Engineered extracellular vesicles for concurrent Anti-PDL1 immunotherapy and chemotherapy

ABSTRACT: 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. Graphical abstract Universal extracellular vesicles as immune checkpoint inhibitors and chemotherapeutics nanocarriers for cancer combination therapy.Image 1 Highlights • It is the first attempt to develop extracellular vesicles (EV) as direct agents for immune checkpoint therapy.• The HLA-I knock-out EVs could be off-the-self universal donors for EV-based therapy.• The EV-based concurrent immunotherapy and chemotherapy can significantly improve treatment efficacy.

SUBMITTER: Chen Y 

PROVIDER: S-EPMC8586263 | biostudies-literature |

REPOSITORIES: biostudies-literature