Personalized Tumor RNA Loaded Lipid-Nanoparticles Prime the Systemic and Intratumoral Milieu for Response to Cancer Immunotherapy.
Personalized Tumor RNA Loaded Lipid-Nanoparticles Prime the Systemic and Intratumoral Milieu for Response to Cancer Immunotherapy.
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DOI：
10.1021/acs.nanolett.8b02179
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发表时间：
2018-10-10
期刊：
影响因子：
10.8
通讯作者：
Mitchell DA
中科院分区：
文献类型：
--
作者：
Sayour EJ;Grippin A;De Leon G;Stover B;Rahman M;Karachi A;Wummer B;Moore G;Castillo-Caro P;Fredenburg K;Sarkisian MR;Huang J;Deleyrolle LP;Sahay B;Carrera-Justiz S;Mendez-Gomez HR;Mitchell DA
由于新型NP设计的生物学反应性未知，将纳米颗粒（NP）转换为人类临床试验的人类临床试验滞后。为了克服这些局限性，简单良好的mRNA脂质NP已作为癌症免疫治疗疫苗发展。虽然已经设计了与肿瘤相关的抗原或新皮特植物编码的RNA脂质-NP的占主导地位，但仍旨在靶向淋巴机器人，但它们仍然受到深刻的肿瘤内和全身免疫抑制的影响，这可能阻碍了激活的T细胞反应。在此，我们表明，无靶的肿瘤RNA（源自整个转录组）的全身定位封装在脂质-NP中，并具有过多的正电荷，质量是外周和肿瘤内环境，以反应免疫疗法。在免疫抗性肿瘤模型中，这些RNA-NP激活了全身和肿瘤内髓样细胞的优势（以PD-L1和CD86的共表达为特征）。添加免疫检查点抑制剂（ICIS）（对用RNA-NP的动物）增加了外围/肿瘤内PD-1+ CD8+细胞，并介导ICIS在ICIS没有赋予治疗益处的设置中介导协同的抗肿瘤功效。这些协同作用是由从浆细胞类动物树突状细胞（PDC）释放的I型干扰素介导的。在翻译研究中，个性化的mRNA-NP在具有自发性恶性神经胶质瘤的客户拥有的犬类中是安全且活跃的。总而言之，我们证明了与诱导的PD-L1表达相关的肿瘤中的广泛免疫激活，可以被治疗。虽然免疫疗法仅对一部分癌症患者仍然有效，但与全身免疫调节RNA-NP的联合治疗可能会扩大其治疗效力。
Translation of nanoparticles (NPs) into human clinical trials for patients with refractory cancers has lagged due to unknown biologic reactivities of novel NP designs. To overcome these limitations, simple well-characterized mRNA lipid-NPs have been developed as cancer immunotherapeutic vaccines. While the preponderance of RNA lipid-NPs encoding for tumor-associated antigens or neoepitopes have been designed to target lymphoid organs, they remain encumbered by the profound intratumoral and systemic immunosuppression that may stymie an activated T cell response. Herein, we show that systemic localization of untargeted tumor RNA (derived from whole transcriptome) encapsulated in lipid-NPs, with excess positive charge, primes the peripheral and intratumoral milieu for response to immunotherapy. In immunologically resistant tumor models, these RNA-NPs activate the preponderance of systemic and intratumoral myeloid cells (characterized by coexpression of PD-L1 and CD86). Addition of immune checkpoint inhibitors (ICIs) (to animals primed with RNA-NPs) augments peripheral/intratumoral PD-1+CD8+ cells and mediates synergistic antitumor efficacy in settings where ICIs alone do not confer therapeutic benefit. These synergistic effects are mediated by type I interferon released from plasmacytoid dendritic cells (pDCs). In translational studies, personalized mRNA-NPs were safe and active in a client-owned canine with a spontaneous malignant glioma. In summary, we demonstrate widespread immune activation from tumor loaded RNA-NPs concomitant with inducible PD-L1 expression that can be therapeutically exploited. While immunotherapy remains effective for only a subset of cancer patients, combination therapy with systemic immunomodulating RNA-NPs may broaden its therapeutic potency.
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影响因子：
--
作者：
Filley AC;Henriquez M;Dey M
通讯作者：
Dey M
影响因子：
82.9
作者：
Gros A;Parkhurst MR;Tran E;Pasetto A;Robbins PF;Ilyas S;Prickett TD;Gartner JJ;Crystal JS;Roberts IM;Trebska-McGowan K;Wunderlich JR;Yang JC;Rosenberg SA
通讯作者：
Rosenberg SA
影响因子：
51.1
作者：
Weller, Michael;Butowski, Nicholas;Sampson, John H.
通讯作者：
Sampson, John H.
影响因子：
17.1
作者：
Rosenberg SA
通讯作者：
Rosenberg SA
DOI：
10.1056/nejmoa1200694
发表时间：
2012-06-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Brahmer JR;Tykodi SS;Chow LQ;Hwu WJ;Topalian SL;Hwu P;Drake CG;Camacho LH;Kauh J;Odunsi K;Pitot HC;Hamid O;Bhatia S;Martins R;Eaton K;Chen S;Salay TM;Alaparthy S;Grosso JF;Korman AJ;Parker SM;Agrawal S;Goldberg SM;Pardoll DM;Gupta A;Wigginton JM
通讯作者：
Wigginton JM