Combination of gp96-Ig Vaccine, Theophylline and Oxygen for the Treatment of Patients With Advanced, Relapsed or Metastatic Non-Small Cell Lung Cancer

This is a proof of principle trial investigating a heat shock protein gp96 Ig-secreting,
allogeneic tumor cell-vaccine (gp96-Ig vaccine) administered in combination with suppression
of adenosinergic pathways by oxygen and Theophylline to patients with non-small cell lung
cancer (NSCLC). Allogeneic, cultured lung adenocarcinoma cells transfected with HLA A1 and
gp96-Ig will be irradiated and injected intradermally into patients suffering from advanced,
relapsed, or metastatic NSCLC. HLA matching is not required. Safety and immunogenicity of
the combined treatment will be studied in three patient cohorts that will receive twice
monthly, weekly or twice weekly vaccination plus Theophylline and oxygen.

Immune response to vaccination of patients will be measured by determining
adenocarcinoma-specific CD8 CTL precursor frequencies. ELI-spot assay for interferon-y
(IFN-y) will be done to measure cytotoxic function of CD8 cells challenged in vitro with
vaccine cells or autologous tumor cells. Multiparameter flow cytometry of CD8 and CD4 cells
will be carried out to assess functional characteristics and to assess adenosine receptor
levels and expression of hypoxia inducible factor-1alpha.

Patients will be randomized in equal allocation (1:1:1) to one of three dose-schedule (DS)
cohorts defined by the frequency of vaccination. All patients will receive a total course
dose of gp96 vaccine. A total of 36 patients, 12 per DS cohort, will be enrolled. We expect
to accrue at a rate of two patients per month except at the onset of study when successive
enrollment will be spaced to allow observation of first course toxicity in the first several
patients. (See Section 3.3.4 for details.) Patients will be followed for a minimum of one
year, thus study duration is expected to be three years.

Inclusion Criteria:

- Histologically confirmed NSCLC (squamous, adeno-, large cell anaplastic,
bronchoalveolar, and non-small cell carcinoma NOS): stage IIIB with malignant pleural
effusion, stage IV, or recurrent disease.

- At least one site of measurable disease.

- Brain metastasis if present and treated must be stable by CT scan or MRI for at least
4 weeks after treatment.

- Patient must have received and failed at least one line of palliative therapy
(chemotherapy or biological therapy)

- Age >= 18 years.

- ECOG performance status 0-2.

- Life expectancy >= 3 months.

- Laboratory parameters

- Hemoglobin levels >= 10.0 (transfusions allowed if necessary).

- ANC >= 1,500.

- Platelets >= 100k.

- Creatinine clearance >= 50 ml/min.

- Total and direct bilirubin: < 3.0 x upper institution limit for normal.

- Liver function tests: AST, ALT, and AlkP < 3.0 x upper institution limit for
normal.

- Signed informed consent.

Exclusion Criteria:

- Active or symptomatic cardiac disease such as congestive heart failure, angina
pectoris or recent myocardial infarction. Patients with history of these conditions
who are stable taking cardiac medications will also be excluded.

- Pregnant or lactating women (negative test for pregnancy is required of women of
childbearing potential).

- Known HIV infection.

- Uncontrolled or untreated brain or spinal cord metastases.

- Active infection.

- Concomitant steroid or other immunosuppressive therapy.

- Other active malignancies present within the past three years, except for basal
and/or squamous cell carcinoma(s) or in situ cervical cancer.

- Meningeal carcinomatosis.

- Chemotherapy, radiation therapy, or other anti-tumor therapy during the last three
weeks.

- Immune deficiency syndromes, including the following: rheumatoid arthritis, systemic
lupus erythematousus, Sjogren's disease, sarcoidosis, vasculitis, polymyositis,
glomerulonephritis.

- Compromised lung function:

- FeV1 < 30% of the predicted value, or

- DLCO < 30% of the predicted value, or

- PCO2 > 45 mmHg.