Research and Development, G1 Therapeutics, Inc, Research Triangle Park, North Carolina, USA.
Research and Development, G1 Therapeutics, Inc, Research Triangle Park, North Carolina, USA
J Immunother Cancer. 2020 Oct;8(2). doi: 10.1136/jitc-2020-000847.
Combination treatment with chemotherapy and immune checkpoint inhibitors (ICIs) has demonstrated meaningful clinical benefit to patients. However, chemotherapy-induced damage to the immune system can potentially diminish the efficacy of chemotherapy/ICI combinations. Trilaciclib, a highly potent, selective and reversible cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor in development to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy, has demonstrated proof of concept in recent clinical trials. Furthermore, CDK4/6 inhibition has been shown to augment T-cell activation and antitumor immunity in preclinical settings. Therefore, addition of trilaciclib has the potential to further enhance the efficacy of chemotherapy and ICI combinations.
In murine syngeneic tumor models, a schedule of 3 weekly doses of trilaciclib was combined with chemotherapy/ICI regimens to assess the effect of transient CDK4/6 inhibition on antitumor response and intratumor T-cell proliferation and function. Peripheral T-cell status was also analyzed in patients with small cell lung cancer (SCLC) treated with chemotherapy with or without trilaciclib to gain insights into the effect of transient exposure of trilaciclib on T-cell activation.
Preclinically, the addition of trilaciclib to chemotherapy/ICI regimens enhanced antitumor response and overall survival compared with chemotherapy and ICI combinations alone. This effect is associated with the modulation of the proliferation and composition of T-cell subsets in the tumor microenvironment and increased effector function. Transient exposure of trilaciclib in patients with SCLC during chemotherapy treatment both preserved and increased peripheral lymphocyte counts and enhanced T-cell activation, suggesting that trilaciclib not only preserved but also enhanced immune system function.
Transient CDK4/6 inhibition by trilaciclib was sufficient to enhance and prolong the duration of the antitumor response by chemotherapy/ICI combinations, suggesting a role for the transient cell cycle arrest of tumor immune infiltrates in remodeling the tumor microenvironment. These results provide a rationale for combining trilaciclib with chemotherapy/ICI regimens to improve antitumor efficacy in patients with cancer.
化疗联合免疫检查点抑制剂（ICI）治疗已显示出对患者有显著的临床获益。然而，化疗引起的免疫系统损伤可能会降低化疗/ICI 联合治疗的疗效。 Trilaciclib 是一种正在开发中的高活性、选择性和可逆的细胞周期蛋白依赖性激酶 4 和 6（CDK4/6）抑制剂，可在化疗期间保护造血干细胞和祖细胞及免疫系统功能，最近的临床试验已证明其概念验证。此外，在临床前研究中，CDK4/6 抑制已被证明可增强 T 细胞激活和抗肿瘤免疫。因此，添加 Trilaciclib 有可能进一步提高化疗和 ICI 联合治疗的疗效。
在小鼠同源肿瘤模型中，采用 3 周剂量的 Trilaciclib 方案联合化疗/ICI 方案，评估短暂性 CDK4/6 抑制对抗肿瘤反应以及肿瘤内 T 细胞增殖和功能的影响。还分析了接受化疗加或不加 Trilaciclib 的小细胞肺癌（SCLC）患者的外周 T 细胞状态，以深入了解 Trilaciclib 短暂暴露对 T 细胞激活的影响。
临床前研究表明，与化疗和 ICI 联合治疗相比，Trilaciclib 联合化疗/ICI 方案可增强抗肿瘤反应和总生存期。这种作用与肿瘤微环境中 T 细胞亚群的增殖和组成的调节以及效应功能的增强有关。在接受化疗治疗的 SCLC 患者中，Trilaciclib 短暂暴露不仅能维持而且能增加外周淋巴细胞计数并增强 T 细胞激活，这表明 Trilaciclib 不仅能维持而且能增强免疫系统功能。
Trilaciclib 短暂的 CDK4/6 抑制足以增强和延长化疗/ICI 联合治疗的抗肿瘤反应持续时间，提示肿瘤免疫浸润的短暂细胞周期阻滞在重塑肿瘤微环境方面发挥作用。这些结果为 Trilaciclib 与化疗/ICI 方案联合治疗以提高癌症患者的抗肿瘤疗效提供了依据。
