SCCM Resource Library-Critical Care Immunotherapy

Video Transcription

Hi, this is Steve Pastoris from Memorial Sloan Kettering Cancer Center. I'm delighted to moderate this session on critical care immunotherapy.  The learning objectives of this session are to discuss the current applications of immunotherapy,  describe the adverse events and toxicities associated with immunotherapy, and discuss the future of immunotherapy.  Our speakers for this session are Alfred Ayala from Rhode Island Hospital Brown University School of Medicine, Christina Gutierrez from MD Anderson Cancer Center in Houston, Texas,  and Richard Hotchkiss from the Washington University School of Medicine in St. Louis, Missouri. I just wanted to first thank the Society of Critical Care Medicine and its organizers  for allowing me to present some of this information today and the invitation. With that, I have no relevant financial relationships to disclose that exist.  Also, I happily acknowledge many of the folks who have contributed to some of the things I'll say today, some pictured here in the pre-COVID time.  Today, I've been charged with talking about the basic science behind immunotherapy, especially  as it might apply to sepsis, and so I think it's worthy to start first with a definition of this process, immunotherapy, as we classically think of it as a treatment for a disease,  for example arthritis, autoimmune disease, cancers, by activating or suppressing the immune system.  So the therapies have to be designed to elicit either a response that amplifies or activates the immune response or suppresses it.  In this respect, we're going to talk about this in regards to sepsis, and sepsis is most recently defined, for all of you who already know this from the sepsis 3 discussion, is  a life-threatening organ dysfunction caused by a dysregulated host response to infection. Relative to the host response, we are most interested in discussing the immune aspect  of that response specifically and how it might be involved in balancing the response to infectious  challenge and tissue injury that lead either directly or indirectly to the organ dysfunction and death seen in these patients.  This cartoon simply is a depiction of how we sort of think about these responses as they go forward or the balance between the innate and adaptive immune responses that  are utilized to build an initial inflammatory response to a foreign pathogen which stimulates  and crosstalks to the adaptive or acquired immune response that eventually drives pathogen-specific clearance of the organism.  This acts in the face of ongoing immune resolution, which is usually upregulated almost concomitantly  with the activation of the immune system, and of course the development of wound healing response which is necessary after either infectious or surgical or traumatic injury.  Importantly, when we talk about this, most of the interest has circulated primarily historically  around the early deaths thought to be driven by hypothetically overwhelming inflammation. In this regard, I have to return to an old phraser term, systemic inflammatory response  syndrome, which while a little bit out of vogue, is important to think about when we think about early immune therapeutic modulation.  This is usually described as an inflammatory response affecting the whole body and frequently  as the response to the immune system or infection, but not necessarily just to infection. And historically, when we relate it to sepsis, in the past definitions it was a condition  in which the individual had to meet both SERS criteria as well as have a known infection. These are some of the characteristics of those infections, of the SERS response, and here  it basically drove a hypothesis that sort of drove early immunotherapy in the field for the last, I'd say, 40 years, that sepsis was induced by overwhelming inflammatory response,  which then caused significant tissue injury either directly or indirectly in the septic host that eventually caused this morbidity and mortality.  However, whilst numerous treatments based on anti-inflammatory suppressive or anticoagulant therapies showed promise experimentally, it largely failed to provide survival benefit.  This is simply a list taken from a review by John Marshall of some of these early anti-inflammatory immunosuppressive modulators that were tested and didn't show efficacy.  That said, if it's understood or thought that if patients survive this early phase where they get through this inflammatory response, they move into a state in which they develop  a persistent ongoing immunosuppressive state, which makes them more susceptible to secondary  infections and becomes a part of what we now call persistent immunosuppression and chronic catabolism.  So with that I'll spend the rest of the time talking about this aspect as a target of immunotherapy.  So my objectives with the remainder of the talk will be briefly to overview the process  of antigen presentation as it juxtaposes the innate and adaptive immune arms, define immunosuppression  or paralysis as we see it in sepsis, give some examples and then overview the basic science aspects of immune-activating therapies as opposed to immunosuppressive therapies.  Antigen presentation, this was described over 50 years ago by Lafferty and Cohen and is basically thought to be a two-trigger process, though I do indicate a third aspect of this  which is where the pattern recognition and foreign pathogen recognition and recognition  of necrotic tissue comes into it as an activator or stimulator of almost all of the cell components in antigen presentation.  That said, antigen presentation, as I said, is a two-trigger system. First is processing of a foreign pathogen's antigen, like bacteria, virus, or whatever,  through MHC class I to the T cell receptor, but this signal by itself is not sufficient to drive it.  What is needed is a licensing signal and that's the second component of antigen presentation.  This historically was thought of as a secreted mediator early on, but now it's much clearer  that this is due to the interaction of this family of proteins called checkpoint mediators  which can be co-stimulatory or co-inhibitory in nature and they act to license the antigen-stimulated  T cell to drive the eventual cell-mediated immune and the moral immune components of the adaptive immune response necessary to clear a foreign pathogen.  