4.6 Article

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

Journal

ONCOIMMUNOLOGY
Volume 11, Issue 1, Pages -

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2022.2039432

Keywords

Cancer immunotherapy; T cell engagers; T cell bispecific antibodies; cytokine release syndrome; neutrophil; PBMC

Funding

  1. Roche

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This study investigated the biological mechanisms of cytokine release after treatment with T cell bispecific antibodies (TCBs) and identified T cells as the triggers and monocytes and neutrophils as the amplifiers of the cytokine cascade. Moreover, it demonstrated the contribution of neutrophils to TCB-mediated cytokine release using single-cell RNA sequencing.
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-alpha, IFN-gamma, IL-6 and IL-1 beta 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.

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