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Published on: April 3, 2018
Converting tumor-specific markers into reporters of oncolytic virus infection
Ianko D Iankov1, Matthew L Hillestad, Allan B Dietz
1Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Abstract:
Preferential killing of transformed cells, while keeping normal cells and organs unharmed, is the main goal of cancer gene therapy. Genetically engineered trackable markers and imaging reporters enable noninvasive monitoring of transduction efficiency and pharmacokinetics of anticancer virotherapeutics. However, none of these reporters can differentiate between infection in the targeted tumors and that in the normal tissue. Thus, we constructed oncolytic measles virus (MV) armed with a human light immunoglobulin chain reporter gene for the treatment of multiple myeloma (MM). Excessive production of monoclonal immunoglobulin is a key characteristic and marker for diagnostics of MM. Once expressed in infected target cells, vector-encoded lambda protein recombines with myeloma IgG-kappa immunoglobulin creating a unique IgG-kappa/lambda. A modified immunoassay technique allows precise quantification of converted marker molecules. Only antibody producing cells were able to assemble this chimeric immunoglobulin molecule, whereas other cells secreted only free lambda light chain. Human myeloma xenografts inoculated with lambda chain expressing MV secreted converted IgG-kappa/lambda in the plasma of tumor bearing animals and elevated reporter levels correlated with response to the therapy. This is the first report of a gene therapy vector engineered to discriminate between infection in malignant and normal cells by molecular modification of a tumor-specific protein.
Insights
This study introduces a novel oncolytic measles virus (MV) for multiple myeloma (MM) treatment. The engineered virus uniquely marks infected cancer cells, allowing precise monitoring of gene therapy effectiveness in tumors.
Area of Science:
- Oncolytic virotherapy
- Cancer gene therapy
- Molecular imaging and diagnostics
Background:
- Cancer gene therapy aims to selectively eliminate cancer cells while sparing normal tissues.
- Current imaging reporters for virotherapeutics cannot distinguish between tumor and normal tissue infection.
- Multiple myeloma (MM) is characterized by excessive monoclonal immunoglobulin production.
Purpose of the Study:
- To develop an oncolytic measles virus (MV) for multiple myeloma (MM) treatment.
- To engineer a reporter system within the MV that can differentiate between malignant and normal cell infection.
- To enable noninvasive monitoring of gene therapy efficacy in MM.
Main Methods:
- Construction of an oncolytic measles virus (MV) armed with a human light immunoglobulin chain reporter gene.
- Engineering the reporter to recombine with myeloma's IgG-kappa to form a unique IgG-kappa/lambda marker.
- Utilizing a modified immunoassay to quantify the chimeric immunoglobulin in tumor-bearing animals.
Main Results:
- The lambda-expressing MV successfully infected human myeloma xenografts.
- Infected myeloma cells secreted the unique IgG-kappa/lambda marker into the plasma.
- Elevated reporter levels in plasma correlated with therapeutic response, distinguishing tumor infection.
Conclusions:
- This is the first gene therapy vector engineered to differentiate between malignant and normal cell infection.
- The developed vector enables precise monitoring of oncolytic virotherapy targeting multiple myeloma.
- This approach holds promise for improved cancer gene therapy and diagnostics.