With that in mind, we will look at a few examples of what immunosuppression looks like in the septic patient.  This is simply a definition of immunosuppression as a deliberate or non-deliberate action that leaves or alters the efficacy of the immune response.  Initial descriptions, at least in traumatized or septic patients, go back into the 60s and  70s and these are some of the general characteristics, loss of development of energy, depressed recall  antigen response, leukopenia, leukocytosis, failure to clear infections, decreased monocyte HLA-DR, reprogram or deactivation of cytokine and proliferative responses, and increased  expression of anti-inflammatory mediators and these cell-associated inhibitory checkpoint proteins as well as tectonic material expression.  Some general examples from the literature looks a little like this. This is work from Vinay and colleagues which can show you what the decline in T cell proliferation  looks like in the septic patient when compared to healthy volunteers. Here we show an example of lymphocyte deactivation from the recent study by Hodgkiss in which  he used an ELI spot to show that non-surviving septic patients showed inability to produce cytokine in response to stimulus, in this case interferon gamma and there's the summary  data to the right. This data from Heffernan and all illustrates that the sustained decline in leukocyte and  or lymphocyte numbers is associated with a poor outcome in patients and that can be seen in the red line here.  Patients specifically that do not show a rebound in their lymphocyte numbers almost always show a marked increase in mortality versus patients that show a rebound or no change  in lymphocyte numbers over time which do typically better. This is probably due to the onset of leptosis. This has been studied by a number of groups including our own lab.  It occurs in lymphoid cells as well as myeloid cells and non-immune cells and has been demonstrated in both mouse and human and experimental models.  The sustained decrease in HLA-DR or MHC class II has been associated consistently with pro-prognosis in a variety of different settings.  This is simply data from Vernet et al. in burn injury illustrating that point. And then there's alterations in a variety of regulatory cell populations that can be  immunosuppressive like the T regulatory cell which survives in sepsis while its compatriots effector CD4 cells do not do so well.  Also studies have shown expansion of other cell populations. Here is simply an illustration of the extended increase in myeloid suppressor cells, myeloid  derived suppressor cells from the Moldauer-Effron group and their impact. What others have shown as well as our cells that macrophage monocyte reprogramming exists  and is seen in the form of shifting from M1 to a more anti-inflammatory M2 phenotype, the role of invariant natural killer.  T cells has been seen and recently involvement of innate lymphoid cells such as ILC2s represent  another set of regulatory T cells which shift from a pro-infective to an anti-infective Th2 type phenotype.  This has induced a concept of an alternative hypothesis to the early one I mentioned of modulating aspects of developing trauma shock in sepsis that should improve the capacity  of the critically ill animal to ward off the morbid effects of sepsis. So let's in the final few minutes go through some examples of some of these.  Very quickly the first thing I'll talk about is as I mentioned in Andrew's presentation secretory mediators or growth factors were thought to be important potential co-stimulants  of this process early on. So these were things folks focused on. An example are the interferon and granulocyte macrophage colony stimulating factor family of GMCSS and GCSL.  These were looked at as cytokines that had marked effect on monocyte function in the lab as well as in ex vivo patient materials.  However, in sepsis trauma preclinical trials these agents were somewhat good at consistent  and restoring indices of myeloid dysfunction and reducing infectious episodes to not consistently produce effective overall change in mortality.  People have gone on to look at other cytokines more directed in this case at BMT cell lymphocyte stimulation. An example here is IL-7.  This is the work of Caldwell and Hodgkiss and they demonstrated some time ago that the onset of cell death or leukocytosis in the form of apoptosis or changes in decline in  proliferative capacity to antigen that are seen in sepsis could be modified in at least the experimental setting by adding a cytokine IL-7 back to these sick animals.  This also had a protection on survival. This has resulted in a small phase one clinical trial that has shown that IL-7 can be well  tolerated without inducing more inflammation or organ damage and does have sustained capacity to alter T cell proliferation, however, it was underpowered to really determine if it  had an effect on septic survival. IL-15 is another cytokine of interest and that's been looked at by the Hodgkiss group  here simply looking at apoptosis or cell death and in the septic animals it rises. In the treated animals with IL-15 it can be decreased and again protection is produced  by treating these animals in the experimental setting. So this might also be another agent of interest.  That said, in the final moments I'll talk very briefly about the impact of checkpoint proteins and these cell-bound co-stimulants and co-inhibitors as their use in immunotherapy  in potentially in the septic individual. Some points about membrane-bound co-stimulants, they come in a variety of flavors, in fact there's almost 150 of them now.  Best known are the B7 superfamily, then there is the TNF receptor family and then finally the CD1 superfamily and the selectin family.  Importantly this has historically been thought about primarily in antigen presentation and how antigen-presenting cells talk to T cells, but I want you to see, you'll see that the  data also says that they talk back to the antigen-presenting cell and they're used in talking between non-outside of T cells, between various myeloid compartments as well  as between non-immune compartments there's this interplay. So we'll use probably the best known of these, especially from cancer therapy which  is programmed cell death one, is an example of this kind of therapy and this is simply a little background data on this.  