Our published studies pertaining to more than 100 patients with lung and esophageal cancers and pleural mesotheliomas, or pulmonary metastases from non-thoracic malignancies have clearly demonstrated that Decitabine and romidepsin alone or in combination can modulate gene expression in thoracic malignancies and induce immune responses against these neoplasms. Our goal has always been to couple epigenetic priming regimens with adoptive immunotherapy for thoracic malignancies. Presently, poor biodistribution and systemic toxicities prevent optimal, chronic administration of epigenetic agents necessary to reprogram thoracic malignancies. For example, DNA demethylating agents have very limited bioavailability when administered as oral agents and extremely short half-lives (5min) resulting in poor uptake into solid tumors due to cytidine deaminase (CDA) which is present at high levels throughout the body. To overcome these limitations, we formulated DAC and tetrahydrouridine (a potent, non-toxic inhibitor of CDA) for oral administration in collaboration with the Cleveland Clinic. A phase I/II study of oral DAC/THU and pembrolizumab for patients with inoperable NSCLC, esophageal cancers, or malignant pleural mesotheliomas is currently underway. Virtually all patients have exhibited evidence of systemic epigenetic reprogramming, and impressive, near complete and durable (1 yr) responses have been observed in several patients. To further optimize epigenetic priming of pulmonary malignancies for immune checkpoint blockade while decreasing potential systemic toxicities, we have recently initiated a phase I/II trial to examine the toxicities and potential efficacy of AZA administered via inhalation techniques in combination with M7824, a dual immune checkpoint inhibitor-TGF-beta trap in patients with locally advanced pulmonary metastases. No similar efforts are currently underway elsewhere in the world; this trial is intended to establish the paradigm for evaluation of a series of aerosolized epigenetic agents alone or in combination with adoptive immunotherapy for the treatment of locally advanced pulmonary malignancies. Whereas cancer-testis antigens are expressed in a variety of human malignancies, immune responses to these proteins are uncommon in thoracic oncology patients due to low level, heterogeneous antigen expression, deficient antigen processing/presentation, and local as well as systemic immunosuppression. Our published studies from cell lines and patient biopsies have demonstrated that thoracic malignancies exhibit diverse patterns of CTA expression and heterogeneous responses to epigenetic regimens that up-regulate CTAs. A strategy to overcome these limitations is to immunize patients against a panel of CTAs that potentially can be up-regulated by systemic administration of chromatin remodeling agents. To address this issue, we conducted a phase 2.5 First-in-Human trial to ascertain if a tumor lysate vaccine can induce broad immunity to CTA and determine if metronomic oral cyclophosphamide and celecoxib (cy/cel) enhances vaccine-induced immune responses. Briefly, 21 patients with primary thoracic malignancies or extra-thoracic neoplasms metastatic to the chest rendered NED by conventional therapies were randomized to receive H1299 lung cancer cell lysates with Iscomatrix adjuvant via deep intradermal injection q month x 6 +/- daily cy/cel. The primary endpoint was serologic response to purified CTA 1 month after the 6th vaccination. Exploratory objectives included analysis of serologic reactivity to carbohydrate antigens and assessment of peripheral immune subsets before and after vaccine therapy. All patients exhibited local and systemic inflammatory responses lasting 72-96 hours following vaccinations. There were no dose limiting treatment related toxicities. 14 patients (67%) completed all six vaccinations. With a median follow-up of 64.6 months (range 58.8-68.4), 12 patients are alive and NED; 2 patients are alive with controlled, second malignancies. 11 of 14 surviving patients (79%) received six vaccinations compared to 3 of 7 patients (42%) who succumbed to their malignancies. Seven of 10 patients randomized to vaccine with cy/cel received all six vaccinations; 3 of these 7 patients (43%) died of disease. Seven of 11 patients randomized to vaccine alone completed six vaccinations; none (0%) of these 7 patients have died. 8 patients (57%) exhibited serologic responses to NY-ESO-1. Additional reactivities were observed against GAGE7, XAGE, and MAGE-C2. Reactivities against tumor-associated carbohydrate antigens were uncommon. Vaccine therapy decreased percent Tregs (p=0.067*), PD-1 expression on Tregs (p=0.023*), and PD-L1 expression on CD14+ monocytes (p=0.0089*), classical monocytes (p=0.0159*), and intermediate monocytes (p= 0.0031*). Cy/cel did not impact immune responses or vaccine-induced alterations in peripheral immune subsets. Laboratory metrics of response did not appear to correlate with patient survival. Results of this positive trial have recently been published online and support further vaccination efforts in patients with thoracic malignancies.