Dissecting the mechanism of cytokine release induced by T-cell engagers highlights the contribution of neutrophils.

Autor:	Leclercq G; Roche Pharma Research and Early Development, pRED, Roche Innovation Center Zurich, Zurich, Switzerland.; Department of Pharmaceutical Sciences, Division of Molecular and Systems Toxicology, University of Basel, Basel, Switzerland., Servera LA; Roche Pharma Research and Early Development, pRED, Roche Innovation Center Basel, Basel, Switzerland., Danilin S; Roche Pharma Research and Early Development, pRED, Roche Innovation Center Basel, Basel, Switzerland., Challier J; Roche Pharma Research and Early Development, pRED, Roche Innovation Center Zurich, Zurich, Switzerland., Steinhoff N; Roche Pharma Research and Early Development, pRED, Roche Innovation Center Zurich, Zurich, Switzerland., Bossen C; Roche Pharma Research and Early Development, pRED, Roche Innovation Center Basel, Basel, Switzerland., Odermatt A; Department of Pharmaceutical Sciences, Division of Molecular and Systems Toxicology, University of Basel, Basel, Switzerland., Nicolini V; Roche Pharma Research and Early Development, pRED, Roche Innovation Center Zurich, Zurich, Switzerland., Umaña P; Roche Pharma Research and Early Development, pRED, Roche Innovation Center Zurich, Zurich, Switzerland., Klein C; Roche Pharma Research and Early Development, pRED, Roche Innovation Center Zurich, Zurich, Switzerland., Bacac M; Roche Pharma Research and Early Development, pRED, Roche Innovation Center Zurich, Zurich, Switzerland., Giusti AM; Roche Pharma Research and Early Development, pRED, Roche Innovation Center Zurich, Zurich, Switzerland., Schneider A; Roche Pharma Research and Early Development, pRED, Roche Innovation Center Zurich, Zurich, Switzerland., Haegel H; Roche Pharma Research and Early Development, pRED, Roche Innovation Center Zurich, Zurich, Switzerland.
Jazyk:	angličtina
Zdroj:	Oncoimmunology [Oncoimmunology] 2022 Feb 14; Vol. 11 (1), pp. 2039432. Date of Electronic Publication: 2022 Feb 14 (Print Publication: 2022).
DOI:	10.1080/2162402X.2022.2039432
Abstrakt:	T cell engagers represent a novel promising class of cancer-immunotherapies redirecting T cells to tumor cells and have some promising outcomes in the clinic. These molecules can be associated with a mode-of-action related risk of cytokine release syndrome (CRS) in patients. CRS is characterized by the rapid release of pro-inflammatory cytokines such as TNF-α, IFN-γ, IL-6 and IL-1β and immune cell activation eliciting clinical symptoms of fever, hypoxia and hypotension. In this work, we investigated the biological mechanisms triggering and amplifying cytokine release after treatment with T cell bispecific antibodies (TCBs) employing an in vitro co-culture assay of human PBMCs or total leukocytes (PBMCs + neutrophils) and corresponding target antigen-expressing cells with four different TCBs. We identified T cells as the triggers of the TCB-mediated cytokine cascade and monocytes and neutrophils as downstream amplifier cells. Furthermore, we assessed the chronology of events by neutralization of T-cell derived cytokines. For the first time, we demonstrate the contribution of neutrophils to TCB-mediated cytokine release and confirm these findings by single-cell RNA sequencing of human whole blood incubated with a B-cell depleting TCB. This work could contribute to the construction of mechanistic models of cytokine release and definition of more specific molecular and cellular biomarkers of CRS in the context of treatment with T-cell engagers. In addition, it provides insight for the elaboration of prophylactic mitigation strategies that can reduce the occurrence of CRS and increase the therapeutic index of TCBs. Competing Interests: All authors, except A. Odermatt, are employees of Roche or were employed by Roche at the time of this study and declare patent. All the authors, except A. Odermatt, G. Leclercq, N. Steinhoff, declare ownership of Roche stock. (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)
Databáze:	MEDLINE
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