Cytokine storm

The importance of CD28 came out when the phase I clinical trial with the humanized monoclonal superagonist of the CD28, TGN1412, resulted in an unexpected cytokine storm with multiorgan failure in 2006 in the UK [71],... 

The biological effects observed at tumour sites indicate that BsMAbs effectively penetrate tissue. However, trials are limited by the toxicity caused by induction of a cytokine storm or by the complex pharmacokinetics. Furthermore, T-cell directed BsMAb approaches are hindered by difficulties in mobilizing and activating T and NK effector cells. Recent attention, therefore, has focused on BsMAbs which target myeloid effectors [79]. 

Ward, S., Brett, S.J., Castello-Cortes, A., Brunner, M.D. and Panoskaltsis, N. (2006) Cytokine storm in a phase 1 trial of the Anti-CD28 monoclonal antibody TGN1412. New England Journal of Medicine, 355, 1-11. 

Ganesh Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N. Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412. N Engl J Med 2006 355 1-11. 

Faulkner L, Cooper A, Fantino C, Altmann DM, Sriskandan S The mechanism of superantigen-mediated toxic shock not a simple Thl cytokine storm. J Immunol 2005 175 6870-6877. 

Stebbings R, Findlay L, Edwards C, Eastwood D, Bird C, North D, Mistry Y, Dilger P, Liefooghe E, Cludts I, Fox B, Tarrant G, Robinson J, Meager T, Dolman C, Thorpe SJ, Bristow A, Wadhwa M, Thorpe R, Poole S. Cytokine storm in the Phase 1 trial of monoclonal antibody TGN1412 better understanding the causes to improve preclinical testing of immunotherapeutics. J Immunol 2007 179 3325-3331. 

HuCD3 Decreased cytokine storm from Hu/Mu chimeric antiCD3-IgM compared to murine antiCD3 Choi et al. (2002)... 

Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N... 

SIRS is thought to be a consequence of circulating proinflammatory cytokines, a form of cytokine storm . When persistent, this can lead to multi organ failure, including adult respiratory distress syndrome. When SIRS is associated with a systemic infection, the condition is known as systemic sepsis. 

However, the development of OKT3 and other anti-CD3 monoclonal antibodies was hampered by serious adverse reactions associated with cytokine storm, as a consequence of generalized T-cell activation [76 ]. 

In a preclinical study in rats, semapimod suppressed the induction of cytokine storm by the anticancer cytokine interleukin-2 without reducing its anticancer properties, which allowed larger doses of interleukin-2 to be used [118 ]. However, a subsequent phase I trial in 24 patients with melanomas and renal cancers failed to show an increase in the tolerated dose of interleukin-2. In combination with high-dose interleukin-2, semapimod >25 mg/rn seemed to exacerbate interleukin-2-induced nephrotoxicity, as grade 3-4 rises in creatinine developed in three of six patients at dosages of 25 or 32 mg/m, compared with one of 16 patients at doses under 16 mg/rr. The maximum... 

Reactions following initial infusions of antibody are common, but these can usually be handled by a cautious rate of infusion, appropriate hydration and diuresis, and, if necessary, praned-ication. Twenty six percent of initial reactions are reported to be mild, 48 % moderate, and 26 % severe. The initial infusion reaction to some mAbs, for example, rituximab (see below), may provoke tumor lysis syndrome, cytokine release syndrome, and systemic inflammatory response syndrome. Tumor lysis syndrome, noted particularly with rituximab, can occur following cancer treatment and sometimes without treatment. It is believed to be the result of breakdown products of cancer cells leading to increased levels of some metabolites and reflected in conditions such as hypercalcemia, hyperkalemia, hyperphosphatemia, acute uric acid nephropathy, and acute renal failure. The syndrome can occur in the early stages of mAb therapy and is potentially life-threatening. Cytokine release syndrome, also called cytokine storm, is commonly seen after... 

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