Hoshi Ryunosuke, Gorospe Kristyna A, Labouta Hagar I, Azad Taha, Lee Warren L, Thu Kelsie L
Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, St. George Campus, Toronto, ON M5S 1A8, Canada.
Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON M5B 1T8, Canada.
Pharmaceutics. 2024 Sep 7;16(9):1181. doi: 10.3390/pharmaceutics16091181.
The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint constitutes an inhibitory pathway best known for its regulation of cluster of differentiation 8 (CD8) T cell-mediated immune responses. Engagement of PD-L1 with PD-1 expressed on CD8 T cells activates downstream signaling pathways that culminate in T cell exhaustion and/or apoptosis. Physiologically, these immunosuppressive effects exist to prevent autoimmunity, but cancer cells exploit this pathway by overexpressing PD-L1 to facilitate immune escape. Intravenously (IV) administered immune checkpoint inhibitors (ICIs) that block the interaction between PD-1/PD-L1 have achieved great success in reversing T cell exhaustion and promoting tumor regression in various malignancies. However, these ICIs can cause immune-related adverse events (irAEs) due to off-tumor toxicities which limits their therapeutic potential. Therefore, considerable effort has been channeled into exploring alternative delivery strategies that enhance tumor-directed delivery of PD-1/PD-L1 ICIs and reduce irAEs. Here, we briefly describe PD-1/PD-L1-targeted cancer immunotherapy and associated irAEs. We then provide a detailed review of alternative delivery approaches, including locoregional (LDD)-, oncolytic virus (OV)-, nanoparticle (NP)-, and ultrasound and microbubble (USMB)-mediated delivery that are currently under investigation for enhancing tumor-specific delivery to minimize toxic off-tumor effects. We conclude with a commentary on key challenges associated with these delivery methods and potential strategies to mitigate them.
程序性死亡蛋白1/程序性死亡配体1（PD-1/PD-L1）免疫检查点构成了一条抑制性通路，以其对分化簇8（CD8）T细胞介导的免疫反应的调节而闻名。PD-L1与CD8 T细胞上表达的PD-1结合会激活下游信号通路，最终导致T细胞耗竭和/或凋亡。在生理情况下，这些免疫抑制作用的存在是为了预防自身免疫，但癌细胞通过过度表达PD-L1来利用这一通路以促进免疫逃逸。静脉注射（IV）的阻断PD-1/PD-L1相互作用的免疫检查点抑制剂（ICI）在逆转T细胞耗竭和促进各种恶性肿瘤的肿瘤消退方面取得了巨大成功。然而，由于肿瘤外毒性，这些ICI会导致免疫相关不良事件（irAE），这限制了它们的治疗潜力。因此，人们投入了大量精力来探索替代给药策略，以增强PD-1/PD-L1 ICI的肿瘤靶向递送并减少irAE。在这里，我们简要描述针对PD-1/PD-L1的癌症免疫疗法及相关的irAE。然后，我们详细综述了替代递送方法，包括局部区域（LDD）、溶瘤病毒（OV）、纳米颗粒（NP）以及超声和微泡（USMB）介导的递送，目前这些方法正在研究中，以增强肿瘤特异性递送，将肿瘤外毒性降至最低。我们最后对与这些递送方法相关的关键挑战以及缓解这些挑战的潜在策略进行了评论。
