Cytokine release syndrome Flashcards
What is cytokine release syndrome?
Cytokine release syndrome: a (severe) systemic inflammatory response that is triggered by infections or certain drugs. Term was first coined in the early ‘90s during a trial for an immunosuppressive treatment for solid organ transplantation.
When has therapy-associated cytokine release syndrome been described?
Immunotherapy-associated CRS that have been described:
•After infusion of several antibody-based therapies:
oAnti-thymocyte globulin (ATG), the CD28 superagonist TGN1412, rituximab, obinutuzumab, alemtuzumab, brentuximab, dacetuzumab, nivolumab
•Following administration of non-protein-based cancer drugs:
oOxaliplatin, lenalidomide
•Haploidentical donor stem cell transplantation, graft-versus-host disease
•T cell engaging immunotherapies:
o Bi-specific antibody constructs, chimeric antigen receptor (CAR) T cell therapies
What is the clinical presentation of cytokine release syndrome?
Clinical presentation is quite broad:
•Wide spectrum: From mild (flu-like) to severe (septic shock-like) life-threatening
•Mild:
o Fever, fatigue, headache, rash, arthralgia, and myalgia
•Severe:
oHypotension, high fever, circulatory shock, vascular leakage, disseminated intravascular coagulation, multi-organ system failure, ARDS (Acute respiratory distress syndrome)
•Laboratory:
oCytopenias, elevated CRP, creatinine and liver enzymes, deranged coagulation parameters
o High serum cytokine levels:
TNF
IFN-gamma
IL-6
Later/second wave: IL-10
What is the epidemiology of cytokine release syndrome?
Epidemiology:
• The incidence of CRS in patients receiving cancer immunotherapy varies widely depending on the type of immunotherapeutic agent.
o With most conventional monoclonal antibodies the incidence of CRS is relatively low, whereas T cell engaging cancer immunotherapies carry a particularly high risk of CRS.
• The onset of CRS can occur within a few days, and in the case of CAR T cell therapy, up to several weeks after infusion of the drug.
Although most responding patients experience at least some degree of CRS there seems to be no direct association between the severity of CRS and clinical response.
Some patients show complete remission without obvious signs of CRS, while other patients display severe symptoms and laboratory abnormalities but no clinical response.
What are predictors of cytokine release syndrome severity?
Predictors of CRS severity:
• Disease burden:
o Many CRS-inducing agents display a “first-dose effect”, i.e. the most severe symptoms only occur after the first administered dose and do not recur after the subsequent administrations.
• The administered dose of the active agent
• The strength of T cell activation
• The degree of T cell expansion
• Children seem to be at a higher risk of developing CRS than adults
• There might be a genetic predisposition
What is the cause of cytokine release syndrome?
CRS is usually due to on-target effects induced by binding of the bispecific antibody or CAR T cell receptor to its antigen and subsequent activation of bystander immune cells and non-immune cells, such as endothelial cells.
Activation of the bystander cells results in the massive release of a range of cytokines.
Depending on a number of characteristics of the host, the tumour, and the therapeutic agent the administration of T cell-engaging therapies can set off an inflammatory circuit that overwhelms counter-regulatory homeostatic mechanisms and results in a cytokine storm
Which cytokines are involved in cytokine release syndrome and what do they cause?
Cytokine release syndrome is triggered by the massive release of IFN-γ by activated T cells or the tumour cells themselves. IFN-γ causes fever, chills, headache, dizziness, and fatigue.
Secreted IFN-γ induces activation of other immune cells (macrophages!).
Activated macrophages produce excessive amounts of additional cytokines such as IL-6, TNF-α, and IL-10.
TNF-α elicits flu-like symptoms but also watery diarrhoea, vascular leakage, cardiomyopathy, lung injury, and the synthesis of acute phase proteins.
IL-6 leads to vascular leakage, and activation of the complement and coagulation cascade. In addition, IL-6 likely contributes to cardiomyopathy by promoting myocardial dysfunction.
What induces the release of IFN-γ and TNF-α?
Activation of mainly T cells or lysis of immune cells induces a release of IFN-γ or TNF-α.
What is the origin and role of IL-6 in cytokine release syndrome?
Activation of mainly T cells or lysis of immune cells induces a release of IFN-γ or TNF-α.
This leads to the activation of macrophages, dendritic cells, other immune cells, and endothelial cells.
These cells further release proinflammatory cytokines. Importantly, macrophages and endothelial cells produce large amounts of IL-6
IL-6 in a positive feedback loop manner activates T cells and other immune cells leading to a cytokine storm.
What is the therapeutic handling with each grade of cytokine release syndrome?
Therapeutic handling:
Mild:
o Treat symptomatically
Persistent mild or moderate:
o Treat with oral corticosteroids (prednisone 1 mg/kg daily or equivalent)
o Omit next dose (of ipilimumab) until symptoms resolve or return to baseline
Symptoms worsen, are severe, or are life threatening:
o Treat with high-dose IV corticosteroids
(methylprednisolone 2 mg/kg daily or equivalent)
What is Tocilizumab?
Tocilizumab is an anti-IL6 antibody that helps prevent cytokine release syndrome by blocking the amplification of the inflammatory cascade that IL6 induces and reduces the side effects caused by IL6.
Great advantage: has effect on the cytokine release syndrome and does not interfere with the effectivity of the immunotherapy
What were the goals of the ArtDECO research?
Validation of known phenotypes of Acute Respiratory Distress Syndrome (ARDS):
o Low and high pulmonary fibro-proliferative response with known differential response to corticosteroid treatment
Identification of new phenotypes of ARDS:
o Discovery of novel phenotypes through deep phenotyping via fused patient similarity network analysis is used to integrate patient characteristics, plasma and BALF biomarkers, lung mechanics, gas exchange and quantitative CT-images into subgroups that share characteristics over these datasets.
What was the study design of the ArtDECO research?
Blood samples were taken from patients with COVID-19 pneumonia. A quantitative CT analysis was also done.
If the patients recovered, they stopped taking blood samples.
If the patients went to the ICU with COVID-19 related acute respiratory distress syndrome, they continued taking blood samples and did a quantitative CT analysis.
If the patients recovered or died from COVID-19 related acute respiratory distress syndrome, they stopped taking blood samples.
If the patients got persistent COVID-19 related acute respiratory distress syndrome, they continued taking blood samples and also did quantitative CT analyses, did BAL and gas exchange and lung mechanics.
In this phase of the disease, patients got corticosteroid treatment. Treatment failure was defined as death or mechanical ventilation at 28 days after they arrived in the ICU
What were the lessons learned from the Art-DECO research?
Lessons learned: Logistics: o Coordination is key! o Define bottlenecks, plan ahead o Avoid rushing in o Decisions: All samples in one day vs. batch correction
Sample viability:
o Severely ill patients
o Sample processing in the midst of a lockdown
o Cryopreservation and thawing –> sample recovery was poor, especially on BAL
o Impact on sensitive markers and cell types
How were the different samples analysed in the Art-DECO research?
A broad panel (35 colours) to look at broad immune cell subsets and additional markers for tissue-resident memory cells and macrophages because they could look at broncho-alveolar lavage (BAL).
