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Toca 511 gene transfer and 5-fluorocytosine in combination with temozolomide demonstrates synergistic therapeutic efficacy in a temozolomide-sensitive glioblastoma model

Cancer Gene Therapy volume 20, pages 544–551 (2013)Cite this article

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Abstract

Toca 511 (vocimagene amiretrorepvec), an amphotropic retroviral replicating vector (RRV), can successfully and safely deliver a functional, optimized cytosine deaminase (CD) gene to tumors in orthotopic glioma models. This agent, in conjunction with subsequent oral extended-release 5-fluorocytosine (5-FC) (Toca FC), is currently under investigation in patients with recurrent high-grade glioma . Temozolomide (TMZ) with radiation is the most frequently used first-line treatment for patients with glioblastoma, the most common and aggressive form of primary brain cancer in adults. However, subsets of patients with certain genetic alterations do not respond well to TMZ treatment and the overall median survival for patients who respond remains modest, suggesting that combinatorial approaches may be necessary to significantly improve outcomes. We show that in vitro TMZ delays but does not prevent RRV spread, nor interfere with Toca 511+5-FC-mediated cell killing in glioma tumor cells, and in vivo there is no significant hematologic effect from the combination of 5-FC and the clinically relevant dose of TMZ. A synergistic long-term survival advantage is observed in mice bearing an orthotopic TMZ-sensitive glioma after Toca 511 administration followed by coadministration of TMZ and 5-FC. These results provide support for the investigation of this novel combination treatment strategy in patients with newly diagnosed malignant glioma.

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Acknowledgements

We thank the Christian Doppler Association (Vienna, Austria), ABC2 Foundation (Washington, DC), the National Brain Tumor Society (Watertown, MA), the American Brain Tumor Association (Chicago, IL), Musella Foundation (Hewlett, NY), and Voices Against Brain Cancer (New York, NY) for financial support.

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Author notes

  1. T T Huang and J Hlavaty: These authors contributed equally to this work.

Authors and Affiliations

  1. Tocagen, San Diego, CA, USA

    T T Huang, D Ostertag, F L Espinoza, B Martin, M Rodriguez-Aguirre, C E Ibañez, H E Gruber, D Pertschuk, D J Jolly & J M Robbins

  2. Christian Doppler Laboratory for Gene Therapeutic Vector Development, Institute of Virology, University of Veterinary Medicine, Vienna, Austria

    J Hlavaty, H Petznek & W Gunzburg

  3. Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    N Kasahara

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  1. T T Huang
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Correspondence to J M Robbins.

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Competing interests

TH, DO, FLE, BM, MA, CI, HG, DP, DJ and JR are employees and/or shareholders of Tocagen. JH and WG are recipients of a research grant from Tocagen. NK is a consultant, has ownership interest and is the recipient of a research grant from Tocagen.

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Huang, T., Hlavaty, J., Ostertag, D. et al. Toca 511 gene transfer and 5-fluorocytosine in combination with temozolomide demonstrates synergistic therapeutic efficacy in a temozolomide-sensitive glioblastoma model. Cancer Gene Ther 20, 544–551 (2013). https://doi.org/10.1038/cgt.2013.51

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