Oncotarget

Research Papers:

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

Nancy Y. Villa, Masmudur M. Rahman, Joseph Mamola, Meaghen E. Sharik, Ana Lemos de Matos, Jacquelyn Kilbourne, Kenneth Lowe, Juliane Daggett-Vondras, Julia D'Isabella, Elizabeth Goras, Marta Chesi, P. Leif Bergsagel and Grant McFadden _

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Oncotarget. 2022; 13:490-504. https://doi.org/10.18632/oncotarget.28205

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Abstract

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

Correspondence to:

Grant McFadden, email: grantmcf@asu.edu

Keywords: myxoma virus; multiple myeloma; combination therapy; autologous transplantation; oncolytic virus

Received: December 18, 2021     Accepted: February 14, 2022     Published: March 03, 2022

Copyright: © 2022 Villa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.


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