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Gene Therapy for the Treatment of Brain Tumors

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00001328
First Posted: November 4, 1999
Last Update Posted: July 2, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by:
National Institutes of Health Clinical Center (CC)
  Purpose

Malignant brain tumors are responsible for a significant amount of deaths in children and adults. Even with advances in surgery, radiation therapy, and chemotherapy, many patients diagnosed with a malignant brain tumor survive only months to weeks.

In an attempt to improve the prognosis for these patients, researchers have developed a new approach to brain tumor therapy. This approach makes use of DNA technology to transfer genes sensitive to therapy into the cells of the tumor.

Infections with the herpes simplex virus can cause cold sores in the area of the mouth. A drug called ganciclovir (Cytovene) can kill the virus. Ganciclovir is effective because the herpes virus contains a gene (Herpes-Thymidine Kinase TK gene) that is sensitive to the drug. Researchers have been able to separate this gene from the virus.

Using DNA technology, researchers hope to transfer and implant the TK gene into tumor cells making them sensitive to ganciclovir. In theory, giving patients ganciclovir will kill all tumor cells that have the TK gene incorporated into them.


Condition Intervention Phase
Brain Neoplasm Neoplasm Metastasis Drug: Cytovene (Ganciclovir Sodium) Device: G1TKSVNa.53 Producer Cell Line Phase 1

Study Type: Interventional
Study Design: Primary Purpose: Treatment
Official Title: Gene Therapy for the Treatment of Brain Tumors Using Intra-Tumoral Transduction With the Thymidine Kinase Gene and Intravenous Ganciclovir

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Enrollment: 15
Study Start Date: August 21, 1992
Study Completion Date: April 30, 2010
Primary Completion Date: April 30, 2010 (Final data collection date for primary outcome measure)
Detailed Description:

Malignant brain tumors are responsible for significant morbidity and mortality in both pediatric and adult populations. These common tumors present an enormous therapeutic challenge due to their poor outcome despite radical surgery, high dose radiotherapy and chemotherapy. Survival of patients from the time of diagnosis is measured in months and recurrence after treatment is associated with a life expectancy of weeks.

In an attempt to improve this grim prognosis of patients with malignant brain tumors (both primary tumors and secondary metastasis from systemic cancer such as melanoma, lung and breast cancer), we developed a novel approach to the therapy of brain tumors. This approach makes use of recombinant DNA technology to transfer a sensitivity gene into a brain tumor. This is achieved by direct injection of the tumor with a cell line actively producing a retroviral vector carrying a gene conferring drug sensitivity to the tumor. A retroviral vector is a mouse retrovirus genetically engineered to replace its own genes with a new gene. Such vectors are capable of "infecting" mammalian cells and stably incorporate their new genetic material into the genome of the infected host. The producer cell is an NIH 3T3 cell that has been genetically engineered to continually produce retroviral vectors. The new gene is incorporated into the genome of the tumor cells and expresses the protein which is encoded by the new gene. This protein (the herpes simplex virus enzyme thymidine kinase, HS-tk) sensitizes the tumor cells to an antiviral drug (ganciclovir, GCV) which is a natural substrate for HS-tk. The enzymatic process induced by GCV leads to death of a natural substrate for HS-tk. The enzymatic process induced by GCV leads to death of the cell expressing the herpes TK activity, i.e., death of the tumor cells. Since the HS-tk enzyme which is normally present in mammalian cells has very low affinity for GCV, systemic toxicity related to this mechanism is not observed. This type of in vivo gene transfer has several unique features. First, these retroviral-vectors will only integrate and express their genes in cells which are actively synthesizing DNA. Therefore, surrounding non-proliferating normal brain tissue should not acquire the HS-tk gene and will remain insensitive to GCV. Second, all of the transduced tumor cells (and retroviral vector producing cells) will be killed by the host immune response and/or GCV treatment eliminating potential concern about insertional mutagenesis giving rise to malignant cells.

This is the first clinical attempt to treat malignant tumors in human beings by in-vivo genetic manipulation of tumor's genome.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   19 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

All adults, greater than 18 years of age, with malignant brain tumors (primary and metastatic) who failed all standard therapy for their disease will be eligible to enter the study.

EXCLUSION CRITERIA:

No pregnant women will be entered into the study.

Patients with HIV infection will not be accepted for this study.

  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00001328


Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Institute of Neurological Disorders and Stroke (NINDS)
  More Information

Publications:
Responsible Party: John D. Heiss, M.D./National Institute of Neurological Disorders and Stroke, National Institutes of Health
ClinicalTrials.gov Identifier: NCT00001328     History of Changes
Other Study ID Numbers: 920246
92-N-0246
First Submitted: November 3, 1999
First Posted: November 4, 1999
Last Update Posted: July 2, 2017
Last Verified: April 30, 2010

Keywords provided by National Institutes of Health Clinical Center (CC):
Cancer
Gene Transfer
Recurrent Tumors
Primary Tumors
Metastases
Anti-Viral Drugs
Chemosensitization
Brain Tumors
Gene Therapy
Ganciclovir

Additional relevant MeSH terms:
Neoplasms
Neoplasm Metastasis
Brain Neoplasms
Neoplastic Processes
Pathologic Processes
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Ganciclovir
Ganciclovir triphosphate
Antiviral Agents
Anti-Infective Agents
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action