Our group showed using knockout mouse technology some time ago that you could protect animals from the morbid effects of experimental sepsis, here's the GI tract as an index.  Then we could also show that you could decrease the ectotic effects that CLP produced on these immune tissues and that you could reduce bacterial burden which said that there were  probably impacts on myeloid cells as well as T cells which are normally what we think of when we think of checkpoint therapy in cancer.  Which immune cell populations express PD-1 we could show and others could show that is both seen in lymphoid compartment as well as in some aspects of the myeloid compartment.  And that you can also see this in patients' myeloid cells following septic insult. You could also show that this appeared in neonates using an experimental model as well  as using in an autopsy study we've recently been able to show that in lung biopsies of children who died, neonates who died within 24 hours of birth that there were marked up  regulations with this marker. Hodgkiss and colleagues have shown that antibodies against TNF can alter, can alter, provide  protection against ectosis and restore immune functionality as well as provide a survival benefit in mice and that ex vivo patient samples could be protected.  What about the various ligands? Some quick examples, both PD-L1 and PD-L2 are expressed. However there really is only an advantage using gene deficiency with PD-L1 animals versus  PD-L2 animals which don't seem to provide a survival benefit. Which populations express these ligands? Some examples are here.  It's a large set of various myeloid cells, neutrophils, macrophages, natural killer cells as well as some T cell populations.  This is simply data from a study showing that it's not just leukocytes that express PD-L1  but it can also be seen on parenchymal cells of septic biopsies from patients in that situation.  This is related to organ dysfunction here showing that the GI tract is quite permeable following sepsis in an experimental mouse but PD-L1 gene deficiency attenuates that.  We can also show that endothelial cells using a model of acute lung injury and selective delivery of siRNAs against programmed cell death ligand one or PD-L1 can protect the  animal from these septic, from these injury to the lung and that this is largely due to  targeting of endothelial cell expression with this, again suggesting non-immune cell expression. That said, it's not just these checkpoint proteins that seem to be protective.  Other groups have shown that CTLA-4, 2B4, HVM, BTLA all can be leveraged for protection. Some final aspects are that these ligands as I mentioned are expressed both on immune  and non-immune cells but they also signal both in a trans and interestingly potentially  in a cis fashion which may speak to the unusual biology in a potentially non-redundant activity of some of these ligands. That's simply illustrated in this slide.  And finally, we have data from a last receptor that we've looked at called VISTA and this  is a receptor that seems to have again multiple ligands or pernicious ligand binding but again  we can show that both in mice and in humans that are septic, you can see upregulation in their residual T cell compartment and this is also seen in a model of acute lung injury  in a variety of cell populations, both myeloid as well as non-myeloid endothelial cell and epithelial cells of the lung.  Interestingly, this doesn't provide protection like the other molecule. If anything, it actually makes things worse for survival experimentally and we think that's  due to the role of these regulators on the pro-inflammatory side because there's a marked increase of potentiation of pro-inflammation in this system.  This appears to be related to the upregulation of Tregs and VISTA-expressing Tregs versus the decline of gamma delta T cells expressing this molecule.  So in summary, I think we can show that the expression of these various checkpoint proteins  appear to contribute to the morbidity and mortality seen not only in the acute experimental model of lethal shock and septic challenge but are also frequently elevated in trauma  and ARDS. The ligand interactions are somewhat promiscuous and that also while most checkpoint protein  ligand interactions are classically trans, there are many of these that are cis interactions and their biology remains to be determined.  And while some redundancy exists, there is clearly also some select cellular expression and functional distinct activity that needs to be considered when understanding these  molecules.  And depending on the inhibition of which molecule you use and in which type of patient, it may be possible to sway the outcome of bacterial infection and influence the antimicrobial  defense.  And as I mentioned, these are upregulated also on leukocytes as well as non-immune cells.  And finally, hopefully, Dr. Hodge just will touch on the observation that many of these checkpoint proteins as they've begun to be used in cancer therapy have allowed us leverage  to potentially begin to look at their value in the septic individual.  Thank you very much. And thank you for inviting me to give this talk. I'm Cristina Gutierrez. I'm one of the critical care associate professors at MD Anderson Cancer Center.  And I'm going to be talking about toxicities of immunotherapies and how they present in the ICU, a new horizon in oncological critical care.  These are my disclosures.  And we have three main objectives. We're going to be reviewing the different type of immunotherapies that are used for  cancer patients currently and the pathophysiology of these toxicities.  We'll review some of the most common toxicities that lead to a high morbidity and ICU admission.  And we'll discuss overall some of the treatments that are used for the majority of these toxicities.  So just to give you a little bit of background, at this point, there's been a shift of treating cancer with chemotherapy and moving more towards a more targeted cancer therapy.  