Adjuvant Tumor Lysate Vaccine and Iscomatrix With or Without Metronomic Oral Cyclophosphamide and Celecoxib in Patients With Malignancies Involving Lungs, Esophagus, Pleura, or Mediastinum
Adjuvant Tumor Lysate Vaccine and Iscomatrix With or Without Metronomic Oral Cyclophosphamide and Celecoxib in Patients With Malignancies Involving Lungs, Esophagus, Pleura, or Mediastinum
Background:

 During recent years, cancer-testis (CT) antigens (CTA), particularly those encoded by genes
 on the X chromosome (CT-X genes), have emerged as attractive targets for cancer
 immunotherapy. Whereas malignancies of diverse histologies express a variety of CTAs, immune
 responses to these proteins appear uncommon in cancer patients, possibly due to low-level,
 heterogeneous antigen expression, as well as immunosuppressive regulatory T cells present
 within tumor sites and systemic circulation of these individuals. Conceivably, vaccination of
 cancer patients with tumor cells expressing high levels of CTAs in combination with regimens
 that deplete or inhibit T regulatory cells will induce broad immunity to these antigens. In
 order to examine this issue, patients with primary lung and esophageal cancers, pleural
 mesotheliomas, thoracic sarcomas, thymic neoplasms and mediastinal germ cell tumors, as well
 as sarcomas, melanomas, germ cell tumors, or epithelial malignancies metastatic to lungs,
 pleura or mediastinum with no evidence of disease (NED) or minimal residual disease (MRD)
 following standard multidisciplinary therapy will be vaccinated with H1299 tumor cell lysates
 with Iscomatrix adjuvant. Vaccines will be administered with or without metronomic oral
 cyclophosphamide (50 mg PO BID x 7d q 14d), and celecoxib (400 mg PO BID). Serologic
 responses to a variety of recombinant CTAs as well as immunologic responses to autologous
 tumor or epigenetically modified autologous EBVtransformed lymphocytes will be assessed
 before and after a six month vaccination period.

 Primary Objectives:

 1. To assess the frequency of immunologic responses to CTAs in patients with thoracic
 malignancies following vaccinations with H1299 cell lysate/Iscomatrix(TM) vaccines alone in
 comparison to patients with thoracic malignancies following vaccinations with H1299 cell
 lysate/Iscomatrix vaccines in combination with metronomic cyclophosphamide and celecoxib.

 Secondary Objectives:

 1. 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 thoracic malignancies are at risk of recurrence.

 2. To examine if H1299 cell lysate/Iscomatrix(TM) vaccination enhances immunologic response
 to autologous tumor or epigenetically modified autologous EBV-transformed lymphocytes (B
 cells).

 Eligibility:

 -  Patients with histologically or cytologically proven small cell or non-small cell lung
 cancer (SCLC;NSCLC), esophageal cancer (EsC), malignant pleural mesothelioma (MPM) ,
 thymic or mediastinal germ cell tumors, thoracic sarcomas, or melanomas, sarcomas, or
 epithelial malignancies metastatic to lungs, pleura or mediastinum who have no clinical
 evidence of active disease (NED), or minimal residual disease (MRD) not readily
 accessible by non-invasive biopsy or resection/radiation following standard therapy
 completed within the past 26 weeks.

 -  Patients must be 18 years or older with an ECOG performance status of 0 2.

 -  Patients must have adequate bone marrow, kidney, liver, lung and cardiac function.

 -  Patients may not be on systemic immunosuppressive medications at time vaccinations
 commence.

 Design:

 -  Following recovery from surgery, chemotherapy, or chemo/XRT, patients with NED or MRD
 will be vaccinated via IM injection with H1299 cell lysates and Iscomatrix(TM) adjuvant
 monthly for 6 months.

 -  Vaccines will be administered with or without with metronomic oral cyclophosphamide and
 celecoxib.

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

 -  The trial will randomize 28 evaluable patients per arm to either receive vaccine alone
 or vaccine plus chemotherapy in order to have 80% power to determine if the frequency of
 immune responses on the combination arm exceeds that of the vaccine alone arm, if the
 expected frequencies of immune responses on the two arms were 20% and 50%, using a
 one-sided 0.10 alpha level Fisher s exact test.

 -  Approximately 60 patients will be accrued to this trial.
Background:

 During recent years, cancer-testis (CT) antigens (CTA), particularly those encoded by genes
 on the X chromosome (CT-X genes), have emerged as attractive targets for cancer
 immunotherapy. Whereas malignancies of diverse histologies express a variety of CTAs, immune
 responses to these proteins appear uncommon in cancer patients, possibly due to low-level,
 heterogeneous antigen expression, as well as immunosuppressive regulatory T cells present
 within tumor sites and systemic circulation of these individuals. Conceivably, vaccination of
 cancer patients with tumor cells expressing high levels of CTAs in combination with regimens
 that deplete or inhibit T regulatory cells will induce broad immunity to these antigens. In
 order to examine this issue, patients with primary lung and esophageal cancers, pleural
 mesotheliomas, thoracic sarcomas, thymic neoplasms and mediastinal germ cell tumors, as well
 as sarcomas, melanomas, germ cell tumors, or epithelial malignancies metastatic to lungs,
 pleura or mediastinum with no evidence of disease (NED) or minimal residual disease (MRD)
 following standard multidisciplinary therapy will be vaccinated with H1299 tumor cell lysates
 with Iscomatrix (Trademark) adjuvant. Vaccines will be administered with or without
 metronomic oral cyclophosphamide (50 mg PO BID x 7d q 14d), and celecoxib (400 mg PO BID).
 Serologic responses to a variety of recombinant CTAs as well as immunologic responses to
 autologous tumor or epigenetically modified autologous EBVtransformed lymphocytes will be
 assessed before and after receiving 6 vaccines.

