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

Detailed Description:

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 resectable lung and esophageal cancers, thymic neoplasms, 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 times 7d q 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 EBV-transformed B cells will be assessed before and after vaccination.

Primary Objectives:

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

Secondary Objectives:

• To ascertain if K562-GM cell vaccines induce immunity to CT antigens in patients with thoracic malignancies.
• To examine if oral metronomic cyclophosphamide and celecoxib therapy diminishes the number and percentage of T regulatory cells and diminishes activity of these cells in patients with resected thoracic malignancies at risk of recurrence.

Eligibility:

• Patients with histologically or cytologically proven small cell or non-small cell lung cancer, esophageal cancer, thymoma or thymic carcinoma, and malignant pleural mesothelioma who have undergone resection of their neoplasms.
• 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 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) at the time vaccination commences.

Design:

• Following recovery from surgery and appropriate adjuvant chemotherapy and/or radiation, patients will be vaccinated via intradermal injection with 1.5×10(7) -2.5×10(7) 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 resectable primary small cell or non-small cell lung cancer, esophageal cancer, thymoma, thymic carcinoma, or pleural mesothelioma who have been resected to no evidence of disease (NED).
2. Patients must be evaluated within twelve weeks following surgery or six weeks following completion of adjuvant therapy.
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. Negative HIV antibody titer and HepBsAg
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 practice birth control during and for four months following treatment.
10. Patients must be willing to sign an informed consent.

Exclusion Criteria:

1. Patients who are initially rendered NED 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 two or more 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 requiring anticoagulation 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); pO2 < 60% or pCO2 > 45 on room air arterial blood gas.
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.