Genetically engineered macrophages persist in solid tumors and locally deliver therapeutic proteins to activate immune responses.
Genetically engineered macrophages persist in solid tumors and locally deliver therapeutic proteins to activate immune responses.
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DOI：
10.1136/jitc-2020-001356
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发表时间：
2020-10
影响因子：
10.9
通讯作者：
Crane CA
中科院分区：
文献类型：
--
作者：
Brempelis KJ;Cowan CM;Kreuser SA;Labadie KP;Prieskorn BM;Lieberman NAP;Ene CI;Moyes KW;Chinn H;DeGolier KR;Matsumoto LR;Daniel SK;Yokoyama JK;Davis AD;Hoglund VJ;Smythe KS;Balcaitis SD;Jensen MC;Ellenbogen RG;Campbell JS;Pierce RH;Holland EC;Pillarisetty VG;Crane CA
虽然目前批准的免疫疗法，包括嵌合抗原受体T细胞和检查点阻断抗体，已经成功地用于治疗血液病和一些实体肿瘤，但许多实体肿瘤仍然对这些治疗模式有耐药性。在实体肿瘤中，有效的抗肿瘤免疫反应的发展受到限制的免疫细胞浸润和免疫抑制肿瘤微环境（TME）的阻碍。一种浸润并持续存在于实体TME的免疫疗法，同时提供局部、稳定的治疗水平，以激活或重新激活抗肿瘤免疫，可以克服当前免疫疗法面临的这些挑战。利用慢病毒驱动的工程技术，我们对人类和小鼠巨噬细胞进行编程，以表达治疗有效载荷，包括白细胞介素(IL)-12。体外共培养研究用于评估分泌IL-12的基因工程巨噬细胞（GEMs）对T细胞和GEMs本身的影响。在胶质母细胞瘤和黑色素瘤的同基因小鼠模型以及从晚期胃肠道恶性肿瘤患者分离的人类肿瘤切片中，评估了IL-12 GEMs对TME内基因表达谱和肿瘤负荷的影响。在这里，我们提出了一个细胞免疫治疗平台，使用慢病毒驱动的人类和小鼠巨噬细胞的基因工程来组成性表达蛋白质，包括分泌的细胞因子和全长检查点抗体，以及克服这些障碍的细胞质和表面蛋白质。在胶质母细胞瘤的异种移植小鼠模型中，GEMs转运、持续存在并表达慢病毒有效载荷，并表达一种非信号截断的CD19表面蛋白用于消除。分泌il -12的gem在体外激活T细胞并诱导干扰素γ (IFNγ)，减缓肿瘤生长，从而延长体内生存期。在同基因胶质母细胞瘤模型中，在小鼠骨髓来源的分泌小鼠IL-12的gem治疗的小鼠中也观察到IFNγ信号级联反应。这些发现在由完整MEs组成的离体肿瘤切片中得到了再现。在这种情况下，IL-12 GEMs诱导肿瘤细胞死亡、趋化因子和ifn γ刺激的基因和蛋白。我们的数据表明，GEMs可以精确地将可滴定剂量的治疗性蛋白质递送到TME，以提高安全性、组织外显率、靶向递送和药代动力学。
Though currently approved immunotherapies, including chimeric antigen receptor T cells and checkpoint blockade antibodies, have been successfully used to treat hematological and some solid tumor cancers, many solid tumors remain resistant to these modes of treatment. In solid tumors, the development of effective antitumor immune responses is hampered by restricted immune cell infiltration and an immunosuppressive tumor microenvironment (TME). An immunotherapy that infiltrates and persists in the solid TME, while providing local, stable levels of therapeutic to activate or reinvigorate antitumor immunity could overcome these challenges faced by current immunotherapies. Using lentivirus-driven engineering, we programmed human and murine macrophages to express therapeutic payloads, including Interleukin (IL)-12. In vitro coculture studies were used to evaluate the effect of genetically engineered macrophages (GEMs) secreting IL-12 on T cells and on the GEMs themselves. The effects of IL-12 GEMs on gene expression profiles within the TME and tumor burden were evaluated in syngeneic mouse models of glioblastoma and melanoma and in human tumor slices isolated from patients with advanced gastrointestinal malignancies. Here, we present a cellular immunotherapy platform using lentivirus-driven genetic engineering of human and mouse macrophages to constitutively express proteins, including secreted cytokines and full-length checkpoint antibodies, as well as cytoplasmic and surface proteins that overcomes these barriers. GEMs traffic to, persist in, and express lentiviral payloads in xenograft mouse models of glioblastoma, and express a non-signaling truncated CD19 surface protein for elimination. IL-12-secreting GEMs activated T cells and induced interferon-gamma (IFNγ) in vitro and slowed tumor growth resulting in extended survival in vivo. In a syngeneic glioblastoma model, IFNγ signaling cascades were also observed in mice treated with mouse bone-marrow-derived GEMs secreting murine IL-12. These findings were reproduced in ex vivo tumor slices comprised of intact MEs. In this setting, IL-12 GEMs induced tumor cell death, chemokines and IFNγ-stimulated genes and proteins. Our data demonstrate that GEMs can precisely deliver titratable doses of therapeutic proteins to the TME to improve safety, tissue penetrance, targeted delivery and pharmacokinetics.
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影响因子：
15.9
作者：
Berger, Carolina;Jensen, Michael C.;Riddell, Stanley R.
通讯作者：
Riddell, Stanley R.
DOI：
10.1038/nrclinonc.2016.217
发表时间：
2017-07
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Mantovani A;Marchesi F;Malesci A;Laghi L;Allavena P
通讯作者：
Allavena P
影响因子：
2.6
作者：
Barczak, Wojciech;Suchorska, Wiktoria;Kulcenty, Katarzyna
通讯作者：
Kulcenty, Katarzyna
影响因子：
4.4
作者：
Grohmann, U;Belladonna, ML;Puccetti, P
通讯作者：
Puccetti, P
影响因子：
8.4
作者：
Giaccone, G.;Bazhenova, L. A.;Fakhrai, H.
通讯作者：
Fakhrai, H.