Department of Virology, National Institute of Public Health NIH - National Research Institute, Chocimska 24, 00-791 Warsaw, Poland.
Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Via F. Marzolo 5, 35131 Padua, Italy.
Eur J Pharm Biopharm. 2024 Jun;199:114300. doi: 10.1016/j.ejpb.2024.114300. Epub 2024 Apr 30.
Triple-negative breast cancer (TNBC) is considered one of the most incurable malignancies due to its clinical characteristics, including high invasiveness, high metastatic potential, proneness to relapse, and poor prognosis. Therefore, it remains a critical unmet medical need. On the other hand, poor delivery efficiency continues to reduce the efficacy of anti-cancer therapeutics developed against solid tumours using various strategies, such as genetically engineered oncolytic vectors used as nanocarriers. The study was designed to evaluate the anti-tumour efficacy of a novel combinatorial therapy based on oncolytic adenovirus AdV5/3-D24-ICOSL-CD40L with an anti-PD-1 (pembrolizumab) and paclitaxel (PTX). Here, we first tested the antineoplastic effect in two-dimensional (2D) and three-dimensional (3D) breast cancer models in MDA-MB-231, MDA-MB-468 and MCF-7 cells. Then, to further evaluate the efficacy of combinatorial therapy, including immunological aspects, we established a three-dimensional (3D) co-culture model based on MDA-MB-231 cells with peripheral blood mononuclear cells (PBMCs) to create an integrated system that more closely mimics the complexity of the tumour microenvironment and interacts with the immune system. Treatment with OV as a priming agent, followed by pembrolizumab and then paclitaxel, was the most effective in reducing the tumour volume in TNBC co-cultured spheroids. Further, T-cell phenotyping analyses revealed significantly increased infiltration of CD8+, CD4+ T and Tregs cells. Moreover, the observed anti-tumour effects positively correlated with the level of CD4+ T cell infiltrates, suggesting the development of anti-cancer immunity. Our study demonstrated that combining different immunotherapeutic agents (virus, pembrolizumab) with PTX reduced the tumour volume of the TNBC co-cultured spheroids compared to relevant controls. Importantly, sequential administration of the investigational agents (priming with the vector) further enhanced the anti-cancer efficacy in 3D culture over other groups tested. Taken together, these results support further evaluation of the virus in combination with anti-PD-1 and PTX for the treatment of triple-negative breast cancer patients. Importantly, further studies with in vivo models should be conducted to better understand the translational aspects of tested therapy.
三阴性乳腺癌（TNBC）被认为是最难治愈的恶性肿瘤之一，其临床特征包括高侵袭性、高转移潜能、易复发和预后不良。因此，它仍然是一个亟待解决的医学难题。另一方面，由于采用了各种策略，如作为纳米载体的基因工程溶瘤病毒载体，开发针对实体瘤的抗癌疗法的递送效率仍然很差，从而降低了其疗效。本研究旨在评估新型联合治疗的抗肿瘤疗效，该治疗基于溶瘤腺病毒 AdV5/3-D24-ICOSL-CD40L 与抗 PD-1（pembrolizumab）和紫杉醇（PTX）联合使用。在这里，我们首先在 MDA-MB-231、MDA-MB-468 和 MCF-7 细胞的二维（2D）和三维（3D）乳腺癌模型中测试了抗肿瘤作用。然后，为了进一步评估包括免疫方面在内的联合治疗的疗效，我们建立了基于 MDA-MB-231 细胞与外周血单核细胞（PBMCs）的三维（3D）共培养模型，以创建更紧密模拟肿瘤微环境复杂性并与免疫系统相互作用的综合系统。用 OV 作为起始剂进行治疗，然后用 pembrolizumab 治疗，最后用 paclitaxel 治疗，在 TNBC 共培养球体中最有效地减少肿瘤体积。此外，T 细胞表型分析显示 CD8+、CD4+T 和 Tregs 细胞的浸润显著增加。此外，观察到的抗肿瘤作用与 CD4+T 细胞浸润水平呈正相关，提示抗肿瘤免疫的发展。我们的研究表明，与相关对照相比，联合使用不同的免疫治疗药物（病毒、pembrolizumab）和 PTX 可减少 TNBC 共培养球体的肿瘤体积。重要的是，与其他测试组相比，在 3D 培养中顺序给予研究药物（用载体进行起始治疗）进一步增强了抗癌疗效。总之，这些结果支持进一步评估病毒联合抗 PD-1 和 PTX 治疗三阴性乳腺癌患者。重要的是，应该进行体内模型的进一步研究，以更好地了解测试治疗的转化方面。
