Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies.
Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies.
复制标题
DOI：
10.1126/scitranslmed.aax0876
复制
发表时间：
2020-02-12
影响因子：
17.1
通讯作者：
Danino T
中科院分区：
文献类型：
--
作者：
Gurbatri CR;Lia I;Vincent R;Coker C;Castro S;Treuting PM;Hinchliffe TE;Arpaia N;Danino T
检查点抑制剂已经彻底改变了癌症治疗，但仅在一部分患者中起作用，并可能导致多种毒性，这表明需要更有针对性的递送系统。由于它们优先定殖于肿瘤，微生物是局部递送癌症治疗剂的天然平台。在这里，我们设计了一种益生菌系统，用于使用稳定的裂解释放机制控制生产和肿瘤内释放靶向程序性细胞死亡蛋白-配体1（PD-L1）和细胞毒性T淋巴细胞相关蛋白-4（CTLA-4）的纳米抗体。我们使用计算建模结合裂解回路动力学的实验验证来确定最佳遗传回路参数以获得最大治疗效果。与类似的临床相关抗体相比，单次注射这种工程化系统显示出增强的治疗反应，导致同基因小鼠模型中的肿瘤消退。支持增强全身免疫应答，我们观察到活化T细胞的相对增加、远位效应以及用益生菌递送的检查点抑制剂处理的小鼠中全身T细胞记忆群体的相应增加。最后，我们利用我们平台的模块化，通过与益生菌产生的细胞因子粒细胞-巨噬细胞集落刺激因子（GM-CSF）的有效组合，在免疫原性差的同系小鼠模型中实现增强的治疗功效。总之，这些结果表明，我们的工程益生菌系统桥接了合成生物学和免疫学，以改善检查点阻断递送。工程益生菌系统将检查点阻断纳米抗体局部递送至肿瘤用于持续治疗释放。
Checkpoint inhibitors have revolutionized cancer therapy but only work in a subset of patients and can lead to a multitude of toxicities, suggesting the need for more targeted delivery systems. Because of their preferential colonization of tumors, microbes are a natural platform for the local delivery of cancer therapeutics. Here, we engineer a probiotic bacteria system for the controlled production and intratumoral release of nanobodies targeting programmed cell death protein – ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) using a stabilized lysing release mechanism. We used computational modeling coupled with experimental validation of lysis circuit dynamics to determine the optimal genetic circuit parameters for maximal therapeutic efficacy. A single injection of this engineered system demonstrated an enhanced therapeutic response compared to analogous clinically relevant antibodies, resulting in tumor regression in syngeneic mouse models. Supporting the potentiation of a systemic immune response, we observed a relative increase in activated T cells, an abscopal effect, and corresponding increases in systemic T cell memory populations in mice treated with probiotically-delivered checkpoint inhibitors. Lastly, we leveraged the modularity of our platform to achieve enhanced therapeutic efficacy in a poorly immunogenic syngeneic mouse model through effective combinations with a probiotically-produced cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF). Together, these results demonstrate that our engineered probiotic system bridges synthetic biology and immunology to improve upon checkpoint blockade delivery. An engineered probiotic system locally delivers checkpoint blockade nanobodies to tumors for sustained therapeutic release.
登录
查看更多内容
影响因子：
64.5
作者：
FEARON, ER;PARDOLL, DM;FROST, P
通讯作者：
FROST, P
影响因子：
5.6
作者：
He, Lian;Yang, Huijun;Xia, Liqiu
通讯作者：
Xia, Liqiu
影响因子：
16.6
作者：
Hwang IY;Koh E;Wong A;March JC;Bentley WE;Lee YS;Chang MW
通讯作者：
Chang MW
DOI：
10.1186/s13054-017-1678-1
发表时间：
2017-04-14
期刊：
Critical care (London, England)
影响因子：
--
作者：
Kroschinsky F;Stölzel F;von Bonin S;Beutel G;Kochanek M;Kiehl M;Schellongowski P;Intensive Care in Hematological and Oncological Patients (iCHOP) Collaborative Group
通讯作者：
Intensive Care in Hematological and Oncological Patients (iCHOP) Collaborative Group
影响因子：
10.9
作者：
Kim K;Skora A;Li Z;Tam A;Diaz L;Papadopolous N;Blosser L;Kinzler K;Vogelstein B;Zhou S
通讯作者：
Zhou S