Transplantation of autologous bone marrow pre-loaded ex vivo with oncolytic myxoma virus is efficacious against drug-resistant Vk*MYC mouse myeloma
Metrics: PDF 632 views | Full Text 2248 views | ?
Nancy Y. Villa1,2, Masmudur M. Rahman1, Joseph Mamola1, Meaghen E. Sharik3, Ana Lemos de Matos1, Jacquelyn Kilbourne1, Kenneth Lowe1, Juliane Daggett-Vondras1, Julia D'Isabella1, Elizabeth Goras1, Marta Chesi3, P. Leif Bergsagel3 and Grant McFadden1
1 Biodesign Institute, Center for Immunotherapy, Vaccines and Virotherapy (CIVV), Arizona State University, Tempe, AZ 85281, USA
2 Division of Hematology/Oncology, School of Medicine, Emory University, Atlanta, GA 32322, USA
3 Department of Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA
Keywords: myxoma virus; multiple myeloma; combination therapy; autologous transplantation; oncolytic virus
Received: December 18, 2021 Accepted: February 14, 2022 Published: March 03, 2022
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.