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Mantle cell lymphoma salvage regimen: synergy between a reprogrammed oncolytic virus and two chemotherapeutics

Gene Therapy volume 17, pages 1506–1516 (2010)Cite this article

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Abstract

Measles virus (MV)-PNP HblindantiCD20 is a CD20-targeted and prodrug convertase-armed MV that temporarily controls growth of lymphoma xenografts in severe combined immunodeficiency (SCID) mice in combination with fludarabine phosphate (fludarabine). Herein, we examine the replication of this targeted virus and of a vaccine-lineage MV in disease bulks and circulating cells from mantle cell lymphoma (MCL) patients, and show that only the targeted virus is specific for CD20-expressing cells. We then assessed the efficacy of different regimens of administration of this virus in combination with fludarabine and cyclophosphamide (CPA) in an MCL xenograft model. We show that CPA administration before the beginning of virus treatment enhances oncolytic efficacy, likely through temporary immunosuppression. An interval of 1 week between intravenous virus administration and fludarabine treatment further enhanced oncolysis, by synchronizing maximum prodrug convertase expression with fludarabine availability. Finally, three 23-day courses of triple sequential treatment with CPA, virus and fludarabine treatment resulted in complete regression of the xenografts. Secondary disease symptoms interfered with survival, but average survival times increased from 22 to 77 days. These studies document a reprogrammed oncolytic virus, consolidating the effects of two chemotherapeutics, a concept well suited for a phase I clinical trial for MCL patients for whom conventional therapies have failed.

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Acknowledgements

This work was supported by a Grant of the Alliance for Cancer Gene Therapy, NIH Grant R01 CA139389 and by Grant UN 254 1-1 of the Deutsche Forschungsgemeinschaft (German Research Foundation). We thank Johanna Lampe for excellent support, Mary Stenson and Tammy Rattle for the FACS analyses and help with the patients’ samples, Mary Bennett for excellent secretarial assistance, and Steve Russell and Christof von Kalle for comments on the paper.

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  1. G Ungerechts

    Present address: 3Current address: National Center for Tumor Diseases (NCT) Heidelberg, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany.,

Authors and Affiliations

  1. Department of Molecular Medicine and Virology and Gene Therapy Track, Mayo Clinic College of Medicine, Rochester, MN, USA

    G Ungerechts, M E Frenzke, K-C Yaiw, T Miest & R Cattaneo

  2. Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN, USA

    P B Johnston

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  1. G Ungerechts
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Correspondence to R Cattaneo.

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Patent applications for which RC is an inventor have been licensed to NISCO. Mayo has an equity position in NISCO. Mayo has not yet received royalties from products developed by the company, but may receive these in future.

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Ungerechts, G., Frenzke, M., Yaiw, KC. et al. Mantle cell lymphoma salvage regimen: synergy between a reprogrammed oncolytic virus and two chemotherapeutics. Gene Ther 17, 1506–1516 (2010). https://doi.org/10.1038/gt.2010.103

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