Pilot Study of Allogeneic Tumor Cell Vaccine With Metronomic Oral Cyclophosphamide and Celecoxib in Patients Undergoing Resection of Lung and Esophageal Cancers, Thymic Neoplasms, and Malignant Pleural Mesotheliomas

Background:

During recent years, the cancer-testis (CT) antigens have emerged as attractive targets for
cancer immunotherapy. Whereas lung and esophageal cancers, as well as malignant pleural
mesotheliomas express a variety of CT antigens, immune responses to these antigens appear
uncommon in patients with these malignancies, possibly due to low-level, heterogeneous
antigen expression, as well as immunosuppressive regulatory T cells. Our published studies
indicate that numerous CT antigens can be induced in tumor cells by DNA demethylating agents
and histone deacetylase (HDAC) inhibitors. Conceivably, vaccination of cancer patients with
allogeneic tumor cells expressing high levels of multiple CT antigens in combination with
depletion of T regulatory cells will induce broad immunity to these antigens. In order to
examine this issue, patients with lung and esophageal cancers, thymic neoplasms, primary
thoracic sarcomas, and malignant pleural mesotheliomas will be vaccinated with irradiated
K562 erythroleukemia cells expressing GM-CSF (K562-GM) following completion of appropriate
combined modality therapy. Vaccines will be administered in conjunction with metronomic oral
cyclophosphamide (50 mg PO BID x 7dq 14d), and celecoxib (400 mg PO BID). Serologic responses
to a variety of recombinant CT antigens as well as cell-mediated recognition of autologous
tumor cells and EBVtransformed B cells will be assessed before and after vaccination.

Objective:

-To assess the safety of K562-GM allogeneic tumor cell vaccines in combination with oral
metronomic cyclophosphamide and celecoxib in thoracic oncology patients.

Eligibility:

- Patients with histologically or cytologically proven small cell or non-small cell lung
cancer, esophageal cancer, thymoma or thymic carcinoma, primary thoracic sarcomas, and
malignant pleural mesothelioma with no evidence of disease (NED) or minimal residual
disease (MRD) in the primary site following standard multimodality therapy.

- Patients must be 18 years or older with an ECOG performance status of 0 - 2, without
evidence of unstable or decompensated myocardial disease. Patients must have adequate
pulmonary reserve evidenced by FEV1 and DLCO equal to or greater than 30% predicted;
pCO2 less than 50 mm Hg and pO2 greater than 60 mm Hg on room air ABG; and be on no
immunosuppressive medications except inhaled corticosteroids at the time vaccination
commences.

- Patients must have a platelet count greater than 100,000, an ANC equal to or greater
than 1500 without transfusion or cytokine support, a normal PT, and adequate hepatic
function as evidenced by a total bilirubin of <1.5 x upper limits of normal. Serum
creatinine less than or equal to 1.6 mg/ml or the creatinine clearance must be greater
than 70 ml/min/1.73m(2) at the time vaccination commences.

Design:

- Following recovery from standard combined modality therapy, patients with no evidence of
disease or minimal residual disease will be vaccinated via subcutaneous intradermal
injection with 1x10(8) irradiated K562-GM-tumor cells periodically over 6 months.
Sterility, potency and identity of the vaccines preps will be confirmed before
administration.

- Vaccines will be administered in conjunction with metronomic oral cyclophosphamide and
celecoxib.

- Systemic toxicities, and immunologic response to therapy will be recorded. Pre and post
vaccination serologic responses to a standard panel of CT antigens as well as cell
mediated responses to epigenetically-modified autologous EBV-transformed B and
autologous tumor cells (if available) will be assessed before and after vaccination.

- Numbers/percentages and function of T regulatory cells in peripheral blood will be
assessed before, during, and after vaccinations.

- Patients will be followed in the clinic 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 25 patients will be accrued to this trial.

-INCLUSION CRITERIA:

1. Patients with primary small cell or non-small cell lung cancer, esophageal cancer,
thymoma, thymic carcinoma, primary sarcoma of the chest, or pleural mesothelioma with
no evidence of disease (NED) or minimal residual disease (MRD) in the primary site
following standard multi-modality therapy.

2. Patients must be evaluated within 52 weeks following completion of standard therapy
and have shown no evidence of disease during that time.

3. 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 and
no requirement for anticonvulsant therapy or steroids following treatment.

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. 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 creatinine less than or equal to 1.6 mg/ml or the creatinine clearance must
be greater than 70 ml/min/1.73m(2).

7. 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.

8. 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.

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

10. Patients must be willing to sign an informed consent.

11. Patients must be willing to sign an informed consent.

EXCLUSION CRITERIA:

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

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

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

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

5. 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.

6. 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.

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

8. Patients with any of the following pulmonary function abnormalities will be excluded:
FEV, < 30% predicted; DLCO < 30% predicted (post-bronchodilator); Oxygen Saturation
less than 90% on room air.

9. 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.

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

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