Muñoz Nina M, Williams Malea, Dixon Katherine, Dupuis Crystal, McWatters Amanda, Avritscher Rony, Manrique Soraya Zorro, McHugh Kevin, Murthy Ravi, Tam Alda, Naing Aung, Patel Sapna P, Leach David, Hartgerink Jeffrey D, Young Simon, Prakash Punit, Hwu Patrick, Sheth Rahul A
Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
J Immunother Cancer. 2021 Feb;9(2). doi: 10.1136/jitc-2020-001800.
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.
肿瘤内递送免疫治疗药物是直接解决肿瘤免疫局部障碍的一个极具吸引力的方案。然而，我们之前已经表明，在肿瘤内注射过程中，脱靶递送是一个严重问题；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。本研究的目的是描述每个变量的改变对肿瘤内药物递送和免疫治疗疗效的影响。
在具有超声、荧光透视和CT扫描功能的混合图像引导干预套件中，对大鼠和小鼠同基因肿瘤模型进行肿瘤内注射。通过CT容积成像对肿瘤内药物分布进行定量。使用流式细胞术和单细胞RNA测序评估不同针设计和基于水凝胶的药物递送对干扰素基因（STING）激动剂刺激物免疫反应的影响。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，相对于传统的端孔针，肿瘤内药物沉积提高了约三倍。同样，与端孔STING激动剂递送相比，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”树突状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有实质性改善；然而，注意到该水凝胶在靶肿瘤内产生了针对自身的强烈免疫反应。对肿瘤基质对肿瘤内药物递送的评估表明，与坚硬肿瘤（MC38结肠直肠癌）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药物的精确递送中起关键作用。
