Abstract
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.
Highlights
Multiple myeloma (MM) is the second most common hematological malignancy in the world [1, 2]
In vivo results demonstrate: (i) autologous bone marrow (BM) leukocytes armed ex vivo with myxoma virus (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 second mitochondrial-derived activator of caspases (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
We found that treatment of recipient mice bearing Vk12598 cells with autologous bone marrow (BM) cells ex vivo treated with either un-armed or human TNF-armed MYXV virus constructs and in combination with the second mitochondrial-derived activator of caspases (Smac)-mimetics compound LCL161 and the immune checkpoint inhibitor (ICI) α-PD-1 resulted in long-term survival and decrease of tumor burden in recipient mice
Summary
Multiple myeloma (MM) is the second most common hematological malignancy in the world [1, 2]. MM is characterized by the clonal expansion of malignant plasma cells (PCs) within a permissive bone marrow microenvironment that promotes the survival and proliferation of tumor cells [3–5]. Despite continued advances in new generations of drugs and novel therapies such as CAR-T cells, high dose ablative chemotherapy/radiotherapy along with autologous stem cell transplantation for eligible patients are still standard therapies used to treat myeloma patients [1]. The imminent relapse of the disease and its subsequent acquired resistance to existing drug therapies remain major challenges that still need to be overcome in order to assure long-term patient survival. We reported compelling experimental evidence indicating that the oncolytic myxoma virus (MYXV) can eliminate minimal residual MM disease in the setting of either allogeneic- [6] or autologous-stem [7] cell transplantation in an immunocompetent Balb/c mouse transplanted with mineral-oil induced plasmacytomas (MOPC)315.BM.dsRed cells [8]. We aimed to overcome some of these limitations by using a mouse model of MM that more faithfully recapitulates the development, clinical manifestations and localization of the disease observed in human MM patients
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