Cytokine Receptor Laboratory, Flanders Institute of Biotechnology, VIB-UGent Center for Medical Biotechnology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
CNRS UMR 5235, University Montpellier, Montpellier, France.
Cancer Res. 2018 Jan 15;78(2):463-474. doi: 10.1158/0008-5472.CAN-17-1980. Epub 2017 Nov 29.
An ideal generic cancer immunotherapy should mobilize the immune system to destroy tumor cells without harming healthy cells and remain active in case of recurrence. Furthermore, it should preferably not rely on tumor-specific surface markers, as these are only available in a limited set of malignancies. Despite approval for treatment of various cancers, clinical application of cytokines is still impeded by their multiple toxic side effects. Type I IFN has a long history in the treatment of cancer, but its multifaceted activity pattern and complex side effects prevent its clinical use. Here we develop AcTakines (Activity-on-Target cytokines), optimized (mutated) immunocytokines that are up to 1,000-fold more potent on target cells, allowing specific signaling in selected cell types only. Type I IFN-derived AcTaferon (AFN)-targeting Clec9A dendritic cells (DC) displayed strong antitumor activity in murine melanoma, breast carcinoma, and lymphoma models and against human lymphoma in humanized mice without any detectable toxic side effects. Combined with immune checkpoint blockade, chemotherapy, or low-dose TNF, complete tumor regression and long-lasting tumor immunity were observed, still without adverse effects. Our findings indicate that DC-targeted AFNs provide a novel class of highly efficient, safe, and broad-spectrum off-the-shelf cancer immunotherapeutics with no need for a tumor marker. Targeted type I interferon elicits powerful antitumor efficacy, similar to wild-type IFN, but without any toxic side effects. .
理想的通用癌症免疫疗法应该能够调动免疫系统，在不伤害健康细胞的情况下摧毁肿瘤细胞，并在复发时保持活性。此外，它最好不要依赖肿瘤特异性表面标志物，因为这些标志物只在有限的恶性肿瘤中存在。尽管细胞因子已被批准用于治疗各种癌症，但由于其多种毒性副作用，其临床应用仍然受到限制。I 型干扰素在癌症治疗中有很长的历史，但由于其多方面的活性模式和复杂的副作用，阻止了其临床应用。在这里，我们开发了 AcTakines（针对靶点的细胞因子），这是优化（突变）的免疫细胞因子，在靶细胞上的效力提高了 1000 倍，仅允许在选定的细胞类型中进行特异性信号传递。源自 I 型干扰素的 AcTaferon（AFN）靶向 Clec9A 树突状细胞（DC）在小鼠黑色素瘤、乳腺癌和淋巴瘤模型以及人源化小鼠中的人类淋巴瘤中显示出强烈的抗肿瘤活性，没有任何可检测到的毒性副作用。与免疫检查点阻断、化疗或低剂量 TNF 联合使用时，观察到完全肿瘤消退和持久的肿瘤免疫，仍然没有不良反应。我们的研究结果表明，靶向 DC 的 AFNs 提供了一类新型的高效、安全、广谱的现货癌症免疫疗法，无需肿瘤标志物。靶向 I 型干扰素引发了类似于野生型 IFN 的强大抗肿瘤疗效，但没有任何毒性副作用。
