Influence of injection technique, drug formulation and tumor microenvironment on intratumoral immunotherapy delivery and efficacy.
Influence of injection technique, drug formulation and tumor microenvironment on intratumoral immunotherapy delivery and efficacy.
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注射技术、药物配方及肿瘤微环境对肿瘤内免疫治疗递送及疗效的影响。
DOI：
10.1136/jitc-2020-001800
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发表时间：
2021-03
影响因子：
10.9
通讯作者：
Sheth RA
中科院分区：
文献类型：
--
作者：
Muñoz NM;Williams M;Dixon K;Dupuis C;McWatters A;Avritscher R;Manrique SZ;McHugh K;Murthy R;Tam A;Naing A;Patel SP;Leach D;Hartgerink JD;Young S;Prakash P;Hwu P;Sheth RA
免疫治疗剂的肿瘤内递送代表了直接解决肿瘤免疫的局部障碍的令人信服的解决方案。然而，我们之前已经表明，脱靶递送是肿瘤内注射过程中的一个重大问题;这可能导致药物疗效降低和全身毒性。我们已经确定了影响肿瘤内药物递送的三个变量：注射技术，药物制剂和肿瘤微环境。本研究的目的是表征每个变量中的修饰对肿瘤内药物递送和免疫治疗功效的影响。在具有超声、荧光透视和CT扫描能力的混合图像引导介入套件中，在大鼠和小鼠同源肿瘤模型中进行肿瘤内注射。通过CT容积成像定量肿瘤内药物分布。使用流式细胞术和单细胞RNA测序评估了不同针设计和基于水凝胶的药物递送对干扰素基因刺激物（STING）激动剂的免疫应答的影响。我们还评估了肿瘤硬度对药物注射分布的影响。针设计的变化，特别是使用多侧孔针，导致肿瘤内药物沉积相对于传统端孔针的约三倍改善。同样地，相对于端孔STING激动剂递送，通过多侧孔针递送STING激动剂导致I型干扰素相关基因和“炎性”树突细胞基因特征的表达显著增加。嵌入STING激动剂的基于多结构域肽的水凝胶导致肿瘤内沉积的实质性改善;然而，注意到水凝胶在靶肿瘤内产生针对自身的强烈免疫应答。肿瘤间质对肿瘤内药物递送的评价显示，与坚硬肿瘤（MC 38结直肠）相比，软肿瘤（B16黑色素瘤）的肿瘤内分布改善了两倍以上。注射技术、药物制剂和肿瘤硬度在肿瘤内免疫治疗剂的准确递送中起关键作用。
Intratumoral delivery of immunotherapeutics represents a compelling solution to directly address local barriers to tumor immunity. However, we have previously shown that off-target delivery is a substantial problem during intratumoral injections; this can lead to diminished drug efficacy and systemic toxicities. We have identified three variables that influence intratumoral drug delivery: injection technique, drug formulation and tumor microenvironment. The purpose of this study was to characterize the impact of modifications in each variable on intratumoral drug delivery and immunotherapy efficacy. Intratumoral injections were performed in a hybrid image-guided intervention suite with ultrasound, fluoroscopy and CT scanning capabilities in both rat and mouse syngeneic tumor models. Intratumoral drug distribution was quantified by CT volumetric imaging. The influence of varying needle design and hydrogel-based drug delivery on the immune response to a stimulator of interferon genes (STING) agonist was evaluated using flow cytometry and single cell RNA sequencing. We also evaluated the influence of tumor stiffness on drug injection distribution. Variations in needle design, specifically with the use of a multiside hole needle, led to approximately threefold improvements in intratumoral drug deposition relative to conventional end-hole needles. Likewise, delivery of a STING agonist through a multiside hole needle led to significantly increased expression of type I interferon-associated genes and ‘inflammatory’ dendritic cell gene signatures relative to end-hole STING agonist delivery. A multidomain peptide-based hydrogel embedded with a STING agonist led to substantial improvements in intratumoral deposition; however, the hydrogel was noted to generate a strong immune response against itself within the target tumor. Evaluation of tumor stroma on intratumoral drug delivery revealed that there was a greater than twofold improvement in intratumoral distribution in soft tumors (B16 melanoma) compared with firm tumors (MC38 colorectal). Injection technique, drug formulation and tumor stiffness play key roles in the accurate delivery of intratumoral immunotherapeutics.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
5.8
作者：
Leach DG;Newton JM;Florez MA;Lopez-Silva TL;Jones AA;Young S;Sikora AG;Hartgerink JD
通讯作者：
Hartgerink JD
影响因子：
8.8
作者：
Corrales L;Glickman LH;McWhirter SM;Kanne DB;Sivick KE;Katibah GE;Woo SR;Lemmens E;Banda T;Leong JJ;Metchette K;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
10.1
作者：
Farsaci B;Donahue RN;Coplin MA;Grenga I;Lepone LM;Molinolo AA;Hodge JW
通讯作者：
Hodge JW
影响因子：
28.1
作者：
Wang F;Su H;Xu D;Dai W;Zhang W;Wang Z;Anderson CF;Zheng M;Oh R;Wan F;Cui H
通讯作者：
Cui H