And this has led to really good outcomes in patients with refractory malignancies. However, we're observing more and more toxicities that are very specific and very  unique, some of them which are leading to ICU admission and mortality.  When you think about immunotherapy, there's a broad spectrum of these types of therapy.  However, the three main ones that will probably cause ICU admission include monoclonal antibodies,  in which there's an antibody which is designed so that it recognizes a specific antigen of a specific type of cancer.  Immune checkpoint inhibitors, which were, even though they're a type of monoclonal antibody, we're going to be referring to them in their own, like, separately.  The reason is because their type of toxicities are very unique.  And checkpoint inhibitors, what they do is they will bind to CTLA-4, PD-1, and PD-L1, all of which actually inhibited T-cell activation.  While blocking these receptors, what actually happens is T-cells get activated, and this way you can have an increased activity against tumors.  And the third one is immunofactor cells, which we all know, such as CARs or CAR-T cells.  These cells, what usually happens is you take cells from the patient or from somebody else, and they're modified so that they express a portion of an antibody that will recognize  a specific antigen.  The ones that are known the most and that are currently FDA-approved are CAR-T cells, CD20, which are used for B-cell malignancies.  So when you think about it, these types of immunotherapy have moved from being the type of treatments that were used only on specialized centers and that were only experimental.  And at this point, what we're observing is that they're being used widely and for multiple malignancies.  As you can see here in the charts, you know, it's been an exponential growth in the amount of monoclonal antibodies that are now available and approved by the FDA, and all of these  are different type of CAR-T cells and TCRs that are currently being studied, and more and more are being approved by the FDA for the use of different malignancies.  So this is something you will be observing in your ICU.  Now, why do these toxicities occur? So you can say that probably one of the effects is receptor dependence, such as the case of  rituximab, CAR-T cells, and bevacizumab, in which once you actually bind to a specific antigen, that has a specific effect on the patient's body.  The other side is an inflammatory response. This inflammatory response, we actually observe it pretty much with all of the immunotherapies.  So with CARs, once they get activated, they proliferate and lead to CRS and neurotoxicity, immune checkpoint inhibitors, as they block these receptors, there's an overactivation  of T cells that doesn't only affect the tumors, but it also affects other organs.  Regarding the clinical presentation, you know, it's really a broad presentation and as you can see here, pretty much every single organ can be affected by any one of these  therapies. So it's important to have them as part of your differential diagnoses. The presentation varies. In CARs it can present usually within seven  days after infusion of the cells, but as late as 14 days. Monoclonal antibodies usually days or even hours when you're talking about more of an infusion  reaction, and weeks to months when it comes to immune checkpoint inhibitors, usually three months, but sometimes as long as up to a year. Incidents, it's  fairly common with CARs. Severe toxicities present within 30 to 60 percent of patients. When it comes to immune checkpoint inhibitors, severe  toxicities are a little bit rare, but it can be as common as 12-10 percent, and it varies for other type of monoclonal antibodies. Data on risk factors, it  depends on the type of therapy that you're actually using, and there's still studies ongoing, but usually a tumor burden is actually an important factor.  So what are the main toxicities that you're going to observe? So cytokine release syndrome, you're going to be observing with monoclonal antibodies  in CARs with a different timeline according to each one of them. It can be very similar to infusion reactions when you're thinking about monoclonal  antibodies, but it will usually lead to multi-organ failure as it actually progresses, and there's a triad of presentations including hypoxemia led by  pulmonary edema, fever, and hypotension or shock, and later on, as I said, multiple organs can be affected. When it comes to pulmonary toxicities, all of them  can actually be caused. Immune checkpoint inhibitors can cause pulmonary toxicities between one to ten percent of patients. The  majority of patients present mild presentations, but they can have a mortality as high as fourteen percent, so it's important to keep it in the back of  your mind. As you can see here, you know, the presentation varies when it comes to imaging, so it's also important to take into account other type of infections or  even other diseases that can actually cause presentations like this on imaging. Immune effector cells can cause hypoxemia, mostly due to  non-cardiogenic pulmonary edema and pleural effusions, and there's reports of on-target of tumor toxicity leading to respiratory failure. Monoclonal  antibodies can give you pneumonitis and bronchospasm in the case of retoxema, and thromboembolic events have also been reported with some.  Cardiotoxicities, when it comes to immune checkpoint inhibitors, the presentation is broad. They're fairly uncommon, and I'm going to talk mostly about  myocarditis, as it's definitely fulminant if left untreated, even though it's extremely rare. Its mortality is actually even higher when you compare it to  myocarditis caused by viral infections, for example, and the workup should be the typical that you do for any other patient, which can include also cardiac  MRI and biopsy if needed. One of the things that I would want you to know is that you can still have severe cardiovascular events and death, even in  patients that have a normal echocardiogram, so you need to take the whole picture into account and not rule it out just because your echo is normal.  