Translational Development of Replication-Competent Retrovirus Vectors

Summary

Principal Investigator: Noriyuki Kasahara
Abstract: Glioblastoma multiforme (GBM), the most common primary brain tumor in adults, is associated with a dismal prognosis of only 12-15 months despite aggressive surgery, radiation, and chemotherapy. The lack of effective treatment options has made this disease a target for new strategies such as gene therapy. However, the only major Phase III clinical trial of gene therapy, involving the use of conventional replication-defective retrovirus vectors in GBM patients, resulted in disappointingly low and therapeutically inadequate transduction levels on the order of only 0.02%. The inability of standard replication-defective retroviral vectors to achieve effective transduction of tumors in vivo is therefore a major obstacle to gene therapy for gliomas. The use of replication-competent vectors for gene transfer would be more efficient, as each tumor cell that is successfully transduced would itself become a virus- producing cell, sustaining further transduction events even after initial administration. We have previously demonstrated that direct intratumoral injection of murine leukemia virus (MLV)- based replication-competent retrovirus (RCR) vector preparations can achieve tremendously efficient suicide gene transfer in gliomas, with transduction stringently restricted to the actively dividing tumor cells without evidence of significant spread to extratumoral sites, and resulting in significantly prolonged survival upon prodrug administration, without detectable systemic side effects. Therefore, in collaboration with neurosurgery groups at UCLA, USC, and UCSF, and the National Gene Vector Biorepository (NGVB), here we propose to optimize and implement clinical grade RCR vector production and release testing (Aim 1), to re-validate these clinical grade vectors by confirmatory testing of therapeutic efficacy in at least 2 intracranial glioma models from different species per FDA stipulations, as well as re-validation of preclinical toxicology and follow-up monitoring assays as mandated by FDA guidelines (Aim 2), and to evaluate convection-enhanced delivery and non-invasive NMR imaging methodologies and develop clinical trial protocols (Aim 3). We propose to perform these necessary preclinical translational studies through this U01 mechanism, with the final goal of filing an IND and obtaining approval from the FDA to initiate clinical trials. RELEVANCE (See instructions): Glioblastoma multiforme (GBM;WHO Grade IV malignant glioma), is the most common form of malignant brain tumor in adults, accounting for 50-60% of primary brain tumors, and 7-10% of childhood intracranial neoplasms. Despite major improvements in neuroimaging, neurosurgery, radiotherapy, and supportive care, the overall prognosis for GBMs is still only 12-15 months, and current treatments only delay recurrence. Hence, there is an unmet need to develop effective new approaches against this devastating disease.
Funding Period: 2010-06-01 - 2014-05-31
more information: NIH RePORT

Top Publications

  1. pmc Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector
    Derek Ostertag
    Tocagen, 3030 Bunker Hill St, San Diego, CA 92109, USA
    Neuro Oncol 14:145-59. 2012
  2. ncbi Retroviral replicating vectors in cancer
    Christopher R Logg
    Department of Medicine, University of California, Los Angeles, California, USA
    Methods Enzymol 507:199-228. 2012
  3. pmc Cryptic transcripts from a ubiquitous plasmid origin of replication confound tests for cis-regulatory function
    Nathan A Lemp
    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA
    Nucleic Acids Res 40:7280-90. 2012
  4. pmc Convection-enhanced delivery improves distribution and efficacy of tumor-selective retroviral replicating vectors in a rodent brain tumor model
    D Yin
    Department of Neurosurgery, University of California San Francisco, San Francisco, CA 94103, USA
    Cancer Gene Ther 20:336-41. 2013

Research Grants

  1. Center for Molecular Imaging Research at MGH/HMS
    Ralph Weissleder; Fiscal Year: 2013
  2. M. D. Anderson Cancer Center SPORE in Multiple Myeloma
    ROBERT ZYGMUNT ORLOWSKI; Fiscal Year: 2013
  3. Risk-Based Breast Cancer Screening in Community Settings
    Diana L Miglioretti; Fiscal Year: 2013
  4. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
  5. Molecular and Clinical Approaches to Colon Cancer Precursors
    SEAN VAHRAM TAVTIGIAN; Fiscal Year: 2013
  6. Center for Narcolepsy and Related Disorders (P50)
    Emmanuel J Mignot; Fiscal Year: 2013
  7. JHU ICMIC PROGRAM
    Zaver M Bhujwalla; Fiscal Year: 2013
  8. Mayo SPORE in Brain Cancer
    BRIAN PATRICK O'NEILL; Fiscal Year: 2013

Detail Information

Publications4

  1. pmc Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector
    Derek Ostertag
    Tocagen, 3030 Bunker Hill St, San Diego, CA 92109, USA
    Neuro Oncol 14:145-59. 2012
    ..This concept is under investigation in an ongoing phase I/II clinical trial of Toca 511 in combination with 5-FC in patients with recurrent high-grade glioma (www.clinicaltrials.gov NCT01156584)...
  2. ncbi Retroviral replicating vectors in cancer
    Christopher R Logg
    Department of Medicine, University of California, Los Angeles, California, USA
    Methods Enzymol 507:199-228. 2012
    ....
  3. pmc Cryptic transcripts from a ubiquitous plasmid origin of replication confound tests for cis-regulatory function
    Nathan A Lemp
    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA
    Nucleic Acids Res 40:7280-90. 2012
    ..Computational estimation of the frequency of cryptic 3' ss in genomic sequences suggests that misattribution of cis-regulatory function may be a common occurrence...
  4. pmc Convection-enhanced delivery improves distribution and efficacy of tumor-selective retroviral replicating vectors in a rodent brain tumor model
    D Yin
    Department of Neurosurgery, University of California San Francisco, San Francisco, CA 94103, USA
    Cancer Gene Ther 20:336-41. 2013
    ..We conclude that delivery of RRV into the glioma by CED provides much wider vector distribution than simple injection, and this correlated with better therapeutic outcomes...

Research Grants30

  1. Center for Molecular Imaging Research at MGH/HMS
    Ralph Weissleder; Fiscal Year: 2013
    ....
  2. M. D. Anderson Cancer Center SPORE in Multiple Myeloma
    ROBERT ZYGMUNT ORLOWSKI; Fiscal Year: 2013
    ..abstract_text> ..
  3. Risk-Based Breast Cancer Screening in Community Settings
    Diana L Miglioretti; Fiscal Year: 2013
    ..The program represents an integrated effort to improve screening with the overall aim of averting deaths from breast cancer while minimizing harms. ..
  4. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
    ..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
  5. Molecular and Clinical Approaches to Colon Cancer Precursors
    SEAN VAHRAM TAVTIGIAN; Fiscal Year: 2013
    ..abstract_text> ..
  6. Center for Narcolepsy and Related Disorders (P50)
    Emmanuel J Mignot; Fiscal Year: 2013
    ..We also want to understand why the immune system destroys hypocretin neurons in narcolepsy and to prevent/cure it. ..
  7. JHU ICMIC PROGRAM
    Zaver M Bhujwalla; Fiscal Year: 2013
    ..The Career Development Component is structured with the purpose of creating independently funded investigators who will, in the future, become leaders in the field. ..
  8. Mayo SPORE in Brain Cancer
    BRIAN PATRICK O'NEILL; Fiscal Year: 2013
    ..D.) D. Animal Core (Director: J.N. Sarkaria, M.D.;Co-Director: I.F. Parney, M.D., Ph.D.) E. Clinical Research Core (Director: J.C. Buckner, M.D.;Co-Director: D. H. Lachance, M.D.) Developmental Research Portfolio ..