Scholarlink

<p>While T-cell Bispecifics (TCBs) are promising molecules for cancer treatment, their clinical development remains challenging due to Cytokine Release Syndrome (CRS). There is currently no method to accurately predict the doses expected to trigger CRS from pre-clinical data, resulting in the selection of non optimal First-In-Human (FIH) doses, far from the doses expected to show clinical benefit, to address safety concerns. In this work, a retrospective analysis aiming to identify which <i>in vitro</i> assay (focusing on tumor cell killing and cytokine release) is predictive of CRS at the first administration of TCBs developed for oncology indications at Roche is presented. A concentration threshold of C<sub>max</sub> 25-times the <i>in vitro</i> tumor cell killing EC50 from the most sensitive assay (or 96% of the maximum killing effect) has been identified and can be used to guide the selection of clinical dose associated with no CRS. Above this concentration threshold, any CRS without distinction from grades 1–3 have been observed. This work demonstrates that <i>in vitro</i> tumor cell killing assay can be used to determine a FIH for TCBs at which no CRS is expected (at least for TCBs similar to the one used in this analysis). It also suggests that CRS events are connected to the intended pharmacological effect (tumor cell killing). This work can guide the selection of TCB FIH clinical doses, allowing higher starting dose compared to the minimum anticipated biological effect approach, therefore increasing patients’ benefit.</p> Graphical Abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Leveraging in vitro Tumor Cell Killing and Cytokine Release to Predict Cytokine Release Syndrome Associated with CD3 T-cell Bispecifics in Oncology: a Retrospective Analysis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月18日

查看全文
  • Apolline Lefèvre,
  • Zinnia P. Parra-Guillen,
  • Iñaki F. Trocóniz,
  • Christophe Boetsch,
  • Nicolas Frances

摘要

While T-cell Bispecifics (TCBs) are promising molecules for cancer treatment, their clinical development remains challenging due to Cytokine Release Syndrome (CRS). There is currently no method to accurately predict the doses expected to trigger CRS from pre-clinical data, resulting in the selection of non optimal First-In-Human (FIH) doses, far from the doses expected to show clinical benefit, to address safety concerns. In this work, a retrospective analysis aiming to identify which in vitro assay (focusing on tumor cell killing and cytokine release) is predictive of CRS at the first administration of TCBs developed for oncology indications at Roche is presented. A concentration threshold of Cmax 25-times the in vitro tumor cell killing EC50 from the most sensitive assay (or 96% of the maximum killing effect) has been identified and can be used to guide the selection of clinical dose associated with no CRS. Above this concentration threshold, any CRS without distinction from grades 1–3 have been observed. This work demonstrates that in vitro tumor cell killing assay can be used to determine a FIH for TCBs at which no CRS is expected (at least for TCBs similar to the one used in this analysis). It also suggests that CRS events are connected to the intended pharmacological effect (tumor cell killing). This work can guide the selection of TCB FIH clinical doses, allowing higher starting dose compared to the minimum anticipated biological effect approach, therefore increasing patients’ benefit.

Graphical Abstract