Research ArticleCancer

Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma

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Science Translational Medicine  01 Jun 2016:
Vol. 8, Issue 341, pp. 341ra75
DOI: 10.1126/scitranslmed.aad9784

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  • RE: Enzyme engineering pertaining to vocimagen amiretrorepvec

    We thank Dr. Stoddard for his kind and complimentary comments on our study and agree with him that early-stage clinical trials, like this one, should be attentive to acknowledging the preceding preclinical contributions that led to the clinical trial.
    Dr. Stoddard and his collaborators’ important contribution to the development and optimization of the yeast cytosine deaminase gene for therapeutic use [1], has been cited in several published articles that detailed the pre-clinical development of Toca 511. Specifically, in articles describing the design and development of Toca 511, Dr. Stoddard and his collaborators contribution is referenced, along with others whose previous work contributed to the development of the viral vector (Toca 511) used in this trial [2, 3]. Given space limitations in the manuscript criteria in Science Translational Medicine, we felt that these two references in our article provided the opportunity for interested parties to investigate the design, selection, and pre-clinical translational work necessary to bring Toca 511 into the clinic. We expect that any such interested parties will understand the contribution he and his collaborators made, which were described in a recent news article [4], and no disrespect to these investigators was intended. We thank Dr. Stoddard and his team providing some of the important historical discoveries that gave confidence to the creation of Toca 511.


    Michael A. Vogelbaum MD, PhD...

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    Competing Interests: None declared.
  • Enzyme engineering pertaining to vocimagen amiretrorepvec

    My laboratory and I have recently read and enjoyed this study and applaud both the effort and results reported in this clinical trial. This work is of particular significance to myself, as I have lost both my mother and two close scientific colleagues to glioblastomas.

    We have noted that the text of the article described the clinical reagent 'vocimagen amiretrorepvec' as "nonlytic, retroviral replicating vector (RRV) that delivers a yeast cytosine deaminase". We would like to point out that the enzyme incorporated into this reagent appears to actually be a rationally engineered variant of yeast cytosine deaminase, originally created in our laboratory, in which a series of point mutations were incorporated to render the enzyme more active and more thermostable under in vivo conditions of use. The original description of the engineering of this enzyme for this purpose was reported in Korkegian et al. (2005) "Computational stabilization of an enzyme" Science 308: 857 - 860. The incorporation of that same engineered enzyme variant into the retroviral vector used in this study was subsequently described and cited in Ostertag et al. (2012) "Tumor eradication after delivery of cytosine deaminase and 5-FC" Neuro-oncology 14 (2): 145–159.

    We believe that the literature leading up to, this clinical trial provides an outstanding example of the close relationship between basic studies of biological form, function and mechanism,...

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    Competing Interests: None declared.

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