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CAR T cell administration results in cytokine release syndrome (CRS). But what is the mechanism that induces the CRS in CART therapy? Also, what factors correlate with CRS severity? CAR structure? Or tumor burden?

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CRS in CAR T therapy is likely the result of hyperactivation of a large number of immune cells, either by antigen-specific/co-stimulatory activation (T cells) or by non-specific activation due to significantly elevated pro-inflammatory cytokines. CRS is the most prevalent adverse effect following CAR T infusion, but does not always happen. These two reviews provide a lot of detail, and reference many primary studies, but I will summarize briefly below:

1) http://www.nature.com/articles/mto201611

2) http://www.bloodjournal.org/content/124/2/188?sso-checked=true

In patients with CRS, it manifests clinically whenever maximal activation of the infused T cells occurs. From ref 1,

"In the setting of early CAR T-cell trials utilizing “first-generation” constructs (without costimulatory signaling elements), insufficient T-cell proliferation/cytokine production and lack of antitumor response were noted.30 The addition of costimulatory signaling in second-generation CAR design (CD28 or 41BB) translated to improved T-cell activation/expansion, cytokine production, and most notably dramatic antitumor responses in patients with hematologic malignancies.3,31,32"

So the 2nd-gen CAR design leads to better antitumor responses, but can also cause an intense burst of cytokine release that sets off a sort of 'chain reaction' wherein many other native immune cells also begin to massively release cytokines. One of the key pathogenic cytokines in this cascade appears to be IL6. From ref 2,

"Emerging evidence implicates IL-6 as a central mediator of toxicity in CRS...[]... IL-6R is cell associated on macrophages, neutrophils, hepatocytes, and some T cells..[]... High levels of IL-6, present in the context of CRS, likely initiates a proinflammatory IL-6-mediated signaling cascade"

and from ref 1,

"As an effective alternative IL-6 receptor (IL-6R) blockade with the Food and Drug Administration-approved mAb, tocilizumab has demonstrated near-immediate reversal of CRS.3,35 Investigators are now determining the effect of IL-6R blockade on CAR T-cell proliferation, persistence, and most importantly, antitumor effect. Despite this unknown, the use of IL-6R blockade has generally been accepted as front-line treatment for sCRS following CAR T-cell infusion.23,31,36"

Finally, it does appear that tumor burden has been correlated with CRS severity, presumably because of the higher antigen load available to activate the CAR T cells. From ref 1 and 2, respectively,

" It has been demonstrated that the degree of CRS severity is dictated by disease burden at the time of infusion as patients with high tumor burden experience a more sCRS.3,31,32"

"In recent reports of CRS following adoptive T-cell therapy for cancer,10,14,8,28 the incidence and severity of the syndrome also appears greater when patients have large tumor burdens, presumably because this leads higher levels of T-cell activation."

Hope this helps. Clearly there is a long way to go in terms of predicting and managing these adverse events.

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