Immunofactor cells, they usually present with cardiomyopathy and arrhythmias, and shock is also presented in the case of CRS. And monoclonal antibodies, you can  have ischemic events, either from thrombosis, basal spasm, or Cooney syndrome, which is a type of allergic reaction. Arrhythmias have been  described, cardiomyopathy, such as with rituximab, and shock secondary to infusion reactions. In neurotoxicities, they're rare, however, as more patients  are being treated, the incidence have actually increased. What is important is that these patients have a very high significant morbidity and mortality. The  majority of these patients don't really have neurological recovery, only less than 13% do, and more than 50% of patients are dead after three months. As  you can see here, the presentation is broad, from Guillain-Barré, myasthenia, PRESS, transverse myelitis, cerebral edema, so it's important to have a broad  differential diagnosis and make sure that you're treating other causes for any of these presentations concomitantly. The neurotoxicity from CARS, it's very  typical. It usually appears within a week or so after infusion of the cells, and once you see a patient, you'll never forget it. They start with decreased  attention, some mild aphasia, and very quickly progress to global aphasia, seizures, status epilepticus, and in some cases, it can be severe and cause cerebral  edema. And monoclonal antibodies, some have described ICANS, strokes, PRESS, and aseptic meningitis. Other organ toxicities that you'll have to keep in  the back of your mind, you know nephrotoxicities from both monoclonal antibodies and immune checkpoint inhibitors, and even with CARS.  Endocrinologically, I guess it's important to note that immune checkpoint inhibitors can cause panhypopituitarism, with your patients having hypo or  hyperthyroidism, adrenal crisis, DI, and nuanced diabetes has also been reported with patients presenting as DKA or HHS. GI has also been reported, and HLH, which  can be, even though it's rare, it's been reported with all of the types of immunotherapy. When you're talking about treatment, you can sort of have a  general approach. Fortunately, there's multiple guidelines that have been published for the treatment of these therapies and their toxicities. However,  in general, you know, I would want you to take into account that, you know, supportive care by the ICU, rapid diagnosis, and close communication with the oncologist  are going to be extremely important. Due to the broad presentation of these patients, your differential diagnosis is going to be very broad, so it's going to  be important that while you keep this in the back of your mind, toxicities from the therapy, at the same time you're also diagnosing most common  causes for any of these other toxicities or causes of organ failure concomitantly and making sure that you're treating these patients. In the  case of immune checkpoint inhibitors and monoclonal antibodies, you should discontinue the agent when you're talking about grade 3 and 4 toxicities.  And overall, you know, we recommend immunosuppressive therapy, corticosteroids and anti-cytokine therapy, which has been used with most of the toxicities. For  those patients that are refractory, you can use cyclophosphamide, tacrolimus, microphenolate, and plasmapheresis and IVIG, which has been recommended in the  majority of neurotoxicities from immune checkpoint inhibitors. It's important to note that about 10% of the patients with severe toxicities from immune  checkpoint inhibitors will not respond to corticosteroids, so it's very important to have clear guidelines within your institution or at least have a close  communication with your oncologist so that you know how to treat those patients that are showing that they're refractory or that they're extremely ill  and you actually have to act quicker and be more aggressive when it comes to immunosuppression.  So in conclusion, you know, these new therapies are changing the spectrum of the presentation of the oncological patients in the ICU. Our most common  clinical presentations when patients get admitted to the ICU, such as respiratory failure, arrhythmia, shock, can now present from any of these other therapies. So  it's very important that you have to do a good review of what cancer therapies the patient has received recently and make sure that this is not one of the  potential causes. As always, you know, discussions with the oncology are very important, but in this case, you know, it's going to have to be constant and  persistent and very close so that you can have a good plan of care for these patients. And in general, you know, some of the factors that we use for the  oncological population sort of decide whether or not if you should continue aggressive care, such as stage of the disease, respiratory failure, acute  kidney injury, might not be good guidelines in this type of toxicities, taking into account that a lot of these patients, the toxicity might be  reversible when you consider, for example, CRS or you consider ICANS or some of the toxicities from the monoclonal antibodies. Therefore, you should be  taking more into account whether or not if reversibility from this toxicity is possible before discussing prognosis. I'd like to thank you all for the  invitation, and I hope this was useful. Hi, this is Dr. Richard Hodgkiss. I'm very honored to be able to speak to you  today on clinical implications of immunotherapy. I have some disclosures. I'm a PI on a clinical trial with IL-7 and sepsis and COVID-19. The other  important one really is we're an NIGMS-funded award, SPIES award, multi-center trial in which we're using the ELISPOT assay to immunophenotype  patients with sepsis. There's a patent pending from WashU, University of Florida, and University of Cincinnati with Dr. Moldauer and Caldwell.  As you know, sepsis is a protracted immunologic defect with frequent readmissions to the hospital for new infections. I think there's a great  deal of evidence that one of the key pathologic defects in sepsis is the profound immune suppression which occurs in a large number of septic patients.  I believe that this fact that sepsis, the defect, persists for a considerable length of time and also that the patients, as shown here on this slide,  a very high readmission rate really highlights the remarkable degree of immune suppression. In this particular study of over 3,000 patients, about  42.6% of those that survived sepsis were re-hospitalized within 90 days.  