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Enhanced inhibition of syngeneic murine tumors by combinatorial therapy with genetically engineered HSV-1 expressing CCL2 and IL-12

Cancer Gene Therapy volume 12, pages 359–368 (2005)Cite this article

Abstract

Herpes simplex viruses type 1 (HSV-1) that lack the γ134.5 gene are unable to replicate in the central nervous system (CNS), but maintain replication competence in actively dividing tumors. To determine if antitumor therapy by M002, a γ134.5− HSV that expresses interleukin-12 (IL-12), could be augmented by combinatorial therapy with another γ134.5-deleted HSV-1 engineered to express the chemokine CCL2, Neuro-2a tumors were established subcutaneously in the syngeneic A/J mouse strain. Tumors received multiple injections intratumorally either of saline, the parent, non-cytokine-expressing virus R3659, M002, M010 (γ134.5− HSV expressing CCL2), or a combination of M002 and M010. Efficacies were evaluated by monitoring inhibition of tumor growth over time. Results demonstrated the following: (1) inhibition of tumor growth was most pronounced in tumors treated with a combination of M002 and M010; (2) enhanced tumor growth inhibition for the combinatorial treatment group was statistically significant compared to either M002 or M010 alone; and (3) the variability between slopes of the tumor growth rates within an individual treatment group appeared to be virus-dependent, and was reproducible between experiments. Our results demonstrate that combinatorial cytokine/chemokine γ134.5− HSV therapies can provide superior antitumor effects in experimental tumors as a model for malignancies arising in the brain.

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Acknowledgements

We thank Dr Bernard Roizman, University of Chicago, for helpful discussion and comments throughout the course of this work. We thank Cammy Love, Karen Mardis and Sharon Samuel for excellent technical assistance with this work. Studies performed by the authors were initiated and supported in part by NCI P01 CA 71933 (RJW), by the Brain Tumor Society's Neal P Levitan Leadership Chair of Research Award (JNP), the NINDS Mentored Clinical Scientist Development Award (1K08NSO1942) (JMM), the American Association for Neurological Surgeons Young Investigator Award (JMM), the American Cancer Society Institutional Awards (JMM) and the American Brain Tumor Association (JMM).

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Authors and Affiliations

  1. Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Jacqueline N Parker & Richard J Whitley

  2. Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Sreelatha Meleth

  3. Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Kenneth B Hughes & Richard J Whitley

  4. Brain Tumor Research Laboratories, University of Alabama at Birmingham, Birmingham, Alabama, USA

    G Yancey Gillespie

  5. Division of Neurosurgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA

    G Yancey Gillespie & James M Markert

  6. Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Richard J Whitley

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  1. Jacqueline N Parker
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Correspondence to James M Markert.

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Parker, J., Meleth, S., Hughes, K. et al. Enhanced inhibition of syngeneic murine tumors by combinatorial therapy with genetically engineered HSV-1 expressing CCL2 and IL-12. Cancer Gene Ther 12, 359–368 (2005). https://doi.org/10.1038/sj.cgt.7700784

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