Okay, so I'm gonna talk today about novel immune modulators for sepsis and will we get one? Now, I don't want to give away the punchline. I hope that someday we will get one But today we might not be there and we'll talk about it. So my conflicts of interest I have no significant financial disclosures to report as related to this talk I do have a patent pending for whole blood le spot. I'm also a member of immune functional diagnostics I don't receive any direct financial compensation. We could potentially in the future For this group, this is not surprising sepsis is a serious threat worldwide both public health at the United States and Accounts for more than two hundred and seventy thousand and at least eleven million deaths respectively And if you think about sepsis You've got a pathogen that induces an infection that then causes a maladaptive host immune response both causing anti-inflammatory and pro-inflammatory media mediators that certainly Interact with other downstream and upstream effects including causing endothelial dysfunction microvascular regional blood flow redistribution hemostasis and coagulation issues Leukocyte activation mitochondrial dysfunction and if left unchecked will ultimately lead to death now sadly Every three seconds in this world. Someone will die from sepsis The classic thinking was that there was an initial hyper inflammatory state that led secondarily then to an Hypo or immune paralyzed state we know now that that's probably not true Your immune effector cells and the different tissues in your body have different and divergent host immune Responses and that in different parts of how your sepsis elapses those immune effector cells may have different immune Phenotypes, we know that there are some patients that have a predominant early hyper inflammatory state have rises in IL-1-beta TNF-alpha IL-6 after danger associated molecular patterns release You have a release of oxidative stress and cause vascular defects leading towards hypotension and subsequently multi organ failure And then there's other Individuals who also either have concomitant hypoinflammation or immune paralysis if you will and those individuals are demonstrated by lymphocyte apoptosis cellular reprogramming changes in your Treg and T cells Elevated MDS C's and these individuals have a prolonged immune suppression that leads towards a higher increased mortality It's not surprising to this group That your highest mortality is not actually upon your index hospitalization with sepsis But it's over the ensuing follow-up months And we think that that's in part because of the degree of immune suppression that your immune system has endured Hmm so when I think about a modern vision of what looks like the innate and adaptive Responses as these are maladaptive and muddled One of the things that comes to mind is how to understand what exactly is going on in a patient in real time What is going to occur as you look at this patient prospectively and what can you do to intervene? What exactly are you intervening upon and is your intervention going to have benefits? Now we have endured in this world Hundreds now of studies for targeted therapies whether they're anti-inflammatory therapies Therapies that are direct corticosteroid trials a number of different trials And if you look at this forest plot Most of these are actually have benefit but cross that no effect line right there and you need about 10,000 patients in each of these studies to demonstrate efficacy And one of the problems and primarily in Demonstrating efficacy is that we've recruited most of these patients with a one-size-fits-all approach We have inadequate statistical power to show clinically relevant studies We ignore the wide spectrum of host immune responses We treat everyone as if their immune system is exactly the same and then randomize them to one drug or another It's not surprising why we've failed so far And if you think about where we should go we should direct these immune based therapeutic approaches Specifically to the immune effector cells that are actually maladaptive at that time point in the patient's course And so these are some immune endotype assessments that individuals like myself and many others Laboratories are conducting so that we could provide a real-time Understanding of what's going on in the immune system and then attempt to target our therapies to that There is a promise of immune modulation These are substances that modify or regulate the immune system. They can regulate that of inflammation They can enhance host offense. They can prevent organ dysfunction and they can restore immune function But it is a balancing act How do you carefully? Boost someone's immune system or create an anti-inflammatory effect to specific cytokine downstream effects Without inducing further injury We do know that for instance when individuals who have we think have hypo inflammation you give them corticosteroids You worsen their lymphopenia You make them susceptible to development of fungal and candidal infections And we've seen that time and again in a number of different disease entities including kovat most recently especially in places like India which saw an increase in Canada and fungal infection after high-dose corticosteroids and a Subpopulation that likely had profound immune suppression and so there's a balancing act of the mini of activation in sepsis so Currently if you look at what's going on in clinical trials There's more than 10 promising drugs that are currently in development as we speak Many in this audience probably do know though that there's been sort of a moratorium at the pharmaceutical level to want to conduct more sepsis trials and in part that's because we need to do a