Dendritic cells and T cells deliver oncolytic reovirus for tumour killing despite pre-existing anti-viral immunity

Abstract

Reovirus is a naturally occurring oncolytic virus currently in early clinical trials. However, the rapid induction of neutralizing antibodies represents a major obstacle to successful systemic delivery. This study addresses, for the first time, the ability of cellular carriers in the form of T cells and dendritic cells (DC) to protect reovirus from systemic neutralization. In addition, the ability of these cellular carriers to manipulate the subsequent balance of anti-viral versus anti-tumour immune response is explored. Reovirus, either neat or loaded onto DC or T cells, was delivered intravenously into reovirus-naive or reovirus-immune C57Bl/6 mice bearing lymph node B16tk melanoma metastases. Three and 10 days after treatment, reovirus delivery, carrier cell trafficking, metastatic clearance and priming of anti-tumour/anti-viral immunity were assessed. In naive mice, reovirus delivered either neat or through cell carriage was detectable in the tumour-draining lymph nodes 3 days after treatment, though complete clearance of metastases was only obtained when the virus was delivered on T cells or mature DC (mDC); neat reovirus or loaded immature DC (iDC) gave only partial early tumour clearance. Furthermore, only T cells carrying reovirus generated anti-tumour immune responses and long-term tumour clearance; reovirus-loaded DC, in contrast, generated only an anti-viral immune response. In reovirus-immune mice, however, the results were different. Neat reovirus was completely ineffective as a therapy, whereas mDC—though not iDC—as well as T cells, effectively delivered reovirus to melanoma in vivo for therapy and anti-tumour immune priming. Moreover, mDC were more effective than T cells over a range of viral loads. These data show that systemically administered neat reovirus is not optimal for therapy, and that DC may be an appropriate vehicle for carriage of significant levels of reovirus to tumours. The pre-existing immune status against the virus is critical in determining the balance between anti-viral and anti-tumour immunity elicited when reovirus is delivered by cell carriage, and the viral dose and mode of delivery, as well as the immune status of patients, may profoundly affect the success of any clinical anti-tumour viral therapy. These findings are therefore of direct translational relevance for the future design of clinical trials.

Reovirus Virotherapy Overrides Tumor Antigen Presentation Evasion and Promotes Protective Antitumor Immunity

“…Hence, reovirus oncotherapyactivated antitumor immune cells were transferred in reovirus-naive animals and then analyzed for their ability to restrict the growth of freshly implanted tumors. Further, recent reports have shown that reovirus loaded on immune cells can initiate the tumor regression on transfer of these cells (50). Thus, it can be argued that donor immune cells can acquire reovirus during virotherapy of primary tumors and carry it in naive host during transfer, and then restrict the development of secondary tumors after challenge.…”

Dendritic cells serve as a “Trojan horse” for oncolytic adenovirus delivery in the treatment of mouse prostate cancer

“…Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that play critical roles in the activation of antigenspecific naïve T cells [7] and the regulation of the innate immune response [8] . The ability of DCs to deliver CRAds to metastatic melanoma cancer cells in vitro and in vivo has been demonstrated in a previous report [6] . CD40 is highly expressed on the surface of DCs.…”

“…Dendritic cells serve as a "Trojan horse" for oncolytic adenovirus delivery in the treatment of mouse prostate cancer defenses removes virus particles from the circulation, producing a major obstacle to achieving effective systemic delivery [6] . Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that play critical roles in the activation of antigenspecific naïve T cells [7] and the regulation of the innate immune response [8] .…”

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

“…8 Several widely differing approaches aimed to protect circulating viral particles in the bloodstream to enhance tumor delivery are currently the focus of intense research. 9 Treatment with PEGylation, liposome encapsulation, cyclophosphamide or etoposide decreases the titer of neutralizing antibodies (Nabs) against adenoviruses and yield partial recovery of adenoviral infectivity in target cells upon a second injection. 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.…”

“…16 Preclinical studies have shown that different carrier-cell types, including T cells, monocytes, endothelial cells and tumor cells (autologous, allo-or xenogenic), can prevent systemic viral elimination. 9 The idea of using tumor cells as carriers to deliver a replicative virus was first demonstrated in a regional delivery of replication-selective HSV-1 for the intraperitoneal therapy of epithelial ovarian cancer xenografts. 17,18 Later studies, using a model of spontaneous metastases of human breast cancer, showed that intravenously (i.v.)…”