Carrier Cell–mediated Delivery of a Replication-competent Adenovirus for Cancer Gene Therapy

Abstract

Although replication-competent viruses have been developed to treat cancers, their cytotoxic effects are insufficient, as infection is inhibited by the generation of neutralizing antibodies. To address this limitation, we developed a carrier cell system to deliver a replication-competent adenovirus. Carrier cells infected with replication-competent adenovirus were incubated with target cancer cells in a high titer of anti-adenovirus antibody. Carrier cells were injected into syngeneic subcutaneous tumors after immunization with adenovirus. Carrier cell-derived cell fragments containing viral particles were engulfed by proliferative target cancer cells. This engulfment-mediated transfer of adenovirus was not inhibited by the anti-adenovirus antibody and enabled repetitive infection. After the induction of anti-adenoviral cytotoxic T-lymphocyte (CTL) responses by immunization with adenovirus, administration of carrier cells infected with a replication-competent adenovirus induced complete tumor regression. Adenovirus-GM-CSF augmented the anti-tumor effect of carrier cells by increasing anti-adenoviral and anti-tumoral CTL responses and decreased the number of injections of carrier cells required to induce complete tumor regression. This novel carrier cell-mediated viral transfection system might prove useful in a variety of cancer therapies.

Osteosarcoma cells as carriers to allow antitumor activity of canine oncolytic adenovirus in the presence of neutralizing antibodies

“…Previous studies with replication-competent adenovirus-infected carrier-cell systems have reported the use of wild-type HAd5 adenovirus-infected MDA-MG-231 cells 30 and also of granulocyte-macrophage colonystimulating factor-expressing HAd5 loaded into A549 and 293 cells. 10 In this last work, Hamada et al 10 reported that bystander transfection was mediated by carrier-cellderived cell fragments containing viral particles that were engulfed by proliferative target cancer cells. This engulfment-mediated transfer of adenovirus was not inhibited by anti-adenovirus antibodies and enabled repetitive infection.…”

“…However, such modifications were ineffective in the case of third or later injections, owing to an increase in anti-adenovirus antibody titer, and, therefore, could not produce significant antitumor effects. 10 Almost all dogs have circulating anti-CAV antibodies and T-lymphocytes developed as a result of immunization or natural infection. Two serotypes of CAV have been described in dogs: CAV1 and CAV2.…”

“…18,19 Moreover, in an immunocompetent model, tumor carrier cells loaded with adenovirus generated anti-adenovirus and antitumoral cytotoxic T-lymphocytes, the activity of which could be further enhanced by granulocyte-macrophage colony-stimulating factor expression. 10 In this study, we explored the potential of using canine tumor cells as carriers for delivery of oncolytic canine adenovirus to tumor sites in a xenograft animal model. We investigated the suitability of canine OSA cells as a carrier system for the delivery of OCCAV in a xenograft animal model.…”

Anticancer Gene Transfer for Cancer Gene Therapy

“…Briefly, the immune system is by passed by viruses that are camouflaged under a different capsid or shielded with chemical compounds like polyethylene glycol in order to "trick" the immune system and be deliver to the tumor site. Stem cells, cancer stem cells, endothelial cells and progenitors, immune cells and even cancer cells as carriers have been, or are being tested for their efficacy and proof of principle (Iguchi et al, 2012;Hamada et al, 2007;Stoff-Khalili et al, 2007). Another approach to overcome the pre-existing immunity is the temporal immunosuppression using pharmacologic interference to bypass the adaptive and innate immune response.…”

Efficient antitumor effects of carrier cells loaded with a fiber-substituted conditionally replicating adenovirus on CAR-negative tumor cells

“…[8][9][10] In order to overcome these drawbacks, CRAds have been delivered to target cells in vivo using CRAd-infected mesenchymal stem cells or tumor cells as vector. [11][12][13][14][15] In this strategy, cells infected with CRAds are termed 'carrier cells' and use of these cells allows the CRAds to bypass the pre-existing anti-Ad antibodies. 11,15 In addition, use of carrier cells significantly reduces the accumulation of Ad vectors in the liver, because Ad capsid proteins, which are responsible for liver accumulation, are not exposed to the outside of the carrier cells.…”