better job of creating the study design that reflects the biology of the disease and just not new clinical phenotypes But several drugs including monoclonal antibodies are likely to be marketed in the future And when I think about the different classes of immune modulators They certainly tackle many of the different perturbations that we see in a lot of the different organ failures including Sensors including things like plasma protein systems blood lymphatic cells vascular and tissue cells and then targeting specific type kind of chemokines and cytokines Cell dysfunction and then ultimately and invariably attacking things like refractory hypotension I'll be talking about some of the studies that have been done in some of these immune modulators The first one is not uncommon people are well familiar familiar with anakinra So when you think about enter interleukin anti interleukin therapy or IL-1RA IL-1 signaling is mediated by the two distinct ligands IL-1 alpha and IL-1 beta both which act on the IL-1 receptor to trigger inflammation IL-1 beta is mainly released by activated immune cells IL-1 alpha is nearly ubiquitous in alarm and released by injured tissue There was a retrospective analysis that was conducted with 529 sepsis patients that found that anakinra Significantly reduced mortality, but only when your baseline IL-1RA levels were above 2071 and you can see here in Shikori study in 2016 that there was no significant benefit unless you accounted for Understanding the immune defect that was leading towards potentially and driving the underlying disease There's a wonderful study, which I'll allude to later. That's going to use anakinra to a target in children Those patients that have a hyper-inflammatory state which I think is an important study that will hopefully hear great results in the upcoming years If there's one specific immune modulator that probably has the most data or at least the most trials anti-tnf alpha leads the pack with nearly 60 trials that have been conducted to demonstrate the efficacy Of anti-tnf alphas and IL-1 receptor antagonists before the turn of this century There was a meta-analysis that was conducted and i'm showing that here with your forest plot of 17 randomized control trials That involved more than 8,000 septic patients treated with anti-tnf And it did show a small But significant reduction in 28-day all-cause mortality And so when you look here at both these two subgroups by the different time point that these were conducted You can see that in fact there may be a benefit here But the effect was about 1.2 percent benefit and you like I said to demonstrate this in a large-scale clinical trial you would need almost 10,000 patients Probably one of the most famous anti-tnf alpha studies The monarchs study was a randomized control trial that was among 2,634 sepsis patients that were treated with a filamobab and it demonstrated a small modest but significant reduction If your serum IL-6 levels were greater than 1,000 How many people here commonly check IL-6 levels in their ICU? If you were to check an IL-6 level how quickly would you get that cytokine that ELISA result back? So you can see that there's a disconnect we certainly might have a drug that could work If it was deployed in the proper fashion perhaps with using things like an IL-6 level greater than a thousand And so it's certainly feasible that there may be a specific subset of people that might benefit from this therapy additionally azd9773 Looked at two different IV doses with adult patients with sepsis multi-center trials seven different countries Looking at mean number of ventilator free days and they did not see a difference between low dose and high dose nor placebo And the mortality rates were comparable across treatment groups This study did not look at those that had an IL-6 level greater than a thousand So let's move on to targeting the innate immune response or boosting the innate response with gmcsf gmcsf Enhances the host cell killing abilities principally through activation of neutrophils macrophages and monocytes Many folks would want to give this drug specifically where patients would demonstrate either decreased hladr Or decreased response to lps induced whole blood tnf alpha production demonstrating that the patient has underlying immune paralysis And so this drug could be beneficial in the correct population And so a number of different studies including this in 2009 Were specifically started to target By using monocytic hladr and you had to have below a certain level to be to get receive Randomization and then they looked at dose escalation based off that level And this is a busy slide But it does demonstrate that there was at least a signal in some of these immune effector cells including neutrophils monocytes cd4 cd8 Cells and nk and b cells there was some differences between the different groups But sadly, this was a phase one looking at safety and tolerability study. It actually was not Powered initially for mortality, but there was no major mortality benefit What about thymosine alpha it stimulates endogenous interfering gamma secretion and regulates t cells And so potentially using this drug could boost the adaptive Adaptive immune system and so in a meta-analysis of 10 randomized control trials with about 530 patients They did show a significant decrease in the thymosine alpha 1 group compared to control group But a phase 3 rct, which is a little over 1100 patients is currently Waiting for those results to be released But it could have some promise and so we await What about art123 which targets the coagulation system? This is a recombinant human soluble thrombomodulin a glycoprotein with a molecular weight about 64 000 daltons It has both