Opportunities and challenges of combining adoptive cellular therapy with oncolytic virotherapy.

The use of oncolytic viruses (OVs) and adoptive cell therapies (ACT) have independently emerged as promising approaches for cancer immunotherapy. More recently, the combination of such agents to obtain a synergistic anticancer effect has gained attention, particularly in solid tumors, where immune-suppressive barriers of the microenvironment remain a challenge for desirable therapeutic efficacy. While adoptive cell monotherapies may be restricted by an immunologically cold or suppressive tumor microenvironment (TME), OVs can serve to prime the TME by eliciting a wave of cancer-specific immunogenic cell death and inducing enhanced antitumor immunity. While OV/ACT synergy is an attractive approach, immune-suppressive barriers remain, and methods should be considered to optimize approaches for such combination therapy. In this review, we summarize current approaches that aim to overcome these barriers to enable optimal synergistic antitumor effects.

Transplantation of autologous bone marrow pre-loaded ex vivo with oncolytic myxoma virus is efficacious against drug-resistant Vk*MYC mouse myeloma.

Multiple myeloma (MM) is a hematological malignancy of plasma cells that remains incurable despite significant progress with myeloablative regimens and autologous stem cell transplantation for eligible patients and, more recently with T cell redirected immunotherapy. Recently, we reported that ex vivo virotherapy with oncolytic myxoma virus (MYXV) improved MM-free survival in an autologous-transplant Balb/c mouse model. Here, we tested the Vk*MYC transplantable C57BL/6 mouse MM model that more closely recapitulates human disease. In vitro, the murine bortezomib-resistant Vk12598 cell line is fully susceptible to MYXV infection. In vivo results demonstrate: (i) autologous bone marrow (BM) leukocytes armed ex vivo with MYXV exhibit moderate therapeutic effects against MM cells pre-seeded into recipient mice; (ii) Cyclophosphamide in combination with BM/MYXV delays the onset of myeloma in mice seeded with Vk12598 cells; (iii) BM/MYXV synergizes with the Smac-mimetics LCL161 and with immune checkpoint inhibitor α-PD-1 to control the progression of established MM in vivo, resulting in significant improvement of survival rates and decreased of tumor burden; (iv) Survivor mice from (ii) and (iii), when re-challenged with fresh Vk12598 cells, developed acquired anti-MM immunity. These results highlight the utility of autologous BM grafts armed ex vivo with oncolytic MYXV alone or in combination with chemotherapy/immunotherapy to treat drug-resistant MM in vivo.

Autologous Transplantation Using Donor Leukocytes Loaded Ex Vivo with Oncolytic Myxoma Virus Can Eliminate Residual Multiple Myeloma.

Multiple myeloma (MM) is a hematological malignancy of monoclonal plasma cells that remains incurable. Standard treatments for MM include myeloablative regimens and autologous cell transplantation for eligible patients. A major challenge of these treatments is the relapse of the disease due to residual MM in niches that become refractory to treatments. Therefore, novel therapies are needed in order to eliminate minimal residual disease (MRD). Recently, our laboratory reported that virotherapy with oncolytic myxoma virus (MYXV) improved MM-free survival in an allogeneic transplant mouse model. In this study, we demonstrate the capacity of donor autologous murine leukocytes, pre-armed with MYXV, to eliminate MRD in a BALB/c MM model. We report that MYXV-armed bone marrow (BM) carrier leukocytes are therapeutically superior to MYXV-armed peripheral blood mononuclear cells (PBMCs) or free virus. Importantly, when cured survivor mice were re-challenged with fresh myeloma cells, they developed immunity to the same MM that had comprised MRD. In vivo imaging demonstrated that autologous carrier cells armed with MYXV were very efficient at delivery of MYXV into the recipient tumor microenvironment. Finally, we demonstrate that treatment with MYXV activates the secretion of pro-immune molecules from the tumor bed. These results highlight the utility of exploiting autologous leukocytes to enhance tumor delivery of MYXV to treat MRD in vivo.