Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma

Puntel, Mariana; Farrokhi, Catherine; VanderVeen, Nathan; Paran, Christopher; Appelhans, Ashley; Kroeger, Kurt M.; Salem, Alireza; Lacayo, Liliana; Pechnick, Robert N.; Kelson, Kyle R.; Kaur, Sukhpreet; Kennedy, Sean; Palmer, Donna; Ng, Philip; others, and

doi:10.1016/J.TAAP.2013.02.001

Title: Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma

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Abstract

Adenoviral vectors (Ads) are promising gene delivery vehicles due to their high transduction efficiency; however, their clinical usefulness has been hampered by their immunogenicity and the presence of anti-Ad immunity in humans. We reported the efficacy of a gene therapy approach for glioma consisting of intratumoral injection of Ads encoding conditionally cytotoxic herpes simplex type 1 thymidine kinase (Ad-TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Ad-Flt3L). Herein, we report the biodistribution, efficacy, and neurological and systemic effects of a bicistronic high-capacity Ad, i.e., HC-Ad-TK/TetOn-Flt3L. HC-Ads elicit sustained transgene expression, even in the presence of anti-Ad immunity, and can encode large therapeutic cassettes, including regulatory elements to enable turning gene expression “on” or “off” according to clinical need. The inclusion of two therapeutic transgenes within a single vector enables a reduction of the total vector load without adversely impacting efficacy. Because clinically the vectors will be delivered into the surgical cavity, normal regions of the brain parenchyma are likely to be transduced. Thus, we assessed any potential toxicities elicited by escalating doses of HC-Ad-TK/TetOn-Flt3L (1 × 10{sup 8}, 1 × 10{sup 9}, or 1 × 10{sup 10} viral particles [vp]) delivered into the rat brain parenchyma. We assessedmore »« less

Authors:

Puntel, Mariana ^[1]; Farrokhi, Catherine ^[2]; VanderVeen, Nathan; Paran, Christopher; Appelhans, Ashley ^[1]; Kroeger, Kurt M.; Salem, Alireza ^[3]; Lacayo, Liliana ^[2]; Pechnick, Robert N. ^[2]; Kelson, Kyle R.; Kaur, Sukhpreet; Kennedy, Sean ^[3]; Palmer, Donna; Ng, Philip ^[4]; others, and

Department of Neurosurgery, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689 (United States)
Department of Psychiatry and Behavioral Neurosciences, Cedars Sinai Medical Center, Los Angeles, CA 90048 (United States)
Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048 (United States)
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030 (United States)

Publication Date:: Wed May 01 00:00:00 EDT 2013

OSTI Identifier:: 22285286

Resource Type:: Journal Article

Journal Name:: Toxicology and Applied Pharmacology

Additional Journal Information:: Journal Volume: 268; Journal Issue: 3; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; ADENOVIRUS; BRAIN; CLINICAL TRIALS; GENE THERAPY; GENES; GLIOMAS; HERPES SIMPLEX; RATS; THYMIDINE; TOXICITY; TYROSINE

Citation Formats


                    Puntel, Mariana, Department of Cell and Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, Ghulam, Muhammad A.K.M., Farrokhi, Catherine, VanderVeen, Nathan, Paran, Christopher, Appelhans, Ashley, Department of Cell and Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, Kroeger, Kurt M., Salem, Alireza, Lacayo, Liliana, Pechnick, Robert N., Department of Psychiatry and Behavioral Neurosciences, David Geffen School of Medicine, University of California, Los Angeles, CA, Kelson, Kyle R., Kaur, Sukhpreet, Kennedy, Sean, Palmer, Donna, Ng, Philip, and others, and. Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma.  United States: N. p., 2013. 
        Web.  doi:10.1016/J.TAAP.2013.02.001.

