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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Systemic therapy of disseminated myeloma in passively immunized mice using measles virus-infected cell carriers
Chunsheng Liu1, Stephen J Russell, Kah-Whye Peng
1Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Abstract:
Multiple myeloma (MM) is bone marrow plasma cell malignancy. A clinical trial utilizing intravenous administration of oncolytic measles virus (MV) encoding the human sodium-iodide symporter (MV-NIS) is ongoing in myeloma patients. However, intravenously administered MV-NIS is rapidly neutralized by antiviral antibodies. Because myeloma cell lines retain bone marrow tropism, they may be ideal as carriers for delivery of MV-NIS to myeloma deposits. A disseminated human myeloma (KAS 6/1) model was established. Biodistribution of MM1, a myeloma cell line, was determined after intravenous infusion. MM1 cells were found in the spine, femurs, and mandibles of tumor-bearing mice. Lethally irradiated MM1 cells remained susceptible to measles infection and transferred MV to KAS 6/1 cells in the presence of measles immune sera. Mice-bearing disseminated myeloma and passively immunized with measles immune serum were given MV-NIS or lethally irradiated MV-NIS-infected MM1 carriers. The antitumor activity of MV-NIS was evident only in measles naive mice and not in passively immunized mice. In contrast, survivals of both measles naive and immune mice were extended using MV-NIS-infected MM1 cell carriers. Hence, we demonstrate for the first time that systemically administered cells can serve as MV carriers and prolonged survival of mice with pre-existing antimeasles antibodies.
Insights
Myeloma cells can carry oncolytic measles virus (MV-NIS) to tumors, improving survival even in mice with existing measles antibodies. This cell-based delivery overcomes rapid viral neutralization in immune patients.
Area of Science:
- Oncolytic virology
- Cancer biology
- Immunotherapy
Background:
- Multiple myeloma (MM) is a bone marrow malignancy.
- Intravenous oncolytic measles virus (MV-NIS) therapy for MM faces challenges due to rapid neutralization by antiviral antibodies.
- Myeloma cell lines exhibit bone marrow tropism, suggesting potential as delivery vehicles.
Purpose of the Study:
- To investigate the potential of myeloma cell lines as carriers for delivering oncolytic measles virus (MV-NIS) to myeloma deposits.
- To evaluate the efficacy of cell-delivered MV-NIS in overcoming pre-existing measles immunity in a mouse model of disseminated multiple myeloma.
Main Methods:
- Established a disseminated human myeloma (KAS 6/1) mouse model.
- Determined the biodistribution of infused myeloma cell line (MM1) in tumor-bearing mice.
- Assessed the ability of lethally irradiated MM1 cells to transfer MV to myeloma cells in the presence of measles immune serum.
- Compared the antitumor activity and survival outcomes of systemically administered MV-NIS versus MV-NIS-infected MM1 cell carriers in measles-naive and measles-immune mice.
Main Results:
- MM1 cells selectively homed to bone marrow sites including the spine, femurs, and mandibles.
- Lethally irradiated MM1 cells successfully transferred MV to myeloma targets and were effective in the presence of measles immune serum.
- Direct intravenous administration of MV-NIS showed antitumor activity only in measles-naive mice.
- MV-NIS-infected MM1 cell carriers significantly extended survival in both measles-naive and measles-immune mice.
Conclusions:
- Systemically administered myeloma cells can effectively serve as carriers for oncolytic measles virus (MV-NIS).
- This cell-based delivery strategy prolongs survival in mice with multiple myeloma, even in the presence of pre-existing anti-measles antibodies.
- Myeloma cell carriers represent a promising approach to overcome the limitations of direct viral immunotherapy in immune patients.
