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In vivo antitumor activity by dual stromal and tumor-targeted oncolytic measles viruses

Cancer Gene Therapy volume 27, pages 910–922 (2020)Cite this article

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Abstract

The tumor stroma acts as a barrier that limits the efficacy of systemically administered oncolytic viruses (OV). We previously demonstrated that stromal-selective, retargeted oncolytic measles viruses (MVs) delay in vivo tumor progression. To further characterize the contribution of stromal targeting to MV’s overall in vivo efficacy in an experimental cancer model, a dual targeted oncolytic measles virus (MV-CD46-muPA) able to simultaneously infect murine stromal (via murine uPAR) and human cancer (via CD46) cells was developed. MV-CD46-muPA infected, replicated, and induced cytotoxicity in both murine and human cancer cells. Viral infection was successfully transferred from stromal to tumor cells in vitro, leading to tumor cell oncolysis. Systemic administration of MV-CD46-muPA led to improved antitumor effects in colon (HT-29) cancer xenografts compared to vehicle or CD46 only targeted MVs. These effects were associated with improved tumor viral deposition, increased apoptosis, and decreases in murine stromal endothelial cells and fibroblasts. MV-CD46-muPA modulated cell cycle, survival, proliferation, and metabolic pathways, as determined by functional proteomic analysis of treated tumors. The above findings further validate the concept that dual stromal and tumor cell viral targeting enhances the therapeutic effects of systemically administered OVs and support further preclinical and clinical development of stromal directed virotherapies.

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Fig. 1: Characterization of dual targeting MV-CD46-muPA.
Fig. 2: In vitro replication and cytopathic effects of MV in human and murine cancer cells.
Fig. 3: Effects of viral fibroblast targeting on fibroblast–tumor cell interactions in vitro.
Fig. 4: In vivo effects of MV-CD46-muPA on human colon cancer xenografts.
Fig. 5: In vivo effects of virus treatment on tumor stroma.
Fig. 6: In vivo effects of MV viral vectors on expression of cancer cell protein pathways.

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Acknowledgements

This work was supported by a research grant from the National Cancer Institute (1R01CA149659-01 to J.R.M.), and by the Sylvester Comprehensive Cancer Center (J.R.M.). We acknowledge Oliver Umland, PhD. from the University of Miami/DRI flow cytometry core facility for technical assistance in flow cytometry experiments.

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Authors and Affiliations

  1. Division of Medical Oncology, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, USA

    Yuqi Jing, Valery Chavez, Natasha Khatwani & Jaime R. Merchan

  2. Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA

    Natasha Khatwani

  3. Division of Biostatistics and Bioinformatics, Sylvester Comprehensive Cancer, Center, University of Miami Miller School of Medicine, Miami, FL, USA

    Yuguang Ban & Xi Chen

  4. Division of Internal Medicine, University of Miami Miller School of Medicine, Miami, FL, USA

    Andrea P. Espejo

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Contributions

Y.J. contributed with the execution of the in vitro and in vivo experiments described in the report. V.C. contributed with the experiments related to RPPA analysis. N.K. contributed with experiments related to flow cytometry quantification of tumor–stromal cells. Y.B. and X.C. contributed with the pathway analysis and preparation of pathway heat maps of RPPA. A.P.E. contributed with the statistical analysis of the in vitro and in vivo experiments. J.R.M. contributed with the design of the viral vector, overall plan, and design of the in vitro and in vivo experiments, analysis of the data and preparation of the manuscript.

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Correspondence to Jaime R. Merchan.

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Jing, Y., Chavez, V., Khatwani, N. et al. In vivo antitumor activity by dual stromal and tumor-targeted oncolytic measles viruses. Cancer Gene Ther 27, 910–922 (2020). https://doi.org/10.1038/s41417-020-0171-1

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