Alternative Strategies for Delivering Immunotherapeutics Targeting the PD-1/PD-L1 Immune Checkpoint in Cancer

被引:8
作者
Hoshi, Ryunosuke [1 ,2 ]
Gorospe, Kristyna A. [1 ,2 ]
Labouta, Hagar I. [2 ,3 ,4 ]
Azad, Taha [5 ,6 ]
Lee, Warren L. [1 ,2 ,7 ,8 ]
Thu, Kelsie L. [1 ,2 ]
机构
[1] Univ Toronto, Temerty Fac Med, Lab Med & Pathobiol, St George Campus, Toronto, ON M5S 1A8, Canada
[2] St Michaels Hosp, Keenan Res Ctr Biomed Sci, Toronto, ON M5B 1T8, Canada
[3] Univ Toronto, Leslie Dan Fac Pharm, St George Campus, Toronto, ON M5S 3M2, Canada
[4] Univ Toronto, Fac Appl Sci & Engn, Biomed Engn, St George Campus, Toronto, ON M5S 3E2, Canada
[5] Univ Sherbrooke, Fac Med & Hlth Sci, Microbiol & Infect Dis, Hlth Campus, Sherbrooke, PQ J1K 2R1, Canada
[6] Ctr Hosp Univ Sherbrooke CHUS, Res Ctr, Sherbrooke, PQ J1J 3H5, Canada
[7] Univ Toronto, Temerty Fac Med, Biochem, St George Campus, Toronto, ON M5S 1A8, Canada
[8] Univ Toronto, Temerty Fac Med, Med & Interdept Div Crit Care Med, St George Campus, Toronto, ON M5B 1T8, Canada
关键词
solid tumors; PD-1/PD-L1 immune checkpoint; immunotherapy; immune checkpoint inhibitors; irAEs; locoregional drug delivery; oncolytic virus; nanoparticle; ultrasound and microbubbles; DRUG-DELIVERY; PD-1; BLOCKADE; LUNG-CANCER; TUMOR MICROENVIRONMENT; LIPOSOMAL DOXORUBICIN; ONCOLYTIC VIROTHERAPY; COMBINATION THERAPY; ACQUIRED-RESISTANCE; FOCUSED ULTRASOUND; OPEN-LABEL;
D O I
10.3390/pharmaceutics16091181
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
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页数:33
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