Epigenetic Therapy for Thoracic Malignancies

Division Of Clinical Sciences - Nci

Investigators

Linked publications & trials

Abstract

Our published studies pertaining to laboratory experiments and our related clinical protocols 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 cytidine deaminase) 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 was initialed in late 2017, but was closed this year due to drug stability issues. This was unfortunate as virtually all patients had exhibited evidence of systemic epigenetic reprogramming, and impressive, near complete and durable responses were observed in several patients. To further optimize epigenetic priming of pulmonary malignancies for immune checkpoint blockade while decreasing potential systemic toxicities, we recently initiated preclinical studies to examine the pharmacokinetics and potential efficacy of azacytidine (AZA) administered by aerosolization techniques. We have developed a unique immunocompetent murine pulmonary metastasis model using cancer stem cells isolated from highly lethal syngeneic lung cancer and sarcoma cell lines for systematic, rational evaluation of DNA demethylating agents, LSD1 inhibitors, and cytokines such as IL-12. A phase I/II clinical protocol trial to examine the toxicities and potential efficacy of AZA administered via inhalation techniques in combination with durvalumab as induction therapy for patients with operable NSCLC is presently undergoing FDA review. 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. No such clinical efforts are currently underway elsewhere in the world. Results of our preclinical and translational research efforts were presented as a formal plenary session talk at the Annual Meeting of the AACR in 2023. Cancer-germline antigens comprise a group of shared tumor antigens that are only expressed in cancers arising from somatic cells or immune-privileged sites such as testes, ovary, or placenta. As such, cancer-germline antigens have emerged as highly attractive targets for cancer immunotherapy. Although cancer-germline 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 these proteins. A strategy to overcome these limitations is to immunize patients against a panel of CTAs that potentially can be upregulated by systemic administration of chromatin remodeling agents. Following positive results of a phase 2.5 First-in-Human trial evaluating the use of a cancer cell lysate vaccine as adjuvant therapy in patients with primary thoracic malignancies or tumors metastatic to the lungs, we have written two new protocols using this lysate vaccine (which was developed in our lab) as adjuvant therapy for patients with lung or esophageal cancers. The lung cancer protocol will evaluate the lysate vaccine in combination with the IL-15 super-agonist N-803 as post-operative adjuvant therapy, while the esophageal cancer protocol will evaluate the lysate in combination with the HDAC inhibitor, entinostat, and the immune checkpoint inhibitor, nivolumab following chemo-radiation +/- surgery. Both protocols have been approved by the FDA and NIH IRB and are expected to be open for patient accrual in early Q1 of FY24.