Histone deacetylase 6 (HDAC6) inhibition is associated with an increased pro-inflammatory tumor microenvironment and antitumoral immune responses. Here, we show that the HDAC6 inhibitor AVS100 (SS208) had an antitumoral effect in SM1 melanoma and CT26 colon cancer models and increased the efficacy of anti–programmed cell death protein 1 treatment, leading to complete remission in melanoma and increased response in colon cancer. AVS100 treatment increased pro-inflammatory tumor-infiltrating macrophages and CD8 effector T cells with an inflammatory and T cell effector gene signature. Acquired T cell immunity and long-term protection were evidenced as increased immunodominant T cell clones after AVS100 treatment. Last, AVS100 showed no mutagenicity, toxicity, or adverse effects in preclinical good laboratory practice studies, part of the package that has led to US Food and Drug Administration clearance of an investigational new drug application for initiating clinical trials. This would be a first-in-human combination therapy of pembrolizumab with HDAC6 inhibition for locally advanced or metastatic solid tumors.

中文翻译：

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HDAC6 抑制剂 AVS100 （SS208） 诱导促炎性肿瘤微环境并增强免疫治疗


组蛋白脱乙酰酶 6 （HDAC6） 抑制与促炎性肿瘤微环境和抗肿瘤免疫反应的增加有关。在这里，我们表明 HDAC6 抑制剂 AVS100 （SS208） 在 SM1 黑色素瘤和 CT26 结肠癌模型中具有抗肿瘤作用，并增加了抗程序性细胞死亡蛋白 1 治疗的疗效，导致黑色素瘤完全缓解和结肠癌反应增加。AVS100 治疗增加了促炎性肿瘤浸润性巨噬细胞和具有炎症和 T 细胞效应基因特征的 CD8 效应 T 细胞。获得性 T 细胞免疫和长期保护被证明为 AVS100 处理后免疫显性 T 细胞克隆增加。最后，AVS100 在临床前良好实验室实践研究中未显示致突变性、毒性或不良反应，这是导致美国食品和药物管理局批准启动临床试验的研究性新药申请的一部分。这将是 pembrolizumab 与 HDAC6 抑制治疗局部晚期或转移性实体瘤的首次人体联合疗法。