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, Grant McFadden

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)490-504
Number of pages15
JournalOncotarget
Volume13
Issue number1
DOIs
StatePublished - 2022

Keywords

  • autologous transplantation
  • combination therapy
  • multiple myeloma
  • myxoma virus
  • oncolytic virus

ASJC Scopus subject areas

  • Oncology

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