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                    Puntel, Mariana, Department of Cell and Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, Ghulam, Muhammad A.K.M., Farrokhi, Catherine, VanderVeen, Nathan, Paran, Christopher, Appelhans, Ashley, Department of Cell and Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, Kroeger, Kurt M., Salem, Alireza, Lacayo, Liliana, Pechnick, Robert N., Department of Psychiatry and Behavioral Neurosciences, David Geffen School of Medicine, University of California, Los Angeles, CA, Kelson, Kyle R., Kaur, Sukhpreet, Kennedy, Sean, Palmer, Donna, Ng, Philip, & others, and. Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma.  United States.  https://doi.org/10.1016/J.TAAP.2013.02.001

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                    Puntel, Mariana, Department of Cell and Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, Ghulam, Muhammad A.K.M., Farrokhi, Catherine, VanderVeen, Nathan, Paran, Christopher, Appelhans, Ashley, Department of Cell and Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, Kroeger, Kurt M., Salem, Alireza, Lacayo, Liliana, Pechnick, Robert N., Department of Psychiatry and Behavioral Neurosciences, David Geffen School of Medicine, University of California, Los Angeles, CA, Kelson, Kyle R., Kaur, Sukhpreet, Kennedy, Sean, Palmer, Donna, Ng, Philip, and others, and. 2013.  
        "Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma".  United States.  https://doi.org/10.1016/J.TAAP.2013.02.001.

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@article{osti_22285286,

  title        = {Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma},

  author       = {Puntel, Mariana and Department of Cell and Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689 and Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048 and Ghulam, Muhammad A.K.M. and Farrokhi, Catherine and VanderVeen, Nathan and Paran, Christopher and Appelhans, Ashley and Department of Cell and Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689 and Kroeger, Kurt M. and Salem, Alireza and Lacayo, Liliana and Pechnick, Robert N. and Department of Psychiatry and Behavioral Neurosciences, David Geffen School of Medicine, University of California, Los Angeles, CA and Kelson, Kyle R. and Kaur, Sukhpreet and Kennedy, Sean and Palmer, Donna and Ng, Philip and others, and},

  abstractNote = {Adenoviral vectors (Ads) are promising gene delivery vehicles due to their high transduction efficiency; however, their clinical usefulness has been hampered by their immunogenicity and the presence of anti-Ad immunity in humans. We reported the efficacy of a gene therapy approach for glioma consisting of intratumoral injection of Ads encoding conditionally cytotoxic herpes simplex type 1 thymidine kinase (Ad-TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Ad-Flt3L). Herein, we report the biodistribution, efficacy, and neurological and systemic effects of a bicistronic high-capacity Ad, i.e., HC-Ad-TK/TetOn-Flt3L. HC-Ads elicit sustained transgene expression, even in the presence of anti-Ad immunity, and can encode large therapeutic cassettes, including regulatory elements to enable turning gene expression “on” or “off” according to clinical need. The inclusion of two therapeutic transgenes within a single vector enables a reduction of the total vector load without adversely impacting efficacy. Because clinically the vectors will be delivered into the surgical cavity, normal regions of the brain parenchyma are likely to be transduced. Thus, we assessed any potential toxicities elicited by escalating doses of HC-Ad-TK/TetOn-Flt3L (1 × 10{sup 8}, 1 × 10{sup 9}, or 1 × 10{sup 10} viral particles [vp]) delivered into the rat brain parenchyma. We assessed neuropathology, biodistribution, transgene expression, systemic toxicity, and behavioral impact at acute and chronic time points. The results indicate that doses up to 1 × 10{sup 9} vp of HC-Ad-TK/TetOn-Flt3L can be safely delivered into the normal rat brain and underpin further developments for its implementation in a phase I clinical trial for glioma. - Highlights: ► High capacity Ad vectors elicit sustained therapeutic gene expression in the brain. ► HC-Ad-TK/TetOn-Flt3L encodes two therapeutic genes and a transcriptional switch. ► We performed a dose escalation study at acute and chronic time points. ► Doses up to 1 × 10{sup 9} vp of HC-Ad-TK/TetOn-Flt3L can be safely delivered in the brain. ► Efficacy and safety of HC-Ad-TK/TetOn-Flt3L merits its use in a GBM Phase I trial.},

  doi          = {10.1016/J.TAAP.2013.02.001},

  url          = {https://www.osti.gov/biblio/22285286},
  journal      = {Toxicology and Applied Pharmacology},

  issn         = {0041-008X},

  number       = 3,

  volume       = 268,

  place        = {United States},

  year         = {Wed May 01 00:00:00 EDT 2013},

  month        = {Wed May 01 00:00:00 EDT 2013}

}

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