Severity of the TGN1412 trial disaster cytokine storm correlated with IL‐2 release

Abstract

Aim To determine if cytokine release with a solid phase assay is predictive of adverse responses for a range of therapeutic mAbs.Methods Cytokine ELISAs and a multi-array system were used to compare responses generated by different therapeutic mAbs using a solid phase assay. Flow cytometry was employed to determine the cellular source of those cytokines.Results Only TGN1412 and muromonab-CD3 stimulated CD4+ T-cell mediated cytokine release characterized by significant (all P < 0.0001) IFNγ, TNFα, IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, IL-17 and IL-22 release, comparable with T-cell mitogen. Significantly greater (P < 0.0001) IL-2 release with TGN1412 (2894–6051 pg ml−1) compared with muromonab-CD3 (62–262 pg ml−1) differentiated otherwise comparable cytokine responses. Likewise, TGN1412 stimulated significantly more (P = 0.0001) IL-2 producing CD4+ T-cells than muromonab-CD3 and induced Th1, Th2, Th17 and Th22 subsets that co-release this cytokine. Significant TNFα release was observed with bevacizumab (P = 0.0001), trastuzumab (P = 0.0031) and alemtuzumab (P = 0.0177), but no significant IL-2 release. TGN1412 and muromonab-CD3 caused pro-inflammatory cytokine release despite significantly (both P < 0.0001) increasing numbers of T-cells with a regulatory phenotype.Conclusions The severity of the adverse response to TGN1412 compared with muromonab-CD3 and other therapeutic mAbs correlates with the level of IL-2 release.

Advantages ofPapio anubisfor preclinical testing of immunotoxicity of candidate therapeutic antagonist antibodies targeting CD28

“…In our study, we confirmed the absence of induced proliferation with CD28.2, but recorded significant levels of IFNγ, TNF, IL-6 and IL-12 release. Otherwise, whereas the severity of the adverse response of TGN1412 was correlated with the level of IL-2 release, 30 we observed that level of IFNγ release could be more predictive of agonist properties of divalent anti-CD28 mAbs.…”

Cell Contact–Dependent Priming and Fc Interaction with CD32+ Immune Cells Contribute to the TGN1412-Triggered Cytokine Response

“…7A, 7B). In a recent study the severity of the TGN1412-induced cytokine storm was correlated with the IL-2 release, suggesting that IL-2 production might be used as a prognostic factor in upcoming trials of new biologicals (34). Thus, in addition to cytokine secretion, analysis of costimulatory molecules expression may be also informative for the evaluation of new biologicals.…”

“…1). Because Eastwood et al (34) showed that IL-2 is a marker associated with the induction of a cytokine storm, we addressed whether under the above conditions T cells were present that secreted TNF-a, IFN-g, and IL-2 in parallel. Irrespective of whether T cells derived from PBMCs or HDC-PBMCs, polyfunctional T cells were detected (Fig.…”

Redirected T-Cell Killing of Solid Cancers Targeted with an Anti-CD3/Trop-2–Bispecific Antibody Is Enhanced in Combination with Interferon-α

“…However, IL2 was combined with an F(ab 0 ) 2 fragment of an anti-CD3/ EpCAM quadroma in a clinical trial (40), but treatment was limited because of considerable toxicity most likely caused by induction of secondary cytokines, known as CRS or cytokine storm. Systemic administration of IL2 is known to induce a cytokine storm (41), and the severity of adverse events associated with CRS, such as with the TGN1412 catastrophic trial, is correlated with IL2 release (42). Although it is not without side effects, immunotherapy with IFNa, which is not produced by T cells, is not typically associated with cytokine storm.…”