Cancer immunotherapy using monoclonal antibodies targeting immune checkpoints has undoubtedly revolutionized the cancer treatment landscape in the last decade. Immune checkpoint inhibitors can elicit long-lasting, previously unheard-of responses in a number of tumor entities. Yet, even in such tumors as metastatic melanoma and non-small cell-lung cancer, in which immune checkpoint inhibition has become the first-line treatment of choice, only a minority of patients will benefit considerably from these treatments. This has been attributed to a number of factors, including an immune-suppressive tumor microenvironment (TME). Using different modalities to break these barriers is of utmost importance to expand the population of patients that benefit from immune checkpoint inhibition. The multifunctional cytokine transforming growth factor-β (TGF-β) has long been recognized as an immune-suppressive factor in the TME. A considerable number of drugs have been developed to target TGF-β, yet most of these have since been discontinued. The combination of anti–TGF-β agents with immune checkpoint inhibitors now has the potential to revive this target as a viable immunomodulatory therapeutic approach. Currently, a limited number of small molecular inhibitor and monoclonal antibody candidates that target TGF-β are in clinical development in combination with the following immune checkpoint inhibitors: SRK 181, an antibody inhibiting the activation of latent TGF-β1; NIS 793, a monoclonal antibody targeting TGF-β; and SHR 1701, a fusion protein consisting of an anti-PD-L1 monoclonal antibody fused with the extracellular domain of human TGF-β receptor II. Several small molecular inhibitors are also in development and are briefly reviewed: LY364947, a pyrazole-based small molecular inhibitor of the serine-threonine kinase activity of TGFβRI; SB-431542, an inhibitor targeting several TGF-β superfamily Type I activin receptor-like kinases as well as TGF-β1-induced nuclear Smad3 localization; and galunisertib, an oral small molecular inhibitor of the TGFβRI kinase. One of the most advanced agents in this area is bintrafusp alfa, a bifunctional fusion protein composed of the extracellular domain of TGF-β receptor II fused to a human IgG1 mAb blocking PD-L1. Bintrafusp alfa is currently in advanced clinical development and as an agent in this space with the most clinical experience, is a focused highlight of this review.

使用针对免疫检查点的单克隆抗体的癌症免疫疗法无疑彻底改变了过去十年的癌症治疗格局。免疫检查点抑制剂可以在许多肿瘤实体中引发持久的、以前闻所未闻的反应。然而，即使在转移性黑色素瘤和非小细胞肺癌等肿瘤中，免疫检查点抑制已成为首选治​​疗方法，也只有少数患者会从这些治疗中获益匪浅。这归因于多种因素，包括免疫抑制肿瘤微环境（TME）。使用不同的方式打破这些障碍对于扩大受益于免疫检查点抑制的患者群体至关重要。多功能细胞因子转化生长因子-β (TGF-β) 长期以来被认为是 TME 中的免疫抑制因子。已经开发出相当多的针对 TGF-β 的药物，但其中大多数已停产。抗 TGF-β 药物与免疫检查点抑制剂的组合现在有可能使这一目标成为一种可行的免疫调节治疗方法。目前，有限数量的针对 TGF-β 的小分子抑制剂和单克隆抗体候选物正在与以下免疫检查点抑制剂联合进行临床开发： SRK 181，一种抑制潜在 TGF-β1 激活的抗体；NIS 793，一种针对 TGF-β 的单克隆抗体；SHR 1701，一种融合蛋白，由抗 PD-L1 单克隆抗体与人 TGF-β 受体 II 的胞外结构域融合组成。几种小分子抑制剂也在开发中，并简要回顾一下： LY364947，一种基于吡唑的 TGFβRI 丝氨酸-苏氨酸激酶活性小分子抑制剂；SB-431542，一种针对多种 TGF-β 超家族 I 型激活素受体样激酶以及 TGF-β1 诱导的核 Smad3 定位的抑制剂；和 galunisertib，一种 TGFβRI 激酶的口服小分子抑制剂。该领域最先进的药物之一是 bintrafusp alfa，这是一种双功能融合蛋白，由 TGF-β 受体 II 的胞外结构域与阻断 PD-L1 的人 IgG1 mAb 融合组成。Bintrafusp alfa 目前正处于高级临床开发阶段，作为该领域最具临床经验的药物，是本次审查的重点。