GENE THERAPY

PHASE I CLINICAL GENE THERAPY TRIAL, LOUISIANA STATE UNIVERSITY MEDICAL CENTER. Malignant mesothelioma is a tumor for which there is currently no satisfactory treatment. Mesothelioma is an almost universally fatal disease, regardless of the stage of the tumor at the time of diagnosis. Current treatment modalities include surgery, chemotherapy and radiation therapy, although in some circumstances none of these modalities is superior to no treatment at all. A promising area of research in the treatment of various malignancies is gene therapy. Recent studies have demonstrated the utility of exposing tumor cells to cells transduced to express the Herpes simplex virus gene for thymidine kinase (HSV-TK). By virtue of their expression of HSV-TK, the transduced cells are rendered susceptible to the antiviral drug ganciclovir. Nearby untransduced cells are killed by a so-called bystander effect. A Phase I clinical gene therapy trial for mesothelioma is underway at the Louisiana State University Medical Center of New Orleans. The purpose is to study the safety and to determine the maximal tolerated dose of an HSV-TK-transduced ovarian cancer cell line that is infused into the pleural cavities of patients. This infusion is followed by systemic administration of ganciclovir. The hope is that administration of ganciclovir will result in killing of both the transduced ovarian cancer cells as well as the nearby malignant cells. "Gene therapy for malignant mesothelioma: a novel approach for an incurable cancer with increased incidence in Louisiana", Schwarzenberger, et al., Journal of the Louisiana State Medical Society, 150(4):168-74, April 1998..

PROMISING GENE THERAPY IN TREATMENT OF MALIGNANT MESOTHELIOMA. Modified, nonneurovirulent herpes simplex viruses (HSVs) have shown promise in treatment of brain tumors. However, HSV-1 can infect and cause disintegration of a wide variety of cell types. HSV-1716, a mutant of the virus lacking both copies of the gene coding ICP-34.5, can effectively treat a localized intraperitoneal malignancy. Human malignant mesothelioma cells supported the growth of HSV-1716 and efficiently disintegrated in vitro. Intraperitoneal injection of HSV-1716 into animals with established tumor nodules reduced tumor burden and significantly prolonged survival in an animal model of non-central nervous system-localized human malignancy, without dissemination or persistence, after intraperitoneal injection into mice bearing human tumors. These findings suggest that this virus may be efficacious and safe for use in localized human malignancies of non-neural origin such as malignant mesothelioma. "Use of a 'replication-restricted' herpes virus to treat experimental human malignant mesothelioma", Kucharczyk, et al.., Cancer Research, 57(3):466-71, February 1, 1997. Modified, nonneurovirulent herpes simplex viruses (HSVs) have shown promise in treatment of brain tumors. However, HSV-1 can infect and cause disintegration of a wide variety of cell types. HSV-1716, a mutant of the virus lacking both copies of the gene coding ICP-34.5, can effectively treat a localized intraperitoneal malignancy. Human malignant mesothelioma cells supported the growth of HSV-1716 and efficiently disintegrated in vitro. Intraperitoneal injection of HSV-1716 into animals with established tumor nodules reduced tumor burden and significantly prolonged survival in an animal model of non-central nervous system-localized human malignancy, without dissemination or persistence, after intraperitoneal injection into mice bearing human tumors. These findings suggest that this virus may be efficacious and safe for use in localized human malignancies of non-neural origin such as malignant mesothelioma. "Use of a 'replication-restricted' herpes virus to treat experimental human malignant mesothelioma", Kucharczyk, et al.., Cancer Research, 57(3):466-71, February 1, 1997.

POTENTIAL "SUICIDE" GENE THERAPY FOR MALIGNANT MESOTHELIOMA. Replication -defective adenovirus vectors were generated in which the gene of interest B lacZ, luciferase or herpes simplex virus thymidine kinase (HSV-tk) B is driven by the adenovirus major late promoter (MLP) or the human cytomegalovirus immediate-early gene promoter/enhancer (CMV). In vitro experiments with rat and human mesothelioma cell lines revealed that the CMV promoter was stronger than the MLP promoter regarding levels of expression of the luciferase reporter gene and ganciclovir (GCV) killing efficiency after tk gene transfer. Following administration of lacZ recombinant adenovirus into the pleural cavity of rats with established mesothelioma, a widespread distribution of infectious virus particles through the thorax contents was demonstrated. However, a relatively small proportion of tumor cells were transduced. Nevertheless, a strong growth inhibition was observed following treatment with recombinant tk adenovirus and GCV. In a survival study, animals were treated with recombinant tk adenovirus and a 14 days course of GCV. This treatment prolonged symptom-free survival time from 19 days in the controls to 33 days in the treated group. These responses can be best explained by assuming continued tk expression in or around the tumor tissue during GCV treatment. These results confirm and extend earlier findings with the same model and demonstrate the potential of the herpes simplex virus thymidine kinase suicide gene therapy as a local treatment for malignant mesothelioma. "Gene therapy of experimental malignant mesothelioma using adenovirus vectors encoding the HSV-tk gene", Esandi, et al.,Gene Therapy, 5(4):280-7, April, 1997.