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

• Authors: Nancy Y Villa, Emory University; Masmudur M Rahman, Arizona State University; Joseph Mamola, Arizona State University; Meaghen E Sharik, Mayo Clinic Scottsdale-Phoenix, Arizona; Ana Lemos de Matos, Arizona State University; Jacquelyn Kilbourne, Arizona State University; Kenneth Lowe, Arizona State University; Juliane Daggett-Vondras, Arizona State University; Julia D'Isabella, Arizona State University; Elizabeth Goras, Arizona State University; Marta Chesi, Mayo Clinic, Scottsdale; Leif P Bergsagel, Mayo Clinic, Scottsdale; Grant McFadden, Arizona State University
• Journal Title: Oncotarget
• Volume: Volume 13, Number 1
• Publisher: Impact Journals | 2022-01-01, Pages 490-504
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.18632/ONCOTARGET.28205
• Subjects: Health Sciences, Oncology
• Keywords: myxoma virus; multiple myeloma; combination therapy; autologous transplantation; oncolytic virus

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.