Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Jesse Brown VA Medical Center, Chicago, IL, USA.
EBioMedicine. 2022 Dec;86:104380. doi: 10.1016/j.ebiom.2022.104380. Epub 2022 Nov 28.
Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for solid tumors. However, even in cancers generally considered ICI-sensitive, responses can vary significantly. Thus, there is an ever-increasing interest in identifying novel means of improving therapeutic responses, both for cancers in which ICIs are indicated and those for which they have yet to show significant anti-tumor activity. To this end, Transforming Growth Factor β (TGFβ) signaling is emerging as an important barrier to the efficacy of ICIs. Accordingly, several preclinical studies now support the use of combined TGFβ and immune checkpoint blockade, with near-uniform positive results across a wide range of tumor types. However, as these approaches have started to emerge in clinical trials, the addition of TGFβ inhibitors has often failed to show a meaningful benefit beyond the current generation of ICIs alone. Here, we summarize landmark clinical studies exploring combined TGFβ and immune checkpoint blockade. These studies not only reinforce the difficulty in translating results from rodents to clinical trials in immune-oncology but also underscore the need to re-evaluate the design of trials exploring this approach, incorporating both mechanism-driven combination strategies and novel, predictive biomarkers to identify the patients most likely to derive clinical benefit.
免疫检查点抑制剂（ICIs）改变了实体瘤的治疗模式。然而，即使在通常被认为对 ICI 敏感的癌症中，反应也可能有很大差异。因此，人们越来越有兴趣寻找新的方法来提高治疗反应，包括那些已经表明对 ICI 有显著抗肿瘤活性的癌症和尚未显示出显著抗肿瘤活性的癌症。为此，转化生长因子 β（TGFβ）信号转导正在成为 ICI 疗效的一个重要障碍。因此，现在有几项临床前研究支持联合使用 TGFβ 和免疫检查点阻断，在广泛的肿瘤类型中几乎都得到了一致的积极结果。然而，随着这些方法开始在临床试验中出现，TGFβ 抑制剂的添加往往未能显示出比目前一代 ICI 单独使用更有意义的益处。在这里，我们总结了探索联合 TGFβ 和免疫检查点阻断的标志性临床研究。这些研究不仅强调了将啮齿动物的研究结果转化为免疫肿瘤学临床试验的困难，还强调了需要重新评估探索这一方法的试验设计，包括基于机制的联合策略和新的、预测性的生物标志物，以确定最有可能从临床获益的患者。
