Trial Information

Gene Therapy for the Treatment of Brain Tumors Using Intra-Tumoral Transduction With the Thymidine Kinase Gene and Intravenous Ganciclovir

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.