Systemic administration of human mesenchymal stromal cells infected with polymer-coated oncolytic adenovirus induces efficient pancreatic tumor homing and infiltration

Abstract

Oncolytic adenovirus (oAd)-mediated gene therapy is a promising approach for cancer treatment because of its cancer cell-restricted replication and therapeutic gene expression. However, systemic administration of oAd is severely restricted by their immunogenic nature and poor tumor homing ability, thus oAd cannot be utilized to treat disseminated metastases. In this study, human bone marrow-derived mesenchymal stromal cell (hMSCs) was used as a viral replicationpermissive carrier for oAd with an aim to improve the systemic delivery of the virus to tumor tissues. To overcome the poor delivery of oAd into hMSCs, a relaxin (RLX)-expressing oncolytic Ad (oAd/RLX), which degrades dense tumor extracellular matrix of highly desmoplastic pancreatic cancer, was complexed with biodegradable polymer (poly(ethyleneimine)-conjugated poly(CBA-DAH); PCDP), generating oAd/RLX-PCDP complex. oAd/RLX-PCDP complex enhanced the internalization of oAd into hMSC, leading to superior viral production and release from hMSCs, along with high RLX expression. Furthermore, systemic administration of oAd/ RLX-PCDP-treated hMSCs elicited more potent antitumor effect compared to naked oAd/RLX or oAd/RLX-treated hMSC in pancreatic tumor model. This potent antitumor effect of systemically administered oAd/RLX-PCDP-treated hMSCs was achieved by superior viral replication in tumor tissues than any other treatment group. In conclusion, these results demonstrate that hMSCs are effective carriers for the systemic delivery of oAd to tumor sites and treatment of pancreatic cancer.

RETRACTED: The Oncolytic Virus in Cancer Diagnosis and Treatment

“…Carrier cell research is moving toward using cells that not only provide shielding from antibodies and complement but also detarget from off-target organs, home to tumor sites, and exert their antitumor effector functions. At present, the most commonly used cell carriers are cell carriers including antigen-specific T cell (AST), cytokine-induced killer cell (CIK), mesenchymal stem cells, and blood outgrowth endothelial cells (BOECs) ( 97 – 99 ). An optimal cell carrier must include the following characteristics: first, it must be susceptible to virus’ infection; second, it can assist the virus in locating the tumor tissue while not being recognized by the immune system; finally, it has the ability to release progeny virus to attack distant cancer cells ( 100 ).…”

Materials promoting viral gene delivery

“…Lower immunogenicity was achieved through approaches such as layer-bylayer deposition of PEI with hyaluronic acid 201 or chondroitin sulfate 202 and by cross-linking PEI with cystamine. 203 Moreover cholesterol conjugated to PEI can facilitate cell entry via an energy-and endocytosis-independent membrane translocation pathway, originally known from cell penetrating peptides. 204,205 The amphiphilic combination of bile acids like deoxycholic acid and the cationic PEI efficiently transport cargo 206 and further enhance TE of Ad in CAR negative cells.…”

Improving antitumor efficacy via combinatorial regimens of oncolytic virotherapy

“…Several groups have examined chimeric oncolytic adenovirus with different fiber modifications, which were shown to enhance cellular internalization of viruses into carrier cells [ 146 , 153 ]. Similarly, coating viruses with a biodegradable polymer enhances viral uptake into carrier cells [ 154 ]. Of note, the cytotoxicity of OVs on the carrier cells should be considered to prevent the cells being killed before they reached tumor sites [ 155 ].…”