Treatment of Advanced CNS Malignancies with the Recombinant Adenovirus H5.010RSVTK: A Phase I Trial. University of Pennsylvania Medical Center, Philadelphia

Abstract

Primary CNS malignancies are responsible for approximately 12,000 deaths annually in the United States. There has been little change in the outcome for adults with malignant brain tumors over the past few decades, despite improvements in surgical techniques and advances in radiation therapy. These tumors are uniformly fatal one to two years after diagnosis. The morbidity and mortality of this disease arise from the effects of a locally invasive, non-metastasizing lesion. The patients may suffer from seizures, paralysis, incoordination, aphasia, confusion, memory loss, sensory deficits or visual loss, depending on the regions of the brain affected. In addition, they usually require large doses of corticosteroids early and late in their illness, and may experience disabling side effects of this treatment, such as edema, proximal myopathy, diabetes, fungal infections or deep vein thrombosis. Few patients in the older age group are able to work after the diagnosis. Most of the patients are incapable of self-care for several months before death. The localized transfer of new genes into cancer cells potentially permits the expression of proteins with specific biologic functions that may provide a means to alter the biology of tumor growth through a variety of mechanisms including increasing tumor immunogenicity, inducing the local expression of toxic agents, and sensitization of tumors to chemotherapeutic agents. Gene therapy with the transfer of the drug susceptibility gene Herpes virus thymidine kinase (HSV-TK) has shown promise in a number of animal models, including CNS tumors. This study will evaluate the use of adenovirus-mediated transfer of the HSV-TK gene into primary human brain tumors followed by systemic treatment with ganciclovir. The goals of this phase I study are to evaluate the overall safety and efficacy of this treatment and to gain insight into the parameters that may limit the general applicability of this approach. In this phase I study, patients with recurrent gliomas will receive stereotactic-guided injections of the virus into the brain tumor, followed by intravenous ganciclovir for 14 days. Patients eligible to undergo a palliative debulking procedure will receive the same treatment followed by resection on day 7. At the time of resection a second dose of virus will be administered intra-operatively into the residual, unresectable portion of the tumor, and intravenous ganciclovir will be continued for additional 14 days. Tissue removed at the time of resection will be analyzed for evidence of adenovirus infection, thymidine kinase expression and signs of inflammation. The size and metabolic activity of all tumors will be followed by volumetric MRI scans and Position Emission Tomography Scans, respectively. Patients will be enrolled in groups of three, with each group receiving successively larger doses of adenovirus. This study will quantify the toxicity of this therapy, and provide evidence as to the duration of transgene expression and virus induced inflammation.

In vitro and in vivo asessment of adenovirus 41 as a vector for gene delivery to the intestine

“…Two prototypic viruses, adenovirus serotypes 2 and 5, have been the most extensively characterized biochemically and genetically and, thus, have been widely used in gene therapy and recombinant vaccination trials. [11][12][13][14][15] While these viruses have demonstrated the ability to be potent vectors with promising futures, data concerning their efficiency in transferring genetic material into intestinal epithelial cells are quite limited and somewhat speculative. [16][17][18][19] We have also experienced similar difficulties as in vivo and in vitro transduction studies suggest that, as enterocytes differentiate, Ad 5 transduction efficiency significantly decreases.…”

Adenovirus-mediated expression of HSV1-TK or Fas ligand induces cell death in primary human glioma-derived cell cultures that are resistant to the chemotherapeutic agent CCNU

“…19 Clinical trials assessing the feasibility and adverse side effect of RAds delivering HSV1 -TK for the treatment of GBM have started. 3,8,11 Thirteen patients, nine of whom were diagnosed with GBM, were subjected to a single injection of RAd expressing HSV1 -TK under the control of the Rous sarcoma virus promoter into an intratumoral site, followed by GCV treatment. 8 The study found that the vector dose was safe when the dose did not exceed 2Â10 11 viral particles.…”

“…Total resection is difficult due to the lack of a defined tumor edge and nonapparent infiltration into normal brain tissue. 3 The failure of chemotherapy at present is thought to be due to inadequate drug delivery and the development of drugresistant tumor cells. 4 Gene therapy has been proposed as another tool for the treatment of GBM and could prove to be a useful method of delivering therapeutic proteins to precise areas of the brain.…”

Inhibition of glioma cells in vitro and in vivo using a recombinant adenoviral vector containing an astrocyte-specific promoter

“…Furthermore, adenoviral vectors expressing herpes TK driven by constitutive promoters have shown promising efficiencies both in vitro and in animals, 22,23 and a clinical trial using AdHS-VTK in patients with CNS malignancies has been initiated. 24 Although studies by Dewey et al 25 showed growth inhibition of syngeneic glioma after intratumoral injection of an adenoviral vector expressing HSV-TK (AdHS-VTK) in combination with systemic GCV treatment, these investigators also observed active inflammation in the brain 3 months after injection of recombinant AdHSVTK. The use of an astrocyte-specific promoter could possibly reduce the host's immune response in the CNS to the transgene, as suggested by studies using intrahepatic injection of adenoviral vectors.…”