 Primary Objectives:

 -To assess the frequency of immunologic responses to CTAs in patients with thoracic
 malignancies following vaccinations with H1299 cell lysate/Iscomatrix (Trademark) vaccines
 alone in comparison to patients with thoracic malignancies following vaccinations with H1299
 cell lysate/Iscomatrix (Trademark) vaccines in combination with metronomic cyclophosphamide
 and celecoxib.

 Eligibility:

 -Patients with histologically or cytologically proven small cell or non-small cell lung
 cancer (SCLC;NSCLC), esophageal cancer (EsC), malignant pleural mesothelioma (MPM) , thymic
 or mediastinal germ cell tumors, thoracic sarcomas, or melanomas, sarcomas, or

 epithelial malignancies metastatic to lungs, pleura or mediastinum who have no clinical
 evidence of active disease (NED), or minimal residual disease (MRD) not readily accessible by
 non-invasive biopsy or resection/radiation following standard therapy completed within the
 past 56 weeks.

 -  Patients must be 18 years or older with an ECOG performance status of 0 - 2.

 -  Patients must have adequate bone marrow, kidney, liver, lung and cardiac function.

 -  Patients may not be on systemic immunosuppressive medications at time vaccinations
 commence.

 Design:

 -  Following recovery from surgery, chemotherapy, or chemo/XRT, patients with NED or MRD
 will be vaccinated via deep subcutaneous (SQ) injection with H1299 cell lysates and
 Iscomatrix (Trademark) adjuvant monthly until 6 vaccinations have been given.

 -  Vaccines will be administered with or without with metronomic oral cyclophosphamide and
 celecoxib.

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

 -  The trial will randomize 28 evaluable patients per arm to either receive vaccine alone
 or vaccine plus chemotherapy in order to have 80% power to determine if the frequency of
 immune responses on the combination arm exceeds that of the vaccine alone arm, if the
 expected frequencies of immune responses on the two arms were 20% and 50%, using a
 one-sided 0.10 alpha level Fisher s exact test.

 -  Approximately 60 patients will be accrued to this trial.
-  INCLUSION CRITERIA

 2.1.1.1 Patients with histologically or cytologically proven lung or esophageal cancers,
 thymic or mediastinal germ cell tumors, malignant pleural mesotheliomas, or primary
 thoracic sarcomas, as well as patients with sarcomas, melanomas, germ cell tumors, or
 epithelial malignancies metastatic to the lungs, mediastinum, or pleura that have no
 clinical evidence of active disease (NED) or minimal residual disease (MRD) not readily
 accessible by non-invasive biopsy or resection/radiation following standard therapy.

 2.1.1.2 Diagnosis must be confirmed by the NCI Laboratory of Pathology.

 2.1.1.3 Patients must be enrolled within 56 weeks following completion of therapy.

 2.1.1.4 Patients must have completed standard therapy for their malignancy and recovered
 from all toxicities to less than or equal to Grade 2 within 3 weeks prior to enrollment.

 2.1.1.5 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.

 2.1.1.6 Patients must have an ECOG performance status of 0 2

 2.1.1.7 Patients must be 18 years of age or older due to the unknown effects of immunologic
 responses to this vaccine during childhood and adolescent development.

 2.1.1.8 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/mm3

 -  Platelet count greater than 100,000/mm3

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

 -  PT within 2 seconds of the ULN

 -  Total bilirubin <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/1.73m2.

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

 2.1.1.10 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.

 2.1.1.11 The effects of the study treatment on the developing human fetus are unknown;
 thus, women of childbearing potential and men must agree to use adequate contraception
 (hormonal or barrier method of birth control; abstinence) within 28 days prior to study
 entry, for the duration of study participation and up to 120 days after the last dose of
 the drug. Should a woman become pregnant or suspect she is pregnant while she or her
 partner is participating in this study, she should inform her treating physician
 immediately.

 2.1.1.12 Patients must be willing to sign an informed consent.

 2.1.1.13 Ability and willingness to co-enroll on the screening and tissue collection
 protocol 06C0014, 'Prospective Evaluation of Genetic and Epigenetic Alterations in Patients
 with Thoracic Malignancies'.

 EXCLUSION CRITERIA

 2.1.2.1 Patients who are initially rendered NED or have MRD following standard therapy but
 exhibit disease progression prior to initiation of vaccination will be excluded from the
 study.

 2.1.2.2 Patients requiring chronic systemic treatment with steroids will be excluded.

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

 2.1.2.4 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.

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

 2.1.2.6 Patients with any of the following pulmonary function abnormalities will be
 excluded: FEV, < 30% predicted; DLCO < 30% predicted (post-bronchodilator); oxygen
 saturation less than 92% on room air.

 2.1.2.7 Female patients who are pregnant or breastfeeding. Because there is unknown,
 potentially harmful effects of immune response to CT-X antigens and stem cell proteins that
 may be expressed in placenta, fetus, and neonates.

 2.1.2.8 Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
 arrhythmia, or psychiatric illness/social situations 3 months prior to enrollment that
 would limit compliance with study requirements.