6 and IL8 are acutely through the roof. And like 12 hours later grew gram negative rods from blood culture.
- [17:52]
B
Kidding.
- [17:53]
C
So, you know, I think that that was a situation where we could have jumped and said, okay, we're going to add it wasn't a primary hlh, so they hadn't gotten a toposide. And we discussed giving etoposide and obviously we're pleased to have not given cytotoxic chemotherapy to someone who was eventually going to have proved to have gram negative sepsis. So.
- [18:15]
B
So are there some of these markers that would make you start to think real seriously about sepsis rather than the HLH or AHAs? Because that's come up. I've certainly had my share of patients who we thought it was HLH, we thought it was AHAs, at least for a period of time. And then eventually it turns out probably the de. Infection, maybe infection triggering some of those things.
- [18:34]
C
But, but infection, yeah, I, I think that this is a, a little bit of an unmet need. But I think that you just. First of all, we need to stop calling HLH a diagnosis in the way that we want it to be like a causal diagnosis. And we need to start referring to it almost like it's a physiologic state, like shock. You wouldn't say a patient has shock and that's the end of it. You might say they're in shock and it's due to cardiogenitor or whatever causes. And I think HLH is similar where, oh, the patient's in HLH and we think it's primary or we think that it's mostly ebv, but they've also got whatever. So I think that's one part of it and another is, you know, we just had a patient transferred very recently who had sickle cell disease and was having DNS findings and things were a little bit concerning and had a ferritin that was through the roof and was a bit cytopenic, but the SIAL2 receptor was normal. And hindsight is 20 20. But that's, that's a patient that we really should have thought hard about. This isn't hlh. And that patient definitely was starting to go down the whole toposide intrathecal methotrexate, you know, things that are fairly specific to a certain flavor of, you know, primary HLH patient who, you know, ultimately that wasn't what the patient needed. And the ultimate diagnosis was actually a very sort of weird, rare complication of sickle cell called fat embolization syndrome, really where, you know, HLH treatment is not the right thing. So we send so many tests because none of them are perfect. But if you're positing that they have a disease caused by systemic overwhelming T cell activation and you don't see a lot of gamma or IL2 receptor, you really should like, stop for a minute and go back and think really hard about the assumptions that you've made that have gotten you to think that this is where you thought it was. And infections ehrlichiosis can be really hard to diagnose. PCR takes a while to come back and it can look a lot like. But you can also have a lot of complement activation in primary hlh. And which patients do and don't get to that is really unclear.
- [20:55]
B
So you don't have any way of thinking that through because we have seen a number of HLHs that had complement activation. And the question is, do we have queas and lice and should we be giving two different insecticides here or.
- [21:07]
C
Yeah, well, I mean, I. I don't know that they're completely unrelated. It's just a matter of how impressive a presentation it was. We had two patients that ended up having FHL 5 in the same part of our ICU at the same time. And one of them was a very sort of slow burn, was actually diagnosed because of some GI symptoms before the cellularity and sort of watched the T cell activation blossom before our eyes and easy to get on top of and had almost no complement activation and eyelids were normal. And another patient came in acutely, very shocky, hypocomplementemic C5B9 through the roof and had essentially the same disease. And so I think we know that even familial HLH requires a trigger. And the nature of that trigger and the nature of what else is happening in that patient probably affect the dynamics of some of these other physiologic processes. And so not every patient with a cytotoxic impairment has to have complement activation, but a good number of them have. And so because it's a rare disease, it's going to be really hard to get like the clinical data to substantiate exactly algorithmically when you're going to give a complement inhibitor and when you aren't. But you use the safest treatments first, and then you reevaluate the patient. And just like we look harder for liver inflammation, if the LFTs are higher, it's because they're telling us a certain location and physiologic process. And so, you know, if you get a C5B9 and it's really quite high, then you might want to think harder about adding that, especially if, you know, that patient's renal function is not where I want it to be or, you know, there's evidence of organ damage that is consistent with that halfway being activated. So I think that's how we use these is really kind of as biomarkers of physiologic processes that we think may or may not be happening in our patient, that they're not binary, they're quantifiable. It's like you can have a lot of confluent activation. You can have a little bit, and you can track it over time.
- [23:20]
B
So we talked about car T kind of, and a bunch of stuff around there. Other transplants, bone marrow transplant, liver transplants even. I had somebody recently post liver transplant began to look like some sort of weird hyperinflammatory syndrome. Didn't seem to be infectious, didn't seem to be rejection. Wasn't clear what was going on. Do you approach those guys differently? Do you have thoughts about approaching them?
