期刊
BIOACTIVE MATERIALS
卷 9, 期 -, 页码 251-265出版社
KEAI PUBLISHING LTD
DOI: 10.1016/j.bioactmat.2021.07.012
关键词
CRISPR/Cas9; PD-1/PD-L1; Extracellular vesicles; Immune checkpoint inhibitors; Drug delivery
资金
- National Cancer Institute [1R01CA230339, 1R01CA255948]
- Jiangsu Provincial Medical Youth Talent Award [QNRC2016054]
- Nanjing Medical Science and Technology Development Foundation Major Program [ZDX16008]
- Precision Medicine Project of Wuxi Municipal Commission of Health and Family Planning [J201805]
- Youth scientific research project of Wuxi municipal health commission [Q201951]
- Top Talent Support Program for young and middle-aged people of Wuxi Health Committee [HB2020003]
Research shows that engineered universal EVs carrying PD-1 proteins are effective in reducing cancer cell proliferation, inducing apoptosis, and blocking PD-L1 mediated T cell suppression. These EVs demonstrate strong anti-tumor activity in tumor models, with efficacy comparable to clinical anti-PD1 monoclonal antibodies.
Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 have been approved for the treatment of a variety of cancers. However, the efficacy of antibody-based ICIs could be further improved by mitigating anti-drug antibodies, proteolytic cleavage, and on-target off-tumor toxicity. One strategy for accomplishing this is through the use of extracellular vesicles (EVs), cell derived submicron vesicles with many unique properties. We constructed an engineered MDA-MB-231 cell line for harvesting EVs. This was accomplished by overexpressing a high-affinity variant human PD-1 protein (havPD-1), while simultaneously knocking out intrinsic PD-L1 and beta-2 microglobulin. The engineered havPD-1 EVs reduced PD-L1 overexpressing cancer cell proliferation and induced cellular apoptosis. Moreover, the EVs were shown to efficiently block PD-L1 mediated T cell suppression. Meanwhile antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not observed. The havPD-1 EVs treatment resulted in robust anti-tumor activity in both preventative co-implantation and therapeutic xenograft tumor models reconstituted with human T cells. The efficacy of the havPD-1 EVs was shown to be comparable to clinical anti-PD1 monoclonal antibodies. Additionally, loading the havPD-1 EVs with a potent PARP inhibitor was shown to further augment treatment efficacy. In brief, the engineered universal EVs harboring havPD-1 proteins can be used for cancer concurrent immunotherapy and chemotherapy.
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