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Eltahir, Mohamed
Publications (2 of 2) Show all publications
Fletcher, E. A. K., Eltahir, M., Lindqvist, F., Rieth, J., Törnqvist, G., Leja-Jarblad, J. & Mangsbo, S. (2018). Extracorporeal human whole blood in motion, as a tool to predict first-infusion reactions and mechanism-of-action of immunotherapeutics. International Immunopharmacology, 54, 1-11
Open this publication in new window or tab >>Extracorporeal human whole blood in motion, as a tool to predict first-infusion reactions and mechanism-of-action of immunotherapeutics
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2018 (English)In: International Immunopharmacology, ISSN 1567-5769, E-ISSN 1878-1705, Vol. 54, p. 1-11Article in journal (Refereed) Published
Abstract [en]

First infusion reactions along with severe anaphylactic responses can occur as a result of systemic administration of therapeutic antibodies. The underlying mechanisms by which monoclonal antibodies induce cytokine release syndrome (CRS) can involve direct agonistic effects via the drug target, or a combination of target-engagement along with innate receptor interactions. Despite the wide variety of pathways and cells that can play a role in CRS, many currently used assays are devoid of one or more components that must be present for these responses to occur. One assay that has not been assessed for its capacity to predict CRS is the modified Chandler loop model. Herein we evaluate a plethora of commercially available monoclonal antibodies to evaluate the modified Chandler loop model's potential in CRS prediction. We demonstrate that in a 4-hour loop assay, both the superagonistic antibodies, anti-CD3 (OKT3) and anti-CD28 (ANC28.1), display a clear cytokine response with a mixed adaptive/innate cytokine source. OKT3 induce TNFα and IFN-γ release in 20 out of 23 donors tested, whereas ANC28.1 induce TNF-α, IL-2 and IFN-γ release in all donors tested (n = 18–22). On the other hand, non-agonistic antibodies associated with no or low infusion reactions in the clinic, namely cetuximab and natalizumab, neither induce cytokine release nor cause false positive responses. A TGN1412-like antibody also display a clear cytokine release with an adaptive cytokine profile (IFN-γ and IL-2) and all donors (n = 9) induce a distinct IL-2 response. Additionally, the value of an intact complement system in the assay is highlighted by the possibility to dissect out the mechanism-of-action of alemtuzumab and rituximab. The loop assay can either complement lymph node-like assays or stand-alone to investigate drug/blood interactions during preclinical development, or for individual safety screening prior to first-in-man clinical trial.

Keywords
Cytokine release syndrome, CRS, Immunotoxicity, Cytokine release assay, Anti-CD28, Alemtuzumab, OKT3
National Category
Immunology in the medical area Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-346359 (URN)10.1016/j.intimp.2017.10.021 (DOI)000423887900001 ()29100032 (PubMedID)
Funder
Swedish Research Council, K2013-79X-22263-01-2Swedish Society for Medical Research (SSMF)
Available from: 2018-03-16 Created: 2018-03-16 Last updated: 2018-03-16Bibliographically approved
Backman, M., La Fleur, L., Kurppa, P., Djureinovic, D., Elfving, H., Brunnström, H., . . . Micke, P.Extending the immune phenotypes of lung cancer: Oasis in the desert.
Open this publication in new window or tab >>Extending the immune phenotypes of lung cancer: Oasis in the desert
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction: Tumor infiltrating immune cells are key elements of the tumor microenvironment and mediate the anti-tumor effects of immunotherapy. The aim of the study was to characterize patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to tumor mutations and clinicopathological parameters. 

Methods: Lymphocytes (CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+) and PD-L1+ were annotated on a tissue microarray including 357 operated NSCLC cases. Somatic mutations and tumor mutational burden were analyzed by targeted sequencing for 82 genes, and transcriptomic immune patterns were established in 197 patients based on RNAseq data. 

Results: We identified somatic mutations (TP53, NF1, KEAP1, CSMD3, LRP1B) that correlated with specific immune cell infiltrates. Hierarchical clustering revealed four immune classes: with (1) high immune cell infiltration (“inflamed”), (2) low immune cell infiltration (“desert”), (3) a mixed phenotype, and (4) a new phenotype with an overall muted inflammatory cell pattern but with an imprint of NK and plasma cells. This latter class exhibited low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, TGFB1), but was linked to better survival and therefore designated “oasis”. Otherwise, the four immune classes were not related to the presence of specific mutations (EGFR, KRAS, TP53) or histologic subtypes. 

Conclusion: We present a compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC and identified the novel immune class “oasis”. The immune classification helps to better define the immunogenic potency of NSCLC in the era of immunotherapy. 

Keywords
Immune infiltration, PD-L1, checkpoint therapy, tumor microenvironment
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-390316 (URN)
Available from: 2019-08-08 Created: 2019-08-08 Last updated: 2019-08-20
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