VI. Appendices 
A 
Pharmacology and Toxicity of Ganciclovir 
24-25 
B 
Recombinant Adenovirus-Mediated Gene 
Transfer in Non-Human Primate CNS 
26-27 
C 
Phase 1 Clinical Trial of Recombinant Adenovirus for the 
Treatment of Cystic Fibrosis 
27-31 
D 
Clinical Trial Design and Schedule of Tests and Procedures 
32 
E 
The Clinical Spectrum of Wild-Type Adenovirus Infections of 
Human CNS 
33 
F 
Ethics Advisory Board 
33-35 
G 
Isolation and Production of H5.010RSV77<' Adenovirus 
35-42 
H 
Toxicity Criteria 
44-47 
1 
Standard Operating Procedures 
48-72 
I Abstracts 
I.B. Scientific 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 
arises 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 is 
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 Positron 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. 
I.B. Non-Technlcal Abstract 
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Recombinant DNA Research, Volume 20 
