Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Via F. Marzolo 5, 35131 Padua, Italy.
Department of Virology, National Institute of Public Health NIH - National Research Institute, Chocimska 24, 00-791 Warsaw, Poland.
J Control Release. 2024 Dec;376:777-793. doi: 10.1016/j.jconrel.2024.10.057. Epub 2024 Nov 1.
Malignant melanoma, a rapidly spreading form of skin cancer, is becoming more prevalent worldwide. While surgery is successful in treating early-stage melanoma, patients with advanced disease have only a 20 % chance of surviving beyond five years. Melanomas with mutations in the NRAS gene are characterized for a more aggressive tumor biology, poorer prognosis and shorter survival. Hence, new therapeutic strategies are needed, especially for this specific group of patients. Novel approaches, such as cancer vaccines, offer promising solutions by stimulating the anti-tumor immune response. Nevertheless, their clinical efficacy is still modest and more effective approaches are required. Herein, we propose the systemic administration of the adenovirus-based cancer vaccine complexed in extracellular vesicles (EVs) with the aim of achieving a targeted therapeutic effect. The vaccine was based on previously tested oncolytic adenovirus Ad5/3-D24-ICOSL-CD40L in combination with melanoma-specific antigens targeting NRAS mutations to enhance the anticancer effect. The antineoplastic properties of the oncolytic vaccine were evaluated in xenograft MUG Mel-2 melanoma BALB/c nude mice. Moreover, to mimic the tumor microenvironment, while investigating at the same time immune cell infiltration and drug penetration, we established a 3D co-culture model based on human NRAS mutated MUG Mel-2 spheroids and PBMCs (HLA matched), which displayed a synergistic effect when treated with the cancer vaccine compared to relative controls. Subsequently, we investigated the systemic delivery of the vaccine in EV formulations in a humanized NSG MUG Mel-2 melanoma mouse model. Our study provides a promising strategy for a tumor-targeted vaccine delivery by EVs, resulting in improved anticancer efficacy and increased infiltration of tumor-infiltrating lymphocytes. This study explores the potential of EVs for the selective delivery of cancer vaccines against malignancies, such as NRAS melanoma. Overall, this research could pave the way for applying autologous EVs as a safe and efficacious tool for targeted cancer therapy.
恶性黑色素瘤是一种快速扩散的皮肤癌，在全球范围内变得越来越普遍。虽然手术在治疗早期黑色素瘤方面取得了成功，但患有晚期疾病的患者五年后存活的机会只有 20%。NRAS 基因突变的黑色素瘤具有更具侵袭性的肿瘤生物学、更差的预后和更短的生存期。因此，需要新的治疗策略，特别是针对这一特定患者群体。新的方法，如癌症疫苗，通过刺激抗肿瘤免疫反应提供了有希望的解决方案。然而，它们的临床疗效仍然有限，需要更有效的方法。在此，我们提出了一种系统给药的方法，即将基于腺病毒的癌症疫苗与细胞外囊泡（EVs）复合，以达到靶向治疗的效果。该疫苗是基于之前经过测试的溶瘤腺病毒 Ad5/3-D24-ICOSL-CD40L 与针对 NRAS 突变的黑色素瘤特异性抗原联合使用，以增强抗癌效果。在异种移植 MUG Mel-2 黑色素瘤 BALB/c 裸鼠模型中评估了溶瘤疫苗的抗肿瘤特性。此外，为了模拟肿瘤微环境，同时研究免疫细胞浸润和药物渗透，我们建立了一个基于人类 NRAS 突变的 MUG Mel-2 球体和 PBMCs（HLA 匹配）的 3D 共培养模型，与相对对照相比，当用癌症疫苗治疗时，显示出协同作用。随后，我们在人源化 NSG MUG Mel-2 黑色素瘤小鼠模型中研究了 EV 制剂中疫苗的全身递送。我们的研究为 EV 介导的肿瘤靶向疫苗递送提供了一种有前途的策略，从而提高了抗癌疗效和肿瘤浸润淋巴细胞的浸润。这项研究探讨了 EV 用于针对 NRAS 黑色素瘤等恶性肿瘤的选择性递送癌症疫苗的潜力。总的来说，这项研究为应用自体 EV 作为一种安全有效的靶向癌症治疗工具铺平了道路。
