Tumor Cell Vaccines With ISCOMATRIX Adjuvant and Celecoxib in Patients Undergoing Resection of Lung and Esophageal Cancers and Malignant Pleural Mesotheliomas

Background:

- Cancer-testis (CT) antigens have emerged as attractive targets for cancer immunotherapy.
Whereas lung and esophageal cancers, thymic Neoplasms, primary thoracic sarcomas, as
well as malignant pleural mesotheliomas express a variety of CT antigens, primary or
vaccine-induced immune responses to these antigens appear uncommon in patients with
these malignancies, possibly due to low-level, heterogeneous antigen expression, and
inadequate vaccination strategies.

- Because numerous CT antigens can be induced in tumor cells by DNA demethylating agents
and HDAC inhibitors, it is conceivable that vaccination of cancer patients with
autologous tumor cells exposed to chromatin remodeling agents will enhance anti-tumor
immunity in these individuals.

- In order to examine this issue, patients with resectable primary neoplasms involving the
lungs, esophagus, or pleura will be vaccinated with autologous tumor cells exposed
exvivo to decitabine and radiation following completion of appropriate combined modality
therapy. Vaccine will be administered in conjunction with ISCOMATRIX adjuvant and oral
celecoxib.

Primary Objective:

- To assess the safety of an epigenetically modified autologous tumor cell vaccine in
conjunction with celecoxib.

Eligibility:

- Patients with histologically or cytologically proven or clinically evident primary
pulmonary carcinoma or sarcoma, esophageal cancer, thymic carcinoma or malignant pleural
mesothelioma undergoing resection of their neoplasms.

- Patients must be 18 years or older with an ECOG performance status of 0 2, with adequate
pulmonary and cardiac function and laboratory values within normal limits.

Design:

- Patients with operable lung and esophageal carcinoma/sarcoma, thymoma, thymic carcinoma
or malignant pleural mesothelioma will undergo resection of their malignancies at the
NCI.

- Portions of the resected tumors will be transferred to the Thoracic Oncology Laboratory
and cells will be processed to establish a cancer cell line.

- Following recovery from surgery and appropriate adjuvant chemotherapy and/or radiation,
patients will be vaccinated with epigenetically-modified autologous tumor cells
periodically over 6 months in conjunction with oral celecoxib.

- Systemic toxicities and delayed type hypersensitivity responses to autologous tumor
cells and serologic responses to a variety of CT antigens will be assessed before and
after vaccination.

- Patients will be followed with routine staging scans until disease recurrence.

- As the exact set of comparisons and analyses to be performed will be determined
following completion of the trial, and will be based on limited numbers of patients, the
analyses will be considered exploratory and hypothesis generating rather than
definitive.

- Approximately 120 patients will be accrued to this trial in order to obtain up to 30
evaluable patients.

- ELIGIBILITY CRITERIA:

INCLUSION CRITERIA PRIOR TO SURGERY (SCREENING CONSENT):

1. Patients with resectable clinically evident or histologically proven primary small
cell or non-small cell lung cancers, esophageal cancers, thymoma, thymic carcinoma,
primary sarcoma of the chest, or pleural mesotheliomas are eligible for treatment.

2. Patients with intracranial metastases, which have been treated by surgery or radiation
therapy may be eligible for study provided there is no evidence of active disease.

3. Patients with prior Decitabine exposure are eligible for study.

4. Patients must have an ECOG performance status of 0 2.

5. Patients must be 18 years of age or older due to the unknown effects of immunologic
responses to germ cell-restricted gene products during childhood and adolescent
development.

6. Seronegative for HIV antibody. Note: The experimental treatment being evaluated in
this protocol depends on an intact immune system. Patients who are HIV seropositive
can have decreased immune competence and thus may be less responsive to the
experimental treatment.

7. Seronegative for active hepatitis B, and seronegative for hepatitis C antibody. If
hepatitis C antibody test is positive, then patient must be tested for the presence of
antigen by RT-PCR and be HCV RNA negative.

