Although oncolytic viruses are attenuated by a variety of stratagems to restrict replication in normal tissues, most cells utilized as carriers are relatively permissive for viral replication, partly due to the fact that they self-renew and cycle (MSCs and NSCs). Therefore, the survival time of a virus-loaded carrier cell is limited [2
]. It is difficult to reliably regulate viral replication in the carrier cells so that timely release of the OV load occurs in the tumor, rather than at other sites trafficked by the loaded carrier before, during or after administration. Intravenous administrations of virus-loaded carrier cells reach the neovasculature in tumors, yet have been reported to not deliver the OV load as efficiently as hoped [4
]. The poor prognosis of patients with malignant tumors such as glioblastoma multiforme, advanced pancreatic adenocarcinoma and diffuse-type gastric carcinoma is also due to tumor cells located relatively far from vessels, further impeding the effect of an OV released by carrier cells in blood vessels [68
]. This problem is also illustrated by the anticancer failures of conventional drug delivery. In addition, abnormal blood flow by contorted and abnormally leaky tumor vessels causes heterogeneous distribution of carrier cells [14
]. Therefore, the half-life of a loaded carrier cell may be a very critical factor for the success of this type of therapy.
To avoid cell lysis during delivery, Qiao et al researched whether membrane attachment of vesicular stomatitis virus (VSV) to carrier T cells, instead of cellular internalization, with low doses of VSV led to lack of replication in the carrier cell and allowed gradual release of the oncolytic VSV [6
]. In fact, the surface-attached VSV seemed to reduce carrier cell lysis, but there was still some shielding of the adhered viruses from host immune responses during intravascular delivery in preimmune mice. Willmon et al. recently reviewed this method in detail [70
Another published approach has been to employ an inhibitor of DNA synthesis to suppress virus replication after carrier cell loading [2
]. Herrlinger et al. used mimosine to arrest the replication of the mutant HSV-1, rRp450, in loaded NPC carrier cells temporarily. This allowed time for neural precursor cell (NPC) migration to tumors in the brain. With mimosine, they reported that the loaded rRp450 virus was retained in the carrier NPCs for more than 2 weeks with restriction of viral replication until mimosine was removed. These NPCs were still able to migrate to the intracerebral glioma after intratumoral injection in mouse brains.
While these methods appear to work relatively well in the experimental systems, additional permutations may be even more effective. It is possible, in fact, that additional genetic engineering of loaded OVs could be attempted in order to achieve a virus whose replication would be restricted in the carrier cell until it reached its tumor target.