The majority of these readmissions were for secondary infections.  Even more startlingly, only one of five severe sepsis survivors remained alive for one year after being discharged without again being readmitted to the  hospital. This shows you the problem with a protracted immune deficiency.  Because of this, you can make a strong argument for targeting the host to combat sepsis. This is really a new paradigm. The old paradigm being so  much of the focus was on the antibody, on the antibiotics and new medications.  However, when you consider why does targeting the host make good sense?  First of all, patients with weakened immune systems, the elderly, patients with comorbidities or alcoholics have the highest mortality from sepsis.  The elderly patients have immunosenescence and the alcoholics and poorly nourished, these are the patients who have the highest incidence in mortality due to their weakened  immunity. Boosting immunity with drug therapies may also be effective in decreasing secondary  infections, which from the previous slide I showed you was such a high incidence and big problem in patients with sepsis. The other advantage to boosting immunity as a way to  control sepsis is that if you can improve host immunity, it will provide protection against a broad range of pathogens, including these multi-drug resistant pathogens, the Canada  oris and others, which are becoming much more problematic in the ICU and which really are  target patients with weakened immune system. To show you the potential power of boosting the  immune system, I'm going to briefly describe this one case report that I was involved in. It was a patient, a 30-year-old female who was, if you remember the Brussels  terrorist train attack in March, 2016, this patient had a bomb blast victim,  severe pelvic femur fractures, a lot of abdominal pelvic soft tissue injury, and some second degree  burns. Her hospital course was complicated by some sepsis, osteomyelitis, and these deep wound infections. Particularly the one that was proving to be the most protracted and  threatening her life was a mucormycosis involving the abdominal viscera. She was on appropriate  antimicrobial surgery. The surgeons tried the best they could to get source control. They did a gastrectomy, splenectomy, and the tissue pathology showed recurrent mucormycosis.  They could not do any more debridement because it was sort of encasing around the great vessels. They did immune phenotyping, and they showed that the patient had a low  antigen presentation molecule, HLAPR, the low absolute lymphocyte count, and evidence of lymphocyte exhaustion with increased PD-1 expression. Based upon this,  they began anti-PD-1 therapy with nivolumab, the checkpoint inhibitor used in cancer, and interferon-gamma on a compassionate basis. The patient slowly improved. She had resolution  of her sepsis and resolution of her mucormycosis. This patient almost certainly would have expired  without. These are usually lethal infections when they're failing surgery and antimicrobial therapy. There was another trial that Bristol Myers Squibb conducted in which they tested  nivolumab in sepsis. These were patients in septic shock. There were 31 patients treated. It was not  a placebo-controlled trial. They were trying to move rapidly to get nivolumab, the trial underway.  They had planned 1,100 patients. They had done a number of trials with other drugs.  In this study in which there were two different doses of nivolumab, the 480 milligrams and the  960 milligrams, the mortality, you can see here at the top panel, was 40% in the patients that got  the 480 milligrams and 37.5, so a combined mortality of 38.7%. I would emphasize these  were patients in septic shock who had very low absolute lymphocyte counts, which identifies them  as a very high mortality expected, at least 40% to 50%. The drug overall was well-tolerated.  None of the deaths were considered to be related to study treatment.  There was no, importantly, evidence for any safety findings or cytokine storm. That was the issue.  Would we have cytokine storm? Sepsis can be considered a race to the death between pathogens  and the host immunocells. This is the kind of way I like to look at it. The pathogens over here,  you see on the left part of the panel, these gram-negative frauds, are fighting against the lymphocyte in the top upper right-hand corner, the neutrophil, and the monocyte.  The key question is, how do we reengage host immunity?  Our lab and many others have spent a great deal of effort looking at the role of the lymphocytes  in sepsis and have shown that in sepsis, I didn't have time to go into it, there's profound apoptosis,  loss of the lymphocytes. In this particular study, we looked at over 529 patients who had severe  sepsis or septic shock. We averaged their absolute lymphocyte counts throughout their hospital  course. We did divide the results up into quartiles. In the blue quartile, as you can see  here, had the lowest absolute lymphocyte count. It was less than 700 lymphocytes per microliter.  They had the highest mortality. It was approximately 50% at 90 days. The second group that had the absolute lymphocyte count from 0.1 to 0.7 to 1,000 lymphocytes per microliter  had the next highest mortality. You can see a clear relationship there, the most lymphopenic.  This was a study from Dr. Ayala's group and with trauma patients. They said, after trauma,  if you fail to normalize your lymphocyte counts, it's associated with increased mortality. You can  see the patients with the highest mortality of approximately 30% had the lowest absolute  lymphocyte count. One of the drugs that we're looking at as an immunotherapy is interleukin-7.  It's a cytokine that's been now used in almost 500 patients. Basically, what it does is it increases the number and function of your lymphocytes. Here you can see a study in HIV  patients in which three different doses of IL-7 were administered. I'm sorry, there were three  different doses of IL-7 administered at once a week intervals for three doses. You can see there  was a dose-dependent effect of IL-7 on the left-hand panel to increase CD4 T-cells quite significantly, two to three-fold higher. Then on the right-hand panel, the CD8 T-cells.  