Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Sci Transl Med. 2019 Sep 4;11(508). doi: 10.1126/scitranslmed.aax8861.
T cell-retargeting therapies have transformed the therapeutic landscape of oncology. Regardless of the modality, T cell activating therapies are commonly accompanied by systemic cytokine release, which can progress to deadly cytokine release syndrome (CRS). Because of incomplete mechanistic understanding of the relationship between T cell activation and systemic cytokine release, optimal toxicity management that retains full therapeutic potential remains unclear. Here, we report the cell type-specific cellular mechanisms that link CD3 bispecific antibody-mediated killing to toxic cytokine release. The immunologic cascade is initiated by T cell triggering, whereas monocytes and macrophages are the primary source of systemic toxic cytokine release. We demonstrate that T cell-generated tumor necrosis factor-α (TNF-α) is the primary mechanism mediating monocyte activation and systemic cytokine release after CD3 bispecific treatment. Prevention of TNF-α release is sufficient to impair systemic release of monocyte cytokines without affecting antitumor efficacy. Systemic cytokine release is only observed upon initial exposure to CD3 bispecific antibody not subsequent doses, indicating a biological distinction between doses. Despite impaired cytokine release after second exposure, T cell cytotoxicity remained unaffected, demonstrating that cytolytic activity of T cells can be achieved in the absence of cytokine release. The mechanistic uncoupling of toxic cytokines and T cell cytolytic activity in the context of CD3 bispecifics provides a biological rationale to clinically explore preventative treatment approaches to mitigate toxicity.
T 细胞重定向疗法改变了肿瘤学的治疗格局。无论采用何种方式，T 细胞激活疗法通常伴随着全身细胞因子释放，这可能发展为致命的细胞因子释放综合征（CRS）。由于对 T 细胞激活与全身细胞因子释放之间关系的机制理解不完全，因此仍不清楚如何在保留充分治疗潜力的同时进行最佳毒性管理。在这里，我们报告了将 CD3 双特异性抗体介导的杀伤与毒性细胞因子释放联系起来的细胞类型特异性细胞机制。免疫级联反应由 T 细胞触发引发，而单核细胞和巨噬细胞是全身毒性细胞因子释放的主要来源。我们证明，T 细胞产生的肿瘤坏死因子-α（TNF-α）是介导 CD3 双特异性治疗后单核细胞激活和全身细胞因子释放的主要机制。预防 TNF-α释放足以损害单核细胞细胞因子的全身释放，而不影响抗肿瘤疗效。仅在初次接触 CD3 双特异性抗体时观察到全身细胞因子释放，而不是随后的剂量，这表明剂量之间存在生物学差异。尽管第二次接触后细胞因子释放受损，但 T 细胞细胞毒性仍未受影响，这表明在没有细胞因子释放的情况下也可以实现 T 细胞的细胞毒性活性。在 CD3 双特异性抗体的背景下，毒性细胞因子和 T 细胞细胞毒性活性的机制分离为临床探索预防治疗方法以减轻毒性提供了生物学依据。
