Harnessing innate lung anti-cancer effector functions with a novel bacterial-derived immunotherapy.
Harnessing innate lung anti-cancer effector functions with a novel bacterial-derived immunotherapy.
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DOI：
10.1080/2162402x.2017.1398875
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发表时间：
2018
期刊：
影响因子：
7.2
通讯作者：
Mullins DW
中科院分区：
文献类型：
--
作者：
Bazett M;Costa AM;Bosiljcic M;Anderson RM;Alexander MP;Wong SWY;Dhanji S;Chen JM;Pankovich J;Lam S;Sutcliffe S;Gunn H;Kalyan S;Mullins DW
众所周知，急性感染会诱导强烈的抗肿瘤免疫反应，但由于缺乏安全、持续地激发治疗反应的有效策略，临床转化受到阻碍。一种新的治疗方法克服了这些局限性，该方法包括重复皮下注射克雷伯氏菌衍生的研究性免疫治疗药物 QBKPN。在肺癌的临床前模型中，QBKPN 给药始终显示出抗癌功效，该功效取决于克雷伯氏菌预暴露，但与适应性免疫无关。相反，QBKPN 诱导了需要 NK 细胞和 NKG2D 参与的抗肿瘤先天免疫。 QBKPN 增加了肺部的 NK 细胞和巨噬细胞，改变了巨噬细胞的极化，并增加了细胞毒性分子的产生。一项针对非小细胞肺癌患者的探索性试验表明，QBKPN 具有良好的耐受性、安全性，并可诱导外周免疫变化，提示巨噬细胞极化以及白细胞上 PD-1 和 PD-L1 表达的减少。这些数据证明了这种利用先天抗肿瘤免疫机制的癌症免疫治疗策略的临床前疗效、临床安全性和耐受性。
Acute infection is known to induce strong anti-tumor immune responses, but clinical translation has been hindered by the lack of an effective strategy to safely and consistently provoke a therapeutic response. These limitations are overcome with a novel treatment approach involving repeated subcutaneous delivery of a Klebsiella-derived investigational immunotherapeutic, QBKPN. In preclinical models of lung cancer, QBKPN administration consistently showed anti-cancer efficacy, which was dependent on Klebsiella pre-exposure, but was independent of adaptive immunity. Rather, QBKPN induced anti-tumor innate immunity that required NK cells and NKG2D engagement. QBKPN increased NK cells and macrophages in the lungs, altered macrophage polarization, and augmented the production of cytotoxic molecules. An exploratory trial in patients with non-small cell lung cancer demonstrated QBKPN was well tolerated, safe, and induced peripheral immune changes suggestive of macrophage polarization and reduction of PD-1 and PD-L1 expression on leukocytes. These data demonstrate preclinical efficacy, and clinical safety and tolerability, for this cancer immunotherapy strategy that exploits innate anti-tumor immune mechanisms.