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Updated: Aug 24, 2026
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Generation of a recombinant Sendai virus that is selectively activated and lyses human tumor cells expressing matrix
H Kinoh1, M Inoue, K Washizawa
11DNAVEC Research Inc., Kannondai, Tsukuba-shi, Ibaraki, Japan.
Abstract:
Malignant tumor cells often express matrix metalloproteinases (MMPs) at a high level to enable their dissemination and metastasis. Sendai virus (SeV), a nonsegmented negative strand RNA virus, spreads in the target tissues in vivo via cleavage activation of the viral fusion glycoprotein by a tissue-specific, trypsin-like enzyme. By deleting the viral matrix protein, we previously generated a recombinant SeV that does not bud to mature virions, but is highly fusogenic and spreads extensively from cell to cell in a trypsin-dependent manner. Here, we changed the tryptic cleavage site of the fusion glycoprotein of this virus to a site susceptible to MMPs. The resulting recombinant virus was no longer activated by trypsin but spread efficiently in cultured cells supplemented with MMP2 or MMP9 and in human tumor cell lines expressing these MMPs. Furthermore, the virus spread extensively in tumor cells xenotrasplanted to nude mice without disseminating to the surrounding normal cells, leading to the inhibition of the tumor growth in the mice. These results demonstrate the selective targeting and killing of human tumor cells by recombinant SeV technology and greatly advance the reemerging concept of oncolytic virotherapy, which currently appears to rely largely upon a natural preference of certain viruses for cancer cells.
Insights
Researchers engineered a modified Sendai virus (SeV) to target and destroy cancer cells. This oncolytic virus selectively infects and replicates in tumor cells expressing specific enzymes, inhibiting tumor growth.
Area of Science:
- Oncolytic virotherapy
- Virology
- Cancer research
Background:
- Malignant tumor cells utilize matrix metalloproteinases (MMPs) for metastasis.
- Sendai virus (SeV) spreads via fusion glycoprotein cleavage by trypsin-like enzymes.
- Recombinant SeV lacking matrix protein is highly fusogenic and spreads cell-to-cell.
Purpose of the Study:
- To engineer a recombinant SeV activated by MMPs instead of trypsin.
- To evaluate the virus's efficacy in targeting and killing human tumor cells.
- To assess the potential of MMP-activated SeV for oncolytic virotherapy.
Main Methods:
- Modified the fusion glycoprotein cleavage site of a matrix-deficient SeV to be MMP-sensitive.
- Tested viral spread in cell cultures supplemented with MMP2/MMP9 and in human tumor cell lines.
- Evaluated tumor growth inhibition in nude mice bearing human tumor xenografts.
Main Results:
- The engineered SeV spread efficiently in MMP2/MMP9-expressing cells and human tumor cell lines.
- The virus selectively spread within xenografted tumor cells without affecting normal tissues.
- Significant inhibition of tumor growth was observed in treated mice.
Conclusions:
- Recombinant SeV technology enables selective targeting and killing of human tumor cells.
- MMP-activated SeV represents a promising advancement in oncolytic virotherapy.
- This approach offers a strategy beyond viruses with natural cancer-cell-targeting preferences.