anti-coagulation anti-inflammatory effects And one thing about this is that it could be used effectively in those patients that meet dic Parameters because it's got an inhibitory effect on pro-inflammatory cytokines so the scarlet trial was performed by and and bruno francois in 2021 and John, louis vincent published in jama two different studies and sadly There was no mortality benefit that was statistically significant with the use of thrombomodulin Similarly, there was an art123 study that has a phase 2 that was done in a little over 300 patients Also demonstrated non-significant reduced mortality, but what's most interesting in most of these studies i'm going to keep telling you about Is that many many if not, all of them actually had phase one safety data. That was promising They had they were tolerated quite well They just didn't demonstrate efficacy across the board. There was a phase three with this drug with 800 patients 28 day all-cause mortality was not statistically significant compared to placebo And then finally when we're targeting the endothelium with adrenomedulin targeted therapy or adres I can't pronounce it today, but each we'll go with what it says on the board here It's a recombinant monoclonal anti-adm antibody that protects endogenous atm from proteolytic decay It increases plasma half-life And it's well tolerated in the adrenos 2 study Enrolled almost 300 patients no difference in mortality Same is true for trem and and and Nagabotide same thing there's been multi-center trials that have been now done phase one phase two tolerated without issues And sadly no difference in mortality And then interleukin-7 buddy of mine. Richard Hotchkiss has been doing a lot of studies with interleukin-7 It's a pluripotent cytokine produced by the bone marrow. It's got anti-apoptotic properties It induces proliferation of naive and memory t-cells restores functional capacity of hyporesponsive and exhausted t-cells So Bruno Francois and Richard and a number of others Published this in GCI insights and what they demonstrated in this small study that IL-7 restored lymphocytes in septic shock It's the IR-7 study. They actually looked in randomized patients. They looked at different doses They demonstrated an increase in absolute lymphocyte count, but the study go back there. Sorry The study was not powered for mortality. So although two different doses demonstrated an improvement in lymphopenia It was not reflected because it was not powered for mortality This study is hopefully transitioning now to a large randomized control trial to be conducted in Australia and New Zealand And then finally Richard and others have also looked at use of anti-programmed cell death protein one and programmed self-delete ligand one or with using nivolumab or a checkpoint inhibitor And they've also conducted a phase one randomized control trial demonstrating that it's quite safe in patients with immune suppression They were able to dose this in 31 patients with septic shock Not powered but still did not demonstrate any benefit in mortality And then finally we're waiting for results of some of the new mesenchymal stem cell Control trials that are being ongoing. There's a phase one and phase two Here's the studies you can look at we're hoping that they will have not only safety profiles which have demonstrated in earlier studies But there could be potentially efficacy And I think this is a really interesting randomized control trial And I just would like to draw attention to the fact that this group actually did something unique Is that they were able to randomize 15 patients per group based off a ferritin level and HLA-DR And what was really unique about this is that based off those levels They were actually able to classify patients with immune paralysis Or hyper inflammation macrovage activation syndrome and then randomized you to recombinant interfering gamma or anakinra And this was a small study and so it wasn't also powered specifically for mortality But did demonstrate that there was perhaps an improvement in SOFA score This is one study Joe Carcillo and Mark Hall I think are doing this in well over a thousand children and it's a I think a very unique design because it takes into account the specific Immune defects and biology of the disease as we know it and can measure at the bedside and uses therapies specifically to that And that's called the PRECISE trial which i'll show you here And here's the clinical trial information if you're interested in learning more about this to me This is the way that we should be conducting randomized control trials for immune modulation And so although this is hard and i'm happy to to share this with some folks This is just a summary of different trials that have been conducted As i've mentioned sadly, we've not reached any efficacy, but I think that we haven't reached efficacy in these trials Because we're probably not targeting the right patients for the right drug Based off the biology that we see before us if we were able to deploy Many of the immune drug immune assays including use of ELISA or ELLA or ELI-SPOT Use of flow cytometry in somewhat real time and be able to actually apply those tests to effectively give patients Drugs that either calm down their hyper-inflammation Or actually boost their immune system when there's an issue And so sadly many of our randomized control trials for immune modulation have failed because we've used this one-size-fits-all Phenomenon and I think as time elapses we're hopefully going to move towards more targeting of patients specifically for those underlying defects And that's where we sit Thank you for your time

sepsis treatment

immune modulators

personalized medicine

immune profiles

PRECISE trial