Ex Vivo Oncolytic Virotherapy with Myxoma Virus Arms Multiple Allogeneic Bone Marrow Transplant Leukocytes to Enhance Graft versus Tumor

Abstract

Allogeneic stem cell transplant-derived T cells have the potential to seek and eliminate sites of residual cancer that escaped primary therapy. Oncolytic myxoma virus (MYXV) exhibits potent anti-cancer efficacy against human cancers like multiple myeloma (MM) and can arm transplant-derived T cells to become more effective cancer killers in vitro and in an immunodeficient xenotransplant murine model. Here, we tested ex vivo MYXV virotherapy against residual murine MM in immunocompetent mice using an allogeneic mouse-mouse model. In contrast to all human MM cell lines previously tested, the murine MM cell line tested here was highly resistant to direct MYXV infection and oncolysis in vitro. Despite this in vitro resistance, we found that ex vivo MYXV-armed allogeneic bone marrow (BM) transplantation dramatically ablated pre-seeded residual MM in vivo. Unexpectedly, we show that both neutrophils and activated T cells from the donor function as virus-armed carrier cells, and MYXV-preloaded cells enhanced MM killing. Our results demonstrate a novel therapeutic paradigm for residual cancer, in which multiple classes of allotransplant leukocytes can be armed by MYXV ex vivo to enhance the graft-versus-tumor effects.

Oncolytic Virotherapy with Myxoma Virus

“…In this case, the mouse MM cell line MOPC315.BM was resistant to direct MYXV binding and infection when tested in vitro. However, the delivery of MYXV with ex vivo loaded allogeneic BM leukocytes in the mice pre-seeded with MM disease, dramatically reduced residual MM in the BM and spleen and extended the survival of mice [29]. These results suggest that MYXV is safe for hematopoietic stem cells and can be used with current treatment modalities for MM, such as monoclonal antibodies, adoptive cell therapies and immune checkpoint inhibitors.…”

“…In a syngeneic mouse model of MM, the systemic delivery of MYXV significantly reduced tumor burden and prolonged the survival of mice [30]. The ability of MYXV to target MM niches was also tested using ex vivo virotherapy with bone marrow (BM) leukocytes in immunocompetent mice, using an allogeneic mouse-mouse transplant model [29]. In this case, the mouse MM cell line MOPC315.BM was resistant to direct MYXV binding and infection when tested in vitro.…”

Report on the NCI Microbial-Based Cancer Therapy Conference

“…In an immunocompetent murine multiple myeloma model, ex vivo donor murine allogenic bone marrow was treated with MYXV. The MYXV-treated bone marrow was then transplanted into a recipient with preseeded residual multiple myeloma, leading to reduced recipient tumor burdens, through mechanisms involving donor-derived MYXV-induced neutrophil and T-cell activation (27).…”

Fighting Cancer with Mathematics and Viruses

“…Although a much-noticed case of durable complete remission of disseminated multiple myeloma has been observed upon systemic treatment with MV-NIS in a phase I study [ 181 ], this patient had unique characteristics favoring therapeutic success: a specific gene signature indicating sensitivity to OVT was detected by sequencing [ 182 ] while anti-measles virus antibody titers were absent in blood serum. However, there are means to overcome antibody neutralization of oncolytic agents: polymer coating [ 183 ], pseudotyping [ 184 , 185 ], complement inhibition [ 186 ] and usage of infected cells as virus carriers [ 187 , 188 , 189 , 190 ].…”