‘What is a cytokine storm? What triggers them?‘
Cytokine storm oroccurs as a result of overzealous immune responses that generate so much cytokine secretion, hypercytokinesis, that rather than stay local as cytokines normally do, they spill over into the systemic circulation, and the outcome can even be fatal.
- Cytokines typically associated with cytokine storm are IL-1, IL-2, IL-6, IFN-, TNF-.
- Symptoms can include headache, nausea, diarrhea, vomiting, fever, weakness, fatigue, hypotension, tachycardia, capillary leaks, liver and kidney dysfunction.
- Septic shock is the most extreme form and could be considered the mother of all cytokine storms.
- Left untreated, such severe cytokine storms can lead to multi-organ failure and be fatal.
- OTOH, ‘flu-like’ symptoms in response to an ongoing infection is a common and much milder form of cytokine storm that many people experience at some point in their lives.
- Disproportionate cytokine responses during acute infections could also be a sign of immunopathology. In such cases, rather than adequate control of infection, such responses help rather than clear it.
Somewhat akin to hormones in being cell-to-cell messengers, cytokines (cytos, cell; kinos, movement) are secreted molecules considered as chemical messengers of the immune system. Structurally cytokines tend to be proteins, glycoproteins or polypeptides.
- After a cell secretes a particular cytokine, it typically, though not always, binds cell-surface receptors specific for that cytokine expressed on other, usually nearby, cells. Such binding triggers a biochemical pathway that cascades its way into the nucleus and leads to turning on or off of specific genes in the responding cell.
- Cytokine-triggered biochemical pathways and ensuing responses are not only unique to a particular cytokine but also to the responding cell. For example, response outcome of the cytokine IL-10 binding its receptor on a B cell or a macrophage is different and emblematic of the inherent properties of these very different responding cells.
Intended for short-range cell-to-cell communication within a tissue microenvironment means cytokine effects at long-range can be unpredictable and typically toxic, simply as a result of potentially exponential increase in the number and type of target cells that could bind them.
- Scientists discovered this the hard way in the early days of cytokine therapy. Originally identified in 1990,
was one of the first cytokines to be tested in clinical trials.
- Eagerness to do so was driven by observations of IL-12’s capacity to drive strong CD4 T cell responses of a type necessary to help activate CD8 T cells to become ‘killer’ cytotoxic cells.
- In turn, cytotoxic CD8 T cells can kill and eliminate cancer cells for example.
- Based on such early evidence of IL-12 potency, in short order, in 1995 . in partnership with injected IL-12 in 17 renal carcinoma patients. Twelve suffered from acute cytokine storm and needed to be hospitalized and two died (1, ).
- More recently, cytokine storm as a concept has started becoming mainstream simply because many newer immunotherapies rapidly entering the clinic are eminently capable of triggering them.
- or TGN1412 is a famous case in point when in a first-in-human study in 2006, six healthy young volunteers (all men) were injected with it. Within hours, all were hospitalized with life-threatening symptoms that culminated in multi-organ failure, a result of cytokine storm. Only timely expert medical care ensured they survived.
- TGN1412 is a humanized IgG4 mAb ( ) whose specific target is the T cell costimulatory molecule CD28.
- It underwent extensive testing in in vivo rodent (rat and mouse) and non-human primate (cynomolgus monkeys) models as well as in vitro human PBMCs ( ), tests that never showed any inkling of what could happen when injected into humans.
- In fact, the cynomolgus monkeys had had no ill effects whatsoever even after being given up to 500 times the dose given to the six healthy young volunteers (3).
- Other mAbs such as , , and have also been observed to trigger cytokine storms in some patients. Targets of such mAbs include CD3, CD52, CD20 or CD19 and CD3 jointly, all cell-surface molecules largely or solely expressed by immune cells such as T and B cells.
- Nowadays, CAR-T ( ) is a rapidly emerging form of cancer immunotherapy where cytokine storms have been seen to develop in a variable fraction of patients in different clinical trials ( , ).
1. Cohen, Jon. “IL-12 deaths: explanation and a puzzle.” Science 270.5238 (1995): 908-908.
2. Leonard, John P., et al. “Effects of single-dose interleukin-12 exposure on interleukin-12–associated toxicity and interferon-γ production.” Blood 90.7 (1997): 2541-2548.
3. Hünig, Thomas. “The storm has cleared: lessons from the CD28 superagonist TGN1412 trial.” Nature Reviews Immunology 12.5 (2012): 317-318.
4. Bonifant, Challice L., et al. “Toxicity and management in CAR T-cell therapy.” Molecular Therapy-Oncolytics 3 (2016).
5. Neelapu, Sattva S., et al. “Chimeric antigen receptor T-cell therapy—assessment and management of toxicities.” Nature Reviews Clinical Oncology 15.1 (2018): 47.