Immune-Mediated Antitumor Activity of Reovirus Is Required for Therapy and Is Independent of Direct Viral Oncolysis and Replication

Abstract

Purpose Reovirus is a naturally occurring oncolytic virus in clinical trials. Although tumor infection by reovirus can generate adaptive antitumor immunity, its therapeutic importance versus direct viral oncolysis is undefined. This study addresses the requirement for viral oncolysis and replication, and the relative importance of antitumor immunity and direct oncolysis in therapy. Experimental Design Nonantigen specific T cells loaded with reovirus were delivered i.v. to C57BL/6 and severe combined immunodeficient mice bearing lymph node and splenic metastases from the murine melanoma, B16ova, with assessment of viral replication, metastatic clearance by tumor colony outgrowth, and immune priming. Human cytotoxic lymphocyte priming assays were done with dendritic cells loaded with Mel888 cells before the addition of reovirus. Results B16ova was resistant to direct oncolysis in vitro, and failed to support reovirus replication in vitro or in vivo. Nevertheless, reovirus purged lymph node and splenic metastases in C57BL/6 mice and generated antitumor immunity. In contrast, reovirus failed to reduce tumor burden in severe combined immunodeficient mice bearing either B16ova or reovirus-sensitive B16tk metastases. In the human system, reovirus acted solely as an adjuvant when added to dendritic cells already loaded with Mel888, supporting priming of specific antitumor cytotoxic lymphocyte, in the absence of significant direct tumor oncolysis; UV-treated nonreplicating reovirus was similarly immunogenic. Conclusion The immune response is critical in mediating the efficacy of reovirus, and does not depend upon direct viral oncolysis or replication. The findings are of direct relevance to fulfilling the potential of this novel anticancer agent.

Reciprocal Human Dendritic Cell–Natural Killer Cell Interactions Induce Antitumor Activity Following Tumor Cell Infection by Oncolytic Reovirus

“…We have previously shown the ability of reovirus-infected Mel888 cells to mature DC in a reovirus-dose dependent manner (11). This maturation is likely to be related to the direct effect of reovirus upon DC (37), as reovirus added after DC are loaded with tumor cells is immunogenic in the absence of tumor cell infection (56). DCMelReo0.1 are phenotypically immature in the absence of NK cells.…”

Prolonged systemic circulation of chimeric oncolytic adenovirus Ad5/3-Cox2L-D24 in patients with metastatic and refractory solid tumors

“…Inflammation caused by oncolysis may also have a key role in anti-tumor efficacy. [5][6][7] Consequently, limiting replication to tumor cells may be important for reducing side effects. The anti-tumor effect of oncolytic viruses is determined in part by their capability for infection of tumor cells.…”

Newly Recruited CD11b+, GR-1+, Ly6Chigh Myeloid Cells Augment Tumor-Associated Immunosuppression Immediately following the Therapeutic Administration of Oncolytic Reovirus

“…These reovirus-induced antitumor immunotherapeutic activities target existing cancer cells and can protect the host against subsequent tumor relapse even after discontinuation of the therapy (15). Following its therapeutic administration, reovirus invokes a sequence of immunological events that ultimately overturns numerous tumor-associated immune evasion mechanisms and facilitates the development of antitumor innate and adaptive immune responses (15)(16)(17)(18)(19)(20)(21). Thus, comprehensive characterization and subsequent therapeutic management of the virus-induced immunological events are absolutely necessary to harness the beneficial effects of reovirus-driven anticancer therapy.…”