Curative one-shot systemic virotherapy in murine myeloma

Abstract

Current therapy for multiple myeloma is complex and prolonged. Antimyeloma drugs are combined in induction, consolidation and/or maintenance protocols to destroy bulky disease, then suppress or eradicate residual disease. Oncolytic viruses have the potential to mediate both tumor debulking and residual disease elimination, but this curative paradigm remains unproven. Here we engineered an oncolytic vesicular stomatitis virus to minimize its neurotoxicity, enhance induction of antimyeloma immunity, and facilitate noninvasive monitoring of its intratumoral spread. Using high resolution imaging, autoradiography and immunohistochemistry, we demonstrate that the intravenously administered virus extravasates from tumor blood vessels in immunocompetent myeloma-bearing mice, nucleating multiple intratumoral infectious centers which expand rapidly and necrose at their centers, ultimately coalescing to cause extensive tumor destruction. This oncolytic tumor debulking phase lasts only for 72 hours after virus administration, and is completed before antiviral antibodies become detectable in the bloodstream. Anti-myeloma T cells, cross-primed as the virus-infected cells provoke an antiviral immune response, then eliminate residual uninfected myeloma cells. The study establishes a curative oncolytic paradigm for multiple myeloma where direct tumor debulking and immune eradication of minimal disease are mediated by a single intravenous dose of a single therapeutic agent. Clinical translation is underway.

Characteristics of Oncolytic Vesicular Stomatitis Virus Displaying Tumor-Targeting Ligands

“…Recently, it was shown in a different tumor model that VSV can infect tumor vasculature directly (51), but this was not evident in our model. We did observe VSV infection immediately adjacent to the intact tumor blood vessels, but not in the lumen, as was observed in a previous study from our laboratory that used a different syngeneic myeloma model (2). Whether the displayed RGD or echistatin peptides can target VSV attachment to endothelial cells is not clear.…”

“…Exploitation of this oncolytic property provides a promising alternative approach for the treatment of cancer. For disseminated cancer, virotherapy should ideally be administered systemically (2,(5)(6)(7), but this route of delivery brings its own set of problems. The major concerns for VSV virotherapy are neurotoxicity, antibody neutralization, and sequestration in off-target organs, especially the liver and spleen.…”

“…VSV has the ability to infect and kill cancer cells while sparing normal cells (1)(2)(3)(4). Exploitation of this oncolytic property provides a promising alternative approach for the treatment of cancer.…”

PI3K inhibitor LY294002 inhibits activation of the Akt/mTOR pathway induced by an oncolytic adenovirus expressing TRAIL and sensitizes multiple myeloma cells to the oncolytic virus

“…The oncolytic adenovirus is a potent member of a potentially new class of antitumor agents that has been previously demonstrated to have activity in MM (27)(28)(29). Among the viruses used for virotherapy of MM, different serotypes of adenovi- ruses have been studied, with the goal of finding a translational application for the treatment of myeloma progressing on prior therapy (30,31).…”

Oncolytic Virotherapy and Multiple Myeloma

“…Antimyeloma drugs are combined in induction; consolidation and/or maintenance protocols to destroy bulky disease, then suppress or eradicate residual disease. OVs have the potential to mediate both tumor debulking and residual disease elimination [5]. Virotherapy is an emerging approach in the early stages of clinical development for MM.…”