8. Patients must be aware of the neoplastic nature of their illnesses, the experimental
nature of the therapy, alternative treatments, potential benefits, and risks.

9. Patients must be willing to sign an informed consent, and undergo resection of their
malignancies at the NCI, to ensure vaccine development.

INCLUSION CRITERIA FOR TREATMENT PHASE OF PROTOCOL (STANDARD CONSENT):

1. Patients must have signed the Screening Consent

2. NCI Laboratory of Pathology confirmation of diagnosis of primary small cell or
nonsmall cell lung cancers, esophageal cancers, thymoma, thymic carcinoma, primary
sarcoma of the chest, or pleural mesotheliomas must have been obtained

3. Patients who were initially rendered NED by surgical resection must remain NED at the
time of treatment.

4. Patients with no more than 3 intracranial metastases, which have been definitively
treated by surgery or radiation therapy may be eligible for the study, provided there
is no evidence of active disease for at least 2 months and no requirement for
anticonvulsant therapy or steroids following treatment.

5. Patients must have an ECOG performance status of 0 2.

6. Patients must have evidence of adequate bone marrow reserve, hepatic and renal
function as evidenced by the following laboratory parameters:

- Absolute neutrophil count greater than 1500/mm(3)

- Platelet count greater than 100,000/mm(3)

- Hemoglobin greater than 8g/dl ( patients may receive transfusions to meet this
parameter

- PT within 2 seconds of the ULN

- Total bilirubin <1.5 times upper limits of normal

- Serum creatin ine less than or equal to 1.6 mg/ml or the creatinine clearance
must be greater than 70 ml/min/1.73M(2).

f. Seronegative for HIV antibody. Note: The experimental treatment being evaluated in this
protocol depends on an intact immune system. Patients who are HIV seropositive can have
decreased immune competence and thus may be less responsive to the experimental treatment.

g. Seronegative for active hepatitis B, and seronegative for hepatitis C antibody. If
hepatitis C antibody test is positive, then patient must be tested for the presence of
antigen by RT-PCR and be HCV RNA negative.

h. Patients must be willing to practice birth control during and for four months following
treatment.

i. Patients must be willing to sign the standard informed consent.

EXCLUSION CRITERIA FOR TREATMENT PHASE OF PROTOCOL:

1. Patients unable/unwilling to undergo resection of their malignancies at the NCI will
be excluded.

2. Patients who are initially rendered NED by combined modality therapy but exhibit
disease progression prior to initiation of vaccination will be excluded from the
treatment portion of the study.

3. Patients who will have received more than two systemic cytotoxic treatment regimens
for their thoracic malignancy by the time vaccination commences will be excluded.

4. Patients requiring corticosteroids (other than inhaled) will be excluded.

5. Patients with life expectancy less than 12 months will be excluded.

6. Patients receiving warfarin anticoagulation, who cannot be transferred to other agents
such as enoxaparin or dabigatran, and for whom anticoagulants cannot be held for up to
24 hours will be excluded.

7. Patients with uncontrolled hypertension (>160/95), unstable coronary disease evidenced
by uncontrolled arrhythmias, unstable angina, decompensated CHF (>NYHA Class II), or
myocardial infarction within 6 months of study will be excluded.

8. Patients with other cardiac diseases may be excluded at the discretion of the PI
following consultation with Cardiology consultants.

9. Patients with any of the following pulmonary function abnormalities will be excluded:
FEV, < 30% predicted; DLCO < 30% predicted (post-bronchodilator); pO2 < 60% or pCO2
greater than or equal to 50 on room air arterial blood gas.

10. Pregnant and/or lactating women will be excluded due to the unknown, potentially
harmful effects of immune response to CT-X antigens and stem cell proteins that may be
expressed in placenta, fetus, and neonates.

11. Patients with active infections, including HIV, will be excluded, due to unknown
effects of the vaccine on lymphoid precursors.

12. Patients with any type of primary immunodeficiencies will be excluded from the study.