Autologous Transplantation Using Donor Leukocytes Loaded Ex Vivo with Oncolytic Myxoma Virus Can Eliminate Residual Multiple Myeloma

Nancy Y. Villa, Masmudur M. Rahman, Joseph Mamola, Julia D'Isabella, Elizabeth Goras, Jacquelyn Kilbourne, Kenneth Lowe, Juliane Daggett-Vondras, Lino Torres, John Christie, Nicole Appel, Anna L. Cox, Jae B. Kim, Grant McFadden

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Multiple myeloma (MM) is a hematological malignancy of monoclonal plasma cells that remains incurable. Standard treatments for MM include myeloablative regimens and autologous cell transplantation for eligible patients. A major challenge of these treatments is the relapse of the disease due to residual MM in niches that become refractory to treatments. Therefore, novel therapies are needed in order to eliminate minimal residual disease (MRD). Recently, our laboratory reported that virotherapy with oncolytic myxoma virus (MYXV) improved MM-free survival in an allogeneic transplant mouse model. In this study, we demonstrate the capacity of donor autologous murine leukocytes, pre-armed with MYXV, to eliminate MRD in a BALB/c MM model. We report that MYXV-armed bone marrow (BM) carrier leukocytes are therapeutically superior to MYXV-armed peripheral blood mononuclear cells (PBMCs) or free virus. Importantly, when cured survivor mice were re-challenged with fresh myeloma cells, they developed immunity to the same MM that had comprised MRD. In vivo imaging demonstrated that autologous carrier cells armed with MYXV were very efficient at delivery of MYXV into the recipient tumor microenvironment. Finally, we demonstrate that treatment with MYXV activates the secretion of pro-immune molecules from the tumor bed. These results highlight the utility of exploiting autologous leukocytes to enhance tumor delivery of MYXV to treat MRD in vivo. McFadden and colleagues found that free MYXV, or in combination with murine autologous BM or PBMCs, has therapeutic effects against murine myeloma residual disease. Moreover, MYXV stimulates an immune response resulting in the activation of IFN-γ and TNF. Importantly, re-challenged survivor mice with fresh MM developed resistance to the disease.

Original languageEnglish (US)
Pages (from-to)171-188
Number of pages18
JournalMolecular Therapy - Oncolytics
Volume18
DOIs
StatePublished - Sep 25 2020

Keywords

  • autologous stem cells transplantation (ASCT)
  • carrier cells
  • minimal residual disease (MRD)
  • multiple myeloma (MM)
  • myxoma virus (MYXV)
  • tumor micreoenvironment (TME)

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research
  • Pharmacology (medical)

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