It was a persistent protracted increase. We did a clinical trial of IL-7 in patients with sepsis.  This was a trial, one of the few trials in sepsis testing therapies that enhance immunity.  It was the first therapeutic trial targeting cells of the adaptive immune system, CD4 and CD8.  It was a randomized double-blind placebo-controlled trial conducted in France, at Limoge in Lyon, and in the United States. Ed Sherwood was our PI on this out of Vanderbilt. We were  a site at Washington University. There were 27 patients. We were looking at safety and the ability of IL-7 to increase this. There were two different dosing regimens, IL-7  either once a week or twice a week. You can see that in the red and the blue, that the IL-7  caused a nice restoration of the absolute lymphocyte count. Here, you can see that in the gray shaded areas, the normal range for most hospitals for the absolute lymphocyte count,  and that IL-7 caused a very nice restoration, either both regimens of IL-7 to the upper range of normal versus the placebo, the black line, and it was sustained.  The IL-7 was well tolerated. The only adverse effect was a gray two to three rash. It increased  T-cell proliferation, activation, and adhesion models. This was a small study. The mortality,  two of 10 of the placebo and five of 17 for 29% of the IL-7 treated. Interestingly, three of the  IL-7 patients that died had failure of source control, and this taught me a lot of things.  The future, we believe, is immunophenotyping septic patients. The key to knowing how to treat the septic patient is are they immune suppressed, and how severely are they depressed,  and innate and adaptive immunity. We believe that the ELI spot assay, it's called the immune  system in addition, it's a functional assay. As I'll show you, it assesses the ability of  the immune cells to produce key cytokines. The spot number is the number of cells producing in  the spot size, the amount of cytokine produced here. Here you can see the ELI spot microwells,  and we can stimulate the T-cells with CD3, CD28 to produce interferon gamma, or you can capture TNF-alpha instead if you use LPS. By looking at the increased versus decreased  response, change in number and cell size, you can get a good idea of the function of the immune  cells. Looking at here, individual cells and cytokine production over time. We recently,  just last month, had a paper published in Journal of Immunology in which we looked at healthy  patients, critically ill non-septic patients, septic survivors, and septic non-survivors. The patients that died are the red dots here. You can see that the septic non-survivors  had much fewer. This is looking at interferon gamma production. It's expressed as two different  ways, spot forming units per microliter of whole blood and spot forming units per thousand lymphocytes. Either way, there was a pretty significant decrease in the number of spots  in the septic patients who died versus the septic survivors. Here you can see we had, this was from our IL-7 trial, and you can see the baseline interferon gamma here to your left.  The patient that had three doses of IL-7, you can see the baseline interferon gamma production  was markedly improved. This was done in duplicate. The good thing about the ELI spot, you may be able  to use it to track your immunotherapy. We recently completed a trial of IL-7 in patients that were  critically ill on ventilators with COVID, and you can see, once again, the IL-7 in the yellow dots caused a nice increase in the absolute lymphocyte count in patients with the COVID  disease. The IL-7 was well tolerated in this particular study. There was no induction of fever.  Our increase in cytokines or decrease in lung function, and there's a multi-center trial  underway now with this. The clinical implications here, we had a recent paper Dr. Opal and I did,  activating immunity to fight a new path. The current paradigm is target the pathogen, antibiotics, antivirals, or antifungals. We believe this is obviously still the most critical  approach. However, we do believe that a new paradigm in which the patient's host immune system will also be evaluated using a variety of methods. We think that ELI spot could be  one very promising. Then, if you document weakened immune system,  targeting the different cell types with drugs which restore T cell function, IL-7 or the  checkpoint inhibitors, or if there's more innate immune dysfunction than a GM-CSF interfering gamma. We believe this combination will eventually become to be the important  approach. In conclusion, sepsis evolves into an immunosuppressive condition.  Immunoadjuvant therapy offers great promise in infectious disease. Consider immune therapy in selected patients with lethal intractable infections on a compassionate basis.  We have a patient in the surgical ICU I was just attending, one who was dying of invasive fungal  infection. We started that patient in IL-7. Clinically, the patient had a very good response  to that. It's an NF1, but there are a number of reasons why I believe that the patient did respond  to the IL-7, helping to get control of the infection. The key to immune adjuvant therapy is a method to rapidly evaluate and follow the robustness of innate and adaptive immunity.  A number of immunoadjuvants are likely to be successful in sepsis, but we believe that IL-7  and anti-PD-1 are particularly attractive because they're well-tolerated and have broad effects on  immunity. I'd like to thank my lab. I always say I have the best lab in WashU. A lot of people agree  with me. A great group. I'd also like to thank Dr. Ken Remy, who's been a close collaborator for  the last several years and both collaborate and has helped in every aspect of the trials,  studied design and outline in every way. He's been a phenomenal colleague. Dr. Monty Mazur also, who's been in the lab the last two years and really helped drive the LA-SPOT studies  and has been highly innovative and is first author on the J-I paper. I think that's  the conclusion of my presentation, and I'd be happy to answer any questions. Thank you very much for this opportunity.

