Cytokine release assays: Current practices and future directions

Finco, Deborah; Grimaldi, Christine; Fort, Madeline M.; Walker, Mindi; Kießling, Andrea; Wolf, Babette; Salcedo, Theodora W.; Faggioni, Raffaella; Schneider, Amy; Ibraghimov, Alex; Scesney, Susanne M.; Serna, De la; Prell, Rodney A.; Stebbings, Richard; Narayanan, Padma K.

doi:10.1016/j.cyto.2013.12.009

Cited by 94 publications

(67 citation statements)

References 35 publications

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“…In addition, PBMCs have been efficiently used to evaluate the safety and immunogenicity of booster vaccinations [27], [28], [29]. Moreover, a cytokine release assay (CRA) with human PBMCs has also been used as an alternative tool to predict the immunotoxicities of monoclonal antibodies and vaccines [30]. Therefore, PBMCs could be used in alternative approaches to predict the potential for immunotoxicity of PMP products.…”

Section: Introductionmentioning

confidence: 99%

Immunotoxicity Assessment of Rice-Derived Recombinant Human Serum Albumin Using Human Peripheral Blood Mononuclear Cells

Cheng

Liu

et al. 2014

PLoS ONE

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Human serum albumin (HSA) is extensively used in clinics to treat a variety of diseases, such as hypoproteinemia, hemorrhagic shock, serious burn injuries, cirrhotic ascites and fetal erythroblastosis. To address supply shortages and high safety risks from limited human donors, we recently developed recombinant technology to produce HSA from rice endosperm. To assess the risk potential of HSA derived from Oryza sativa (OsrHSA) before a First-in-human (FIH) trial, we compared OsrHSA and plasma-derived HSA (pHSA), evaluating the potential for an immune reaction and toxicity using human peripheral blood mononuclear cells (PBMCs). The results indicated that neither OsrHSA nor pHSA stimulated T cell proliferation at 1x and 5x dosages. We also found no significant differences in the profiles of the CD4+ and CD8+ T cell subsets between OsrHSA- and pHSA-treated cells. Furthermore, the results showed that there were no significant differences between OsrHSA and pHSA in the production of cytokines such as interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-10 and IL-4. Our results demonstrated that OsrHSA has equivalent immunotoxicity to pHSA when using the PBMC model. Moreover, this ex vivo system could provide an alternative approach to predict potential risks in novel biopharmaceutical development.

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Section: Introductionmentioning

confidence: 99%

Immunotoxicity Assessment of Rice-Derived Recombinant Human Serum Albumin Using Human Peripheral Blood Mononuclear Cells

Cheng

Liu

et al. 2014

PLoS ONE

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“…Following recent discussion by leaders in the field of cytokine storm assays (10), it is accepted that there are no clear and consistent precepts for the range of cytokine storm assays currently used by the pharmaceutical industry. Since the advent of TGN1412, the unifying gold standard for these assays has been detection of cytokine release by anti‐CD28 superagonists but without a predefined criteria for 1) minimum unit, relative (fold) increase, and identity of cytokines released that constitute an adequate mimic of cytokine release syndrome; 2) profile of control antibodies that do not generally activate cytokine release; 3) physiologic conditions that best model the human in vivo situation; and 4) assessment in tissue from specific target patient groups relevant to the particular biologic drug to be tested (personalized medicine).…”

Section: Discussionmentioning

confidence: 99%

An autologous endothelial cell:peripheral blood mononuclear cell assay that detects cytokine storm responses to biologics

et al. 2015

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There is an urgent unmet need for human tissue bioassays to predict cytokine storm responses to biologics. Current bioassays that detect cytokine storm responses in vitro rely on endothelial cells, usually from umbilical veins or cell lines, cocultured with freshly isolated peripheral blood mononuclear cells (PBMCs) from healthy adult volunteers. These assays therefore comprise cells from 2 separate donors and carry the disadvantage of mismatched tissues and lack the advantage of personalized medicine. Current assays also do not fully delineate mild (such as Campath) and severe (such as TGN1412) cytokine storm-inducing drugs. Here, we report a novel bioassay where endothelial cells grown from stem cells in the peripheral blood (blood outgrowth endothelial cells) and PBMCs from the same donor can be used to create an autologous coculture bioassay that responds by releasing a plethora of cytokines to authentic TGN1412 but only modestly to Campath and not to control antibodies such as Herceptin, Avastin, and Arzerra. This assay performed better than the traditional mixed donor assay in terms of cytokine release to TGN1412 and, thus, we suggest provides significant advancement and a definitive system by which biologics can be tested and paves the way for personalized medicine.-Reed,

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“…As a consequence, different assay formats maybe predictive for individual biologics as illustrated by higher cytokine responses to TGN1412 in assays applying peripheral blood mononuclear cells (PBMCs) in the context of solid phase drug presentation or high density pre-culture (explained by the inhibitory activity of erythrocytes on T cell responses in whole blood) in contrast to superior responses for alemtuzumab in whole blood assays using aqueous presentation (presumably due to the strong contributions of neutrophilic granulocytes in the Fc-mediated cytokine response and the lack of this cell population in PBMC preparations). A comprehensive overview of mechanisms of cytokine release and assay format to assess human hazard has been provided by Bugelski et al (2009) and the ILSI-Health and Environmental Sciences Institute (HESI) Immunotoxicology Committee Cytokine Release Assay Working Group (Finco et al, 2014).…”

Section: Cytokine Release: Key Challenges In Human Translationmentioning

confidence: 99%

Nonclinical safety testing of biopharmaceuticals – Addressing current challenges of these novel and emerging therapies

Brennan

Baumann

Blaich³

et al. 2015

Regulatory Toxicology and Pharmacology

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Cytokine release assays: Current practices and future directions

Cited by 94 publications

References 35 publications

Immunotoxicity Assessment of Rice-Derived Recombinant Human Serum Albumin Using Human Peripheral Blood Mononuclear Cells

Immunotoxicity Assessment of Rice-Derived Recombinant Human Serum Albumin Using Human Peripheral Blood Mononuclear Cells

An autologous endothelial cell:peripheral blood mononuclear cell assay that detects cytokine storm responses to biologics

Nonclinical safety testing of biopharmaceuticals – Addressing current challenges of these novel and emerging therapies

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