Premium
Severity of the TGN 1412 trial disaster cytokine storm correlated with IL ‐2 release
Author(s) -
Eastwood David,
Bird Chris,
Dilger Paula,
Hockley Jason,
Findlay Lucy,
Poole Stephen,
Thorpe Susan J.,
Wadhwa Meenu,
Thorpe Robin,
Stebbings Richard
Publication year - 2013
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12165
Subject(s) - cytokine , flow cytometry , immunology , medicine , cd3 , microbiology and biotechnology , cytokine release syndrome , t cell , biology , immune system , cd8 , chimeric antigen receptor
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 TGN 1412 and muromonab‐ CD 3 stimulated CD 4+ T ‐cell mediated cytokine release characterized by significant (all P < 0.0001) IFN γ, TNF α, 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 TGN 1412 (2894–6051 pg ml −1 ) compared with muromonab‐ CD 3 (62–262 pg ml −1 ) differentiated otherwise comparable cytokine responses. Likewise, TGN 1412 stimulated significantly more ( P = 0.0001) IL ‐2 producing CD 4+ T ‐cells than muromonab‐ CD 3 and induced T h1, T h2, T h17 and T h22 subsets that co‐release this cytokine. Significant TNF α release was observed with bevacizumab ( P = 0.0001), trastuzumab ( P = 0.0031) and alemtuzumab ( P = 0.0177), but no significant IL ‐2 release. TGN 1412 and muromonab‐ CD 3 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 TGN 1412 compared with muromonab‐ CD 3 and other therapeutic mAbs correlates with the level of IL ‐2 release.