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C
Yeah, I think the more medically complex your patient is, the more that there are caveats associated with these kinds of things.
- [23:50]
B
Just when you don't want caveats. What I really want now is for you to tell me which way to go here.
- [23:55]
C
No, I mean, it gets even sort of less clear, right? Because you've got a patient who's post transplant or post chemo or whatever, they've been lymphopenic, there's gonna be T cell activation purely because they're repopulating their lymphoid compartments and how much does that interact with it. Or if you've had a patient who is getting transfused or they've got some hemolysis for other reasons, that's gonna give you some iron load that's gonna push your ferritin higher. And so you have to take sort of iron exposure into account. Practically anybody who's getting this is going to have ferritin sort of in the mix as well. Patients with baseline endothelial activation, how much of that is just related to, you know, wound healing or transplant versus, you know, a new process that's come up. So I think that we're still learning how to use these. And as I said before, it has been hard for me to extrapolate from the literature and from other people's experiences just because so many of the measurement platforms can be so different. And what seems to be really helpful in one context may not be as helpful in your context and vice versa, just depending on how good is that assay. I think there's a lot of. I'll also poke a little bit at multiplex platforms. We really want a 7,000 Plex Aptamer platform for 3,000 Plex without naming companies electrochemiluminescence or proximity ligation detection method. The problem with measuring so many things at the same time is you have to measurement the same dilution. You have to measure them in the same serum versus plasma. And we have identified hook effects in a couple of different multiplex platforms when you run up the dilutions. And so if you were just using those, you would have never detected IL18 signature in stills disease because the hook effect sort of squashed it down. And those patients looked exactly like lots of the other inflamed patients. Same with CXCL9, same with CXL10. So some of these things that are really dynamic, just because it's in your multiplex panel, there's going to be a fair amount of type 2 error. So I think that you can believe the things that you find in those. The positive findings are probably reliable. But extrapolating from some of those, you know, near proteomic things has a bit of type 2 error, particularly for analytes that can run really high because of this hook effect. Sure. And you know, that hook effect, there's not a platform that's immune from it. It's not like anything antibody based. There's lots of ways of reading out signal from antibody based assays. They're all susceptible to hook effects and
- [26:34]
B
we can go back in and dilute it if we're suspicious. Are there times when you would be
- [26:38]
C
particularly suspicious what a commercial platform will have done in its validation of. Yes. And you know, you and I have talked offline about like making sure that your panel has some way of triggering to make sure that it can pick up an aisle 18 of 300,000 and not reported out as 13,000 because that difference matters. But in a research article, they're not going to do that. And especially for things that aren't giving you signal, you're not going to go back and say, well, did you not give me a signal because there's no signal or did you not give me a signal because it's blundered by hook effect? You can't do that for a thousand different analytes. So that's what I mean by challenges. Extrapolating from the literature is that probably more so than in other things like transcriptomics, you know, the platforms and the way that different, different articles and different experiences are measuring things can have a big effect on like what the take home messages are. And so we're trying to sort of squeeze that out. So to your point, like in the ICU with a patient that is status post liver transplant and has a soluble IL2 receptor of 8,000 and an IL18 of 4,000 and a CXCL9 of 30,000 and an IL8 of 3,000, what's dominant here? What do we go after? Everything. Nothing. And I think that's a. Unfortunately there's not a shortcut I can give you except that it helps to have like some oncologists that deal with the things drs and the VOD post transplant. And we didn't even talk about ECMO and the things that that can do to a bunch of these inflammatory biomarkers. So I think that we're still sort of nascent in adding all the caveats and contextualizing each of these things. I don't think that that should lead us to walk away from embracing them. I think that doesn't mean that they're valueless. It's just like any other biomarker. We still use the sedimentation rate. Right. Even though we know that false positives, false negatives, lots of different circumstances and sometimes those false values are diagnostically useful. But that's for a test that is literally just taping some blood to the wall for an hour and like measuring how many red cells are there. You know, I think that as we get more nuanced and like reading cytokine panels, some of those dynamics are going to become even more informative.
- [29:07]
B
You mentioned ecmo. No one has ever called me with an ECMO patient. So do you have thoughts about. I tend to get called more from by adult docs than by pediatric docs. The pediatricians know what they're doing better than I know what I'm doing, so they leave me out of their loop. But ecmo, what. What would we expect if we had a patient really sick after ECMO where everything's on the table? Sepsis, endothelial stuff, thrombosis. I mean, everything's there.
