Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas.
Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas; Texas A&M University, College of Medicine, Bryan, Texas.
Int J Radiat Oncol Biol Phys. 2021 Jun 1;110(2):492-506. doi: 10.1016/j.ijrobp.2020.07.2326. Epub 2020 Aug 5.
Mounting evidence demonstrates that combining radiation therapy (RT) with immunotherapy can reduce tumor burden in a subset of patients. However, conventional systemic delivery of immunotherapeutics is often associated with significant adverse effects, which force treatment cessation. The aim of this study was to investigate a minimally invasive therapeutics delivery approach to improve clinical response while attenuating toxicity.
We used a nanofluidic drug-eluting seed (NDES) for sustained intratumoral delivery of combinational antibodies CD40 and PDL1. To enhance immune and tumor response, we combined the NDES intratumoral platform with RT to treat the 4T1 murine model of advanced triple negative breast cancer. We compared the efficacy of NDES against intraperitoneal administration, which mimics conventional systemic treatment. Tumor growth was recorded, and local and systemic immune responses were assessed via imaging mass cytometry and flow cytometry. Livers and lungs were histologically analyzed for evaluation of toxicity and metastasis, respectively.
The combination of RT and sustained intratumoral immunotherapy delivery of CD40 and PDL1 via NDES (NDES CD40/PDL1) showed an increase in both local and systemic immune response. In combination with RT, NDES CD40/PDL1 achieved significant tumor burden reduction and liver inflammation mitigation compared with systemic treatment. Importantly, our treatment strategy boosted the abscopal effect toward attenuating lung metastatic burden.
Overall, our study demonstrated superior efficacy of combination treatment with RT and sustained intratumoral immunotherapy via NDES, offering promise for improving therapeutic index and clinical response.
越来越多的证据表明，将放射治疗（RT）与免疫疗法相结合可以减轻一部分患者的肿瘤负担。然而，传统的系统免疫疗法常常伴随着严重的不良反应，迫使治疗停止。本研究旨在探索一种微创治疗药物输送方法，以提高临床疗效的同时降低毒性。
我们使用纳米流体药物洗脱种子（NDES）来持续瘤内输送组合抗体 CD40 和 PDL1。为了增强免疫和肿瘤反应，我们将 NDES 瘤内平台与 RT 相结合，用于治疗晚期三阴性乳腺癌的 4T1 小鼠模型。我们比较了 NDES 的疗效与模拟传统系统治疗的腹腔内给药。通过成像质谱流式细胞术和流式细胞术评估肿瘤生长和局部及全身免疫反应。分别对肝脏和肺部进行组织学分析，以评估毒性和转移情况。
RT 与通过 NDES 持续瘤内免疫治疗输送 CD40 和 PDL1 的联合治疗（NDES CD40/PDL1）增加了局部和全身免疫反应。与系统治疗相比，NDES CD40/PDL1 联合 RT 显著减轻了肿瘤负担和肝脏炎症。重要的是，我们的治疗策略增强了针对肺转移灶的远隔效应。
总的来说，本研究表明，RT 与通过 NDES 持续瘤内免疫治疗联合治疗具有更好的疗效，为提高治疗指数和临床疗效提供了希望。