Video Summary

In this video transcript, three different speakers discuss the topic of critical care immunotherapy. The first speaker, Steve Pastoris, introduces the session and the learning objectives, which include discussing the current applications of immunotherapy, describing the adverse events and toxicities associated with immunotherapy, and discussing the future of immunotherapy.<br /><br />The second speaker, Alfred Ayala, discusses the basic science behind immunotherapy as it relates to sepsis. He defines immunotherapy as a treatment that activates or suppresses the immune system to treat diseases such as arthritis, autoimmune disease, and cancer. He explains that in sepsis, immunotherapy is focused on balancing the immune response to infections and tissue injuries that lead to organ dysfunction and death. Ayala also discusses the role of antigen presentation, immune suppression, and immune-activating therapies in sepsis.<br /><br />The third speaker, Christina Gutierrez, focuses on the toxicities of immunotherapy and how they present in the ICU. She explains that immunotherapy, such as monoclonal antibodies, immune checkpoint inhibitors, and immune effector cells, can cause a range of toxicities affecting various organ systems. She emphasizes the importance of rapid diagnosis and close communication with oncologists when managing these toxicities. Gutierrez also highlights the potential of immunosuppressive therapies, such as corticosteroids and anti-cytokine therapy, in treating the toxicities.<br /><br />The video concludes with Richard Hotchkiss discussing the clinical implications of immunotherapy. He emphasizes the importance of targeting the host immune system in sepsis, particularly in patients with weakened immunity. Hotchkiss discusses the potential of immune-boosting therapies, such as interleukin-7 and checkpoint inhibitors, in improving host immunity and decreasing secondary infections. He also highlights the use of immunophenotyping, particularly the ELISPOT assay, to evaluate and track immune function in septic patients.<br /><br />Overall, the video provides an overview of critical care immunotherapy, including its potential applications, associated toxicities, and future implications for sepsis treatment.

Asset Subtitle

Immunology, 2021

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2021 Critical Care Congress held virtually from January 31-February 12, 2021.

Learning Objectives

Discuss the current applications of immunotherapy
Discuss adverse events and toxicities associated with immunotherapy
Discuss the future of immunotherapy in critical illness

Biologic Basis of Immunotherapy
Alfred Ayala

Complications of Immunotherapy in the ICU
Cristina Gutierrez

Clinical Applications of Immunotherapy in the ICU
Richard Hotchkiss

Meta Tag

Content Type Presentation

Knowledge Area Immunology

Knowledge Level Advanced

Membership Level Select

Tag Autoimmune Diseases

Tag Oncology

Tag Infectious Diseases

Year 2021

Keywords

critical care immunotherapy

applications of immunotherapy

toxicities

sepsis

immune response

organ dysfunction

monoclonal antibodies

rapid diagnosis

immune-boosting therapies

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