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

• Type of Material: Article
• 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
• Language: English
• Date: 2022-01-01
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: : © 2022 Villa et al.
• License: Creative Commons Attribution 3.0 IGO License
• Final Published Version (URL): http://dx.doi.org/10.18632/ONCOTARGET.28205
• Title of Journal or Parent Work: Oncotarget
• Volume: 13
• Issue: 1
• Start Page: 490
• End Page: 504
• Grant/Funding Information: This work was funded by an Arizona State University (ASU) start-up grant to GM, NIAID R01 AI080607 to MMR and GM, Mayo Clinic Developmental Research Award from the NCI Myeloma SPORE grant (GR35414), awarded to PLB.
• Keywords: autologous transplantation; myxoma virus; multiple myeloma; combination therapy; oncolytic virus
• Research Categories: Health Sciences, Oncology

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.