- [29:33]
C
Well, okay, so a couple of things. One, it depends what you're pulling off the ECMO circuit. So if they're on renal replacement, especially if it's like hemo filtration, that does pull off a little bit of cytokines. And you know, the paper suggests that it's like maybe 50%. Those patients are really high. Obviously, if you're farreasing a patient, phoresis does a decent job of pulling off even these small molecular weight things, but they reaccumulate really quickly. So you have to ask questions like, when was that drawn after them coming off the faresis circuit?
- [30:11]
B
And why didn't you draw it before you started the pheresis?
- [30:13]
C
Right. You know, why didn't you send it before pheresis? I think what do we see? We routinely see ferritins that are really high. I think IL8s have been pretty high in those patients that we haven't always thought was necessarily bacterial infection or that kind of chemokine activation primarily. And it might have just been, you know, endothelial activation that's somewhat nonspecific. We'll circle back to, you know, ECMO can cause sort of non specific endothelial activation that in lots of contexts will cause those endothelial to make cytokines like IL8. Actually, IL8's not on your list. Maybe for good reason. It's not super specific, but I'd have to hit the literature again and see sort of what specifically has been associated with ECMO other than like lots of reports of lots of cytokine arrangements. But people get ECMO for so many different reasons that there's not like this is what ECMO does to a cytokine panel.
- [31:08]
B
Anything else that you wanted to. You hit every button I wanted to talk about not quite in the order I was thinking we would do it, but you've hit them all. Pretty much. Other thoughts about druggable targets that you see in the future.
- [31:20]
C
I mean, everything on there is druggable. I will say we talked a bit about complement inhibition and I think that there's a lot of new basic immunology data that I think is making the world think differently about complement. We used to think of complement as being produced by the liver and then acting elsewhere. I think now with bulk transcriptomics and now single cell and now spatial transcriptomics, people are finding, oh my gosh, there's all this complement upregulation, there's all these complement receptor expression, it's really dynamic and it's local. And now we have papers suggesting like intracellular complement activation and signaling. And so I don't think we yet know exactly when the right places to do. And we have new complement inhibitors, you know, beyond iclizumab, there's Acopam and things like that. So that's an exciting space. You know, there's more clinical trials that are oncoming. It is remarkable to me that, you know, interferon gamma is like one of the oldest cytokines ever and yet we've only been blocking it clinically for couple of years and in some very specific contexts. And so I think that, you know, we're learning more about that. I think the data in at least non malignant transplant with engraftment have been pretty promising. And that may just be a gamma thing or it might be a T cell activation thing. And there's a number of ways of skinning that cat the chemokines. Experimentally, we haven't been super impressed that blocking CXCL 9 or 10 really does a whole lot to prevent immunopathology. But that's all kind of in model systems and things that are not super relevant. But I think that there's a reason a lot of those programs haven't moved forward a ton. And then of course there's a number of different strategies for blocking IL18 that look pretty promising, but it's still early days. There's nothing that's imminently going to be approved. But the cancer doctors are increasingly using stuff like IL18 to help augment the immune effector cell activation, that there might be a role increasingly for blocking some of these things in a way that is almost obvious because you're adding them to the mix. And now you might want to dial it down a little bit because, you know, maybe you've overshot the mark a little. And I think that's a good situation to be in and one that, you know, from a biomarker standpoint will be interesting to sort of suss out.
- [33:51]
B
Fantastic.
- [33:53]
C
Well, I mean, it's always a delight talking to you guys. This is obviously an evolving subject that I'm passionate about and I know far less about than I should or want to. But I think that we're going to keep using panels like this, like this and getting data closer to real time like we've been talking about for so long, and making sense of it all is a big challenge. I think that computers and algorithms are going to help us there, but we have to. We have to have the training data sets to make them useful, and we're just not there yet.
- [34:27]
B
Thank you again.
- [34:28]
C
Thank you again.
- [34:29]
B
This is Blood, Sweat and Smears from Macheon Diagnostics.
- [34:33]
A
That's it for us here at Blood, Sweat and Smears, a podcast produced by Matrian Diagnostics. You're a reference lab and CRO specializing in thrombosis, hemostasis and rare disease. Thank you for listening. And if you have a question or comment or there's a topic you'd like Dr. Lewis to speak to, please send us an email to blood sweatandsmeersatriondiagnostics.com that's M A C H A O-N diagnostics.com youm can follow Macheon at Twitter ationdx. Be sure to subscribe to subscribe Stay in the know. Share this podcast with clinicians you think might appreciate it, and we hope you'll join us next time here at Blood, Sweat and Smears.