CELL INTELLIGENCE · 肿瘤细胞治疗研究

The recent surge in T-cell-engaging and chimeric antigen receptor (CAR) T-cell therapies is changing the landscape of cancer therapy. Cytokine release syndrome (CRS) is a systemic inflammatory response syndrome that is a well-known complication of these therapies, of which interleukin-6 (IL-6) is a key mediator. Tocilizumab, an IL-6 receptor (IL-6R) antagonist, is approved for the management of CAR T-cell therapy-induced CRS in adults and in pediatric patients aged 2 years old. However, the approved dosing schedule was not based on IL-6R occupancy and may not be the most suitable schedule for T-cell-engaging therapies such as bispecific antibodies (bsAb) due to key differences in the levels of released IL-6, the clinical symptomatology of CRS, and the pharmacology of tocilizumab across settings. In this study, we adapted a previously developed tocilizumab and soluble IL-6R (sIL-6R) population pharmacokinetic model to describe and predict tocilizumab concentrations and sIL-6R occupancy over time in patients with anti-CD20 bsAb-induced CRS following tocilizumab dosing. Using this model, which incorporates target binding and receptor occupancy, we propose a new tocilizumab dosing regimen that is based on quantitative clinical pharmacology, cytokine analyses, and clinical practice patterns in patients with relapsed/refractory B-cell non-Hodgkin's lymphoma (R/R B-NHL) treated with the anti-CD20 bsAb mosunetuzumab or glofitamab. This schedule (up to two 8 mg/kg intravenous tocilizumab doses per CRS event at least 8 hours apart and a maximum of three doses in 6 weeks) can be used to effectively manage acute CRS induced by anti-CD20 bsAb in patients with R/R B-NHL.