M7824, a novel bifunctional anti-PD-L1/TGFβ Trap fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine.
M7824, a novel bifunctional anti-PD-L1/TGFβ Trap fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine.
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DOI：
10.1080/2162402x.2018.1426519
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发表时间：
2018
期刊：
影响因子：
7.2
通讯作者：
Gameiro SR
中科院分区：
文献类型：
--
作者：
Knudson KM;Hicks KC;Luo X;Chen JQ;Schlom J;Gameiro SR
肿瘤通过多种机制逃避宿主免疫监视，包括产生抑制免疫效应功能的肿瘤微环境。TGFβ的分泌和免疫检查点程序性细胞死亡配体-1 （PD-L1）的上调是免疫逃避和肿瘤进展的两个主要因素。在这里，我们检测了一类双功能检查点抑制剂，融合蛋白M7824的有效性，融合蛋白包含与人抗pd - l1重链（αPD-L1） c端连接的人tgf - β rii的细胞外结构域（TGFβ Trap）。我们证明M7824可降低小鼠血浆tgf - β1，与肿瘤中的PD-L1结合，并降低肿瘤微环境中tgf - β诱导的信号传导。在小鼠乳腺癌和结肠癌模型中，与单独靶向TGFβ相比，M7824降低了肿瘤负荷，提高了总生存期。M7824治疗促进了CD8+ T细胞和NK细胞的活化，这两个免疫群体是M7824介导的最佳肿瘤控制所必需的。当与治疗性癌症疫苗联合使用时，M7824优于TGFβ-或α pd - l1靶向治疗。这些发现证明了M7824同时靶向TGFβ和PD-L1/PD-1免疫抑制通路促进抗肿瘤反应和疗效的价值。这些研究还支持M7824作为单一疗法或与其他免疫疗法（如治疗性癌症疫苗）联合使用的潜在临床应用，包括αPD-L1/αPD-1检查点阻断疗法进展的患者。
Tumors evade host immune surveillance through multiple mechanisms, including the generation of a tumor microenvironment that suppresses immune effector function. Secretion of TGFβ and upregulation of immune checkpoint programmed cell death ligand-1 (PD-L1) are two main contributors to immune evasion and tumor progression. Here, we examined the efficacy of a first-in-class bifunctional checkpoint inhibitor, the fusion protein M7824, comprising the extracellular domain of human TGFβRII (TGFβ Trap) linked to the C-terminus of human anti-PD-L1 heavy chain (αPD-L1). We demonstrate that M7824 reduces plasma TGFβ1, binds to PD-L1 in the tumor, and decreases TGFβ-induced signaling in the tumor microenvironment in mice. In murine breast and colon carcinoma models, M7824 decreased tumor burden and increased overall survival as compared to targeting TGFβ alone. M7824 treatment promoted CD8+ T cell and NK cell activation, and both of these immune populations were required for optimal M7824-mediated tumor control. M7824 was superior to TGFβ- or αPD-L1-targeted therapies when in combination with a therapeutic cancer vaccine. These findings demonstrate the value of using M7824 to simultaneously target TGFβ and PD-L1/PD-1 immunosuppressive pathways to promote anti-tumor responses and efficacy. The studies also support the potential clinical use of M7824 as a monotherapy or in combination with other immunotherapies, such as therapeutic cancer vaccines, including for patients who have progressed on αPD-L1/αPD-1 checkpoint blockade therapies.