Mesenchymal progenitor cells as cellular vehicles for delivery of oncolytic adenoviruses

Abstract

Natural and genetically modified oncolytic viruses have been systematically tested as anticancer therapeutics. Among this group, conditionally replicative adenoviruses have been developed for a broad range of tumors with a rapid transition to clinical settings. Unfortunately, clinical trials have shown limited antitumor efficacy partly due to insufficient viral delivery to tumor sites. We investigated the possibility of using mesenchymal progenitor cells (MPC) as virus carriers based on the documented tumorhoming abilities of this cell population. We confirmed preferential tumor homing of MPCs in an animal model of ovarian carcinoma and evaluated the capacity of MPCs to be loaded with oncolytic adenoviruses. We showed that MPCs were efficiently infected with an adenovirus genetically modified for coxsackie and adenovirus receptorindependent infection (Ad5/3), which replicated in the cell carriers. MPCs loaded with Ad5/3 caused total cell killing when cocultured with a cancer cell line. In an animal model of ovarian cancer, MPC-based delivery of the Ad5/3 increased the survival of tumor-bearing mice compared with direct viral injection. Further, tumor imaging confirmed a decrease in tumor burden in animals treated with oncolytic virus delivered by MPC carriers compared with the direct injection of the adenovirus. These data show that MPCs can serve as intermediate carriers for replicative adenoviruses and suggest that the natural homing properties of specific cell types can be used for targeted delivery of these virions. [Mol Cancer Ther 2006;5(3):755 -66]

Les cellules souches mésenchymateuses

“…Les CSM ont également été utilisées pour apporter au site de la tumeur des molécules stimulant la réponse immunitaire telles que l'interleukine-12 (IL-12) [27] ou l'interféron gamma (IFN-) [28]. Enfin, les CSM ont aussi été utilisées comme vecteurs de virus oncolytiques au site tumoral, une stratégie particulièrement efficace dans le cas du cancer de l'ovaire [29] (voir aussi [33])…”

Cell carriers to deliver oncolytic viruses to sites of myeloma tumor growth

“…An assortment of cells have been explored in this regard, including tumor cells, [49][50][51][52] outgrowth endothelial cells, 53 mesenchymal progenitor cells, 54,55 T cells 56,57 and monocytes. 58 There are several criteria that need to be addressed when determining which cell type should be utilized as a carrier for the delivery of a given oncolytic virus: (i) susceptibility to oncolytic virus infection, (ii) protection of the cargo from antibody neutralization, (iii) homing to sites of tumor growth and (iv) transfer of virus progeny to tumor tissue.…”

“…59,60 One study has shown that adenovirus-infected MPCs have tumorhoming capabilities after local or systemic administration. 54,55 A major advantage of MPCs is that they are readily available from healthy donors and can be expanded quickly in cell culture. 61 Therefore, it can be suggested that MPCs have the potential to serve as cell carriers for the treatment of MM, since these cells are derived from the bone marrow and travel via the blood vessels.…”

Potential of tumour cells for delivering oncolytic viruses

“…A fascinating possibility would be, prior to OV/carrier treatment, to begin by injecting cells known to respond to chemotactic molecules and growth factors produced by tumours (for example mesenchymal, endothelial or bone marrow progenitors). [48][49][50][51][52] The natural or built-in chemoresistance of these cells should enhance their participation in tumour vessel formation in patients under chemotherapy. 53 By administering such Trojan horses at the time of primary tumour resection, which often correlates with the release of metastatic growth from anti-angiogenic restrictions, 54 it should be possible to promote their infiltration into the pre-metastatic niche.…”