Antitumor effect of oncolytic virus and paclitaxel encapsulated in extracellular vesicles for lung cancer treatment

Abstract

Standard of care for cancer is commonly a combination of surgery with radiotherapy or chemoradiotherapy. However, in some advanced cancer patients this approach might still remaininefficient and may cause many side effects, including severe complications and even death. Oncolytic viruses exhibit different anti-cancer mechanisms compared with conventional therapies, allowing the possibility for improved effect in cancer therapy. Chemotherapeutics combined with oncolytic viruses exhibit stronger cytotoxic responses and oncolysis. Here, we have investigated the systemic delivery of the oncolytic adenovirus and paclitaxel encapsulated in extracellular vesicles (EV) formulation that, in vitro, significantly increased the transduction ratio and the infectious titer when compared with the virus and paclitaxel alone. We demonstrated that the obtained EV formulation reduced the in vivo tumor growth in animal xenograft model of human lung cancer. Indeed, we found that combined treatment of oncolytic adenovirus and paclitaxel encapsulated in EV has enhanced anticancer effects both in vitro and in vivo in lung cancer models. Transcriptomic comparison carried out on the explanted xenografts from the different treatment groups revealed that only 5.3% of the differentially expressed genes were overlapping indicating that a de novo genetic program is triggered by the presence of the encapsulated paclitaxel: this novel genetic program might be responsible of the observed enhanced antitumor effect. Our work provides a promising approach combining anticancer drugs and viral therapies by intravenous EV delivery as a strategy for the lung cancer treatment.

Combination of immunogenic oncolytic adenovirus ONCOS-102 with anti-PD-1 pembrolizumab exhibits synergistic antitumor effect in humanized A2058 melanoma huNOG mouse model

“…Oncolytic viruses have been tested in preclinical studies and in numerous clinical trials against various tumor types, have a tolerable safety profile, and show varying degrees of efficacy. 8,[10][11][12][31][32][33][34][35][36][37][38][39][40] Their advantages include lysis of infected tumor cells, release of tumor antigens in an immunogenic milieu, and viral infection of adjacent tumor cells. In addition, Figure 5.…”

Extracellular vesicles enhance the targeted delivery of immunogenic oncolytic adenovirus and paclitaxel in immunocompetent mice

“…Extracellular vesicles (EVs), are nano-to micron-sized lipid membrane-bound vesicles secreted into the extracellular environment transporting proteins, lipids and nucleic acids from cell to cell [34,35]. They are naturally occurring cargo delivery agents with the potential to be used as vehicles for drug delivery [36][37][38], in particular for the combined administration of OVs with chemotherapy agents [39]; in addition to endogenous uptake mechanisms, their lipid membrane may further improve the permeability of drugs into target cells [40,41]. It has been reported that EVs have intrinsic cell targeting properties: cell surface structures, such as tetraspanins and integrins, may direct the EV uptake towards specific cells and protect therapeutic agents from opsonization and recognition by phagocytes, leading to a longer half-life and reduced side-effects in healthy cells and tissues [42,43].…”

“…PTX-loaded EVs were prepared as previously described [37,39] by incubating 1 × 10 8 -5 × 10 9 EVs in 1 mL of 5 μM PTX-PBS solution for in vitro samples and 10 μM PTX-PBS solution for in vivo samples, for 1 h at 22 °C. Then, the samples were centrifuged at 170000 ×g for 2 h to pellet the EVs.…”

Poly(cyclodextrin)‐Polydrug Nanocomplexes as Synthetic Oncolytic Virus for Locoregional Melanoma Chemoimmunotherapy

“…[ 17 ] In addition, various chemotherapeutic drugs and checkpoint inhibitors have been explored to enhance the therapeutic outcomes of OV. [ 77–81 ] Nevertheless, uncertainty of potential genetic interference into host cells is indicated as one of the main problems of OV. Herein, pPTX/pCD‐pSNO recapitulated some of the major distinctive antitumor mechanisms of OVs (Scheme 1).…”