Combined Cytotoxic and Immune-Stimulatory Therapy for Glioma

This is a Phase 1, multiple center open label, dose escalation safety study of Ad-hCMV-TK and
Ad-hCMV-Flt3L delivered to the peritumoral region after tumor resection. This study will
combine direct tumor cell killing (TK) and immune-mediated stimulatory (Flt3L) gene transfer
approaches delivered by first generation adenoviral vectors. Treatment with HSV1-TK is
expected to kill transduced brain cells, thus exposing tumor antigen. Treatment with Flt3L, a
cytokine known to cause proliferation of dendritic cells, should cause the migration of
dendritic cells to the peritumoral brain and remaining tumor. There, they will be exposed to
tumor antigens released from dying glioma cells through TK + valacyclovir-induced glioma cell
death, and thus mediate a specific anti-malignant glioma immune response against remaining
malignant glioma cells.

Inclusion Criteria:

- Newly diagnosed supratentorial brain lesion compatible with a high grade glioma by MR
(magnetic resonance) with no prior treatment with either gene therapy, chemotherapy or
radiation treatments that is amenable to attempted gross total resection
(GTR).Intraoperative histological frozen section at the time of tumor resection should
be compatible with high-grade glioma. If intraoperative diagnosis is not high grade
glioma, the patient will not be enrolled. "High grade glioma" can include:Glioblastoma
multiforme (WHO grade IV); Anaplastic astrocytoma (WHO grade III); Anaplastic
oligodendroglioma (WHO grade III); and Anaplastic ependymoma (WHO grade III).

- Karnofsky score ≥70 (Karnofsky scoring system used to quantify general well-being and
activities of daily life; scores range from 0 to 100 where 100 represents perfect
health and 0 represents death)

- CBC (complete blood count)/differential obtained within 14 days prior, with adequate
bone marrow function defined as follows:

- Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;

- Platelets ≥ 100,000 cells/mm3;

- Hemoglobin ≥ 10.0 g/dl (Note: The use of transfusion or other intervention to achieve
Hgb ≥10.0 g/dl is acceptable.);

- Adequate renal function, as defined below:

- BUN (blood urea nitrogen) ≤ 30 mg/dl within 14 days prior.

- Creatinine ≤ 1.7 mg/dl within 14 days prior.

- Adequate hepatic function, as defined below:

- Bilirubin ≤ 2.0 mg/dl within 14 days prior.

- ALT (alanine aminotransferase)/AST (aspartate aminotransferase) ≤ 3x laboratory upper
limit of normal within 14 days prior.

- Male and female; both genders must use contraception if of reproductive capacity

- Capable of informed consent

- 18-75 years of age

- For women of child bearing age, a negative pregnancy test performed within 14 days of
surgery

Exclusion Criteria:

- Diffusely multifocal lesion that is not amenable to GTR (gross total resection)

- Tumors infiltrating the cerebellum, bilateral corpus callosum ("butterfly glioma"),
ventricular system, or brain stem

- Infratentorial high grade glioma

- Primary central nervous system (CNS) disease that would interfere with subject
evaluation

- Current diagnosis of other cancer except curative cervical cancer in situ, basal or
squamous cell carcinoma of the skin.

- Evidence of other significant disease including hematologic, renal or liver disease
that is not explained by the patient's current medical condition or concomitant
disease, (i.e. levels of absolute neutrophil count (ANC), hemoglobin, platelets,
clotting time, serum creatinine, etc). Final decision on inclusion will be made by
physician, concerning suitability of patient for surgery.

- HIV, Hepatitis B, Hepatitis

- Active systemic infection

- Immunosuppressive disorders (chronic steroid therapy, acquired or congenital immune
deficiency syndromes, autoimmune disease)

- Serious medical conditions (CHF (congestive heart failure), angina, diabetes mellitus,
Chronic obstructive pulmonary disease, abnormal bleeding diathesis)

- Any contraindication for undergoing MRI (magnetic resonance imaging)

- Pregnant or lactating females

- Unacceptable anesthesia risk

- Evidence of bleeding diathesis or use of anticoagulant medication or any medication
that may increase the risk of bleeding that cannot be stopped prior to surgery.

- Prior gene therapy

- Allergy to valacyclovir or unable to take oral tablets