Epigenetic Therapy for Thoracic Malignancies

Division Of Clinical Sciences - Nci

Investigators

Linked publications & trials

Abstract

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. 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 preclinical studies to examine the pharmacokinetics and potential efficacy of azacytidine administered by aerosolization techniques. A phase I/II clinical protocol 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 was approved by NIH IRB only to be closed due to a company decision not to further develop M7824. This trial was 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. No similar efforts are currently underway elsewhere in the world. The trial will be reinitiated once we have commitment from a pharmaceutical company for a replacement immune checkpoint inhibitor. Additionally, we have tentative commitment from AstraZeneca to conduct an inhaled AZA trial in combination with Durvalumab in patients with operable early-stage NSCLC. This protocol is being prepared for scientific review. 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. 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 in 21 patients accrued to the trial. 14 patients (67%) completed all six vaccinations. 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 and support further vaccination efforts in patients with thoracic malignancies. Two phase two trials one using the lysate vaccine in combination with the IL-15 superagonist N-803 as post-operative adjuvant therapy in lung cancer patients, and the other using the lysate in combination with entinostat and nivolumab in esophageal cancer patients post chemo-radiation +/- surgery are undergoing FDA and IRB approval at this time and are expected to be open for patient accrual in Autumn of 2022.