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Principal Investigator: DAVID SCHRUMP
Organization: DIVISION OF CLINICAL SCIENCES - NCI
Fiscal Year: 2024
Award: $1,247,492
Funding agency: National Cancer Institute
Our published studies pertaining to laboratory experiments and our related clinical protocols have clearly demonstrated that the DNA demethylating agent, Decitabine (DAC), the class I HDAC inhibitor, romidepsin, and the PRC2 inhibitor, DZNep alone or in combination can modulate gene expression in thoracic malignancies and induce CTL responses against these neoplasms. Our goal has always been to couple epigenetic priming regimens with adoptive immunotherapy for thoracic malignancies. Recently, we conducted two clinical trials using oral DAC and tetrahydrouridine (a potent, non-toxic inhibitor of CDA) in combination with either Nivolumab or Pembrolizumab in patients with inoperable NSCLC, esophageal cancers, or malignant pleural mesotheliomas. Both studies were closed during the COVID pandemic due to drug stability issues. This was unfortunate as virtually all patients exhibited evidence of systemic epigenetic reprogramming, and several patients experienced impressive, near complete and durable responses to the treatment regimens. Presently, poor biodistribution and systemic toxicities prevent optimal, chronic administration of epigenetic agents necessary to reprogram thoracic malignancies. To further optimize epigenetic priming of pulmonary malignancies for immune checkpoint blockade, we have conducted preclinical studies to examine the pharmacokinetics and potential efficacy of DAC as well as a related DNA demethylating agent, azacytidine (AZA) administered by aerosolization techniques. We have developed a unique immunocompetent murine pulmonary metastasis model using cancer stem cells isolated from a highly lethal syngeneic murine lung cancer lines for systematic evaluation of DNA demethylating agents and other epigenetic drugs such as DZNep as well as cytokines such as IL-12 alone or in combination with cancer stem cell vaccines generated in our lab. A phase I/II clinical trial examining the toxicities and potential efficacy of AZA administered via inhalation techniques in combination with durvalumab as induction therapy in patients with operable NSCLC is expected to open in the next several months. Opening of this trial has been delayed due to the need to revise the treatment regimen to stay aligned with rapidly evolving perioperative immunotherapy landscape for early-stage NSCLC. 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 lung cancers and pulmonary metastases. No such clinical efforts are currently underway elsewhere in the world. Although cancer-testis (CT) - also referred to as 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. We and others have demonstrated that CT-genes and genes encoding proteins involved in antigen processing and presentation can be derepressed in cancer cells but not normal cells by epigenetic regimens. 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 a new protocol using this lysate vaccine (which was developed in our lab) as adjuvant therapy for patients with lung or esophageal cancers and mesothelioma rendered NED by SOC, as well as individuals with subclinical thoracic malignancies not warranting SOC intervention. The lysate vaccine will be administered with oral Decitabine and the IL-15 super-agonist N-803. We expect the new protocol to open for patient accrual within the next 12 months. During the past year, we have expanded our translational research efforts related to subjects with germline BAP1 mutations. In 2022 we initiated a protocol (NCT04431024) evaluating the use of dual energy CT (DECT) scans in combination with liquid biopsies and minimally invasive surgical evaluation for early detection of mesothelioma in subjects with BAP1 Cancer Syndrome (BCS). This is the only such protocol in the world and we are currently receiving an average of 3 referrals per month. Results of efforts have been presented at international mesothelioma symposia including the Weinman Symposium at the University of Hawaii Cancer Center in January 2014. A manuscript pertaining to clinical and epigenomic finding from our first 50 patients on this protocol has been submitted for publication. Having identified a surprising number of clinically occult, multicompartment mesotheliomas in these participants, we have initiated a series of small, focused phase II trials (accrual targets of 10-12 patients per trial) examining if oral epigenetic agents can abort progression of subclinical tumors to radiographically evident, life-threatening malignancies. These drugs include oral decitabine/cedazuridine (NCT05960773) and APG-115 (IRB001605; NCT number pending) which target the DNA methylation machinery; additional protocols evaluating CP1209 targeting PRC2, and NBM-BMX- targeting HDAC8 resulting in activation and stabilization of p53 are in preliminary stages of institutional review. These oral agents have been selected for evaluation based on a series of peer reviewed publications from our lab demonstrating disruption of these pathways very early during malignant transformation of human mesothelial cells.
Terms: <5 AZC><5-AC><5-Aza-cytidine><5-Azacytidine><5-Azadeoxycytidine><5-deoxyazacytidine><AZC><Aberrant DNA Methylation><Adjuvant Therapy><Adoptive Cellular Immunotherapy><Adoptive Immunotherapy><Anti-Oncogenes><Antigen Presentation Pathway><Antigen Processing and Presentation><Antigens><Antioncogene Protein p53><Antioncogenes><Apoptosis><Apoptosis Pathway><Azacitidine><Azacytidine><BMX><BMX Non-Receptor Tyrosine Kinase Gene><BMX gene><Biodistribution><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Cancer Center><Cancer Patient><Cancer Suppressor Genes><Cancers><Cell Body><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cells><Cellular Tumor Antigen P53><Chromatin Structure><Chronic><Clinical><Clinical Protocols><Clinical Trials><DNA><DNA Methylation><Data><Decitabine><Deoxyazacytidine><Deoxyribonucleic Acid><Dezocitidine><Drug Kinetics><Drug Stability><Drugs><ETK Gene><Early Diagnosis><Edodekin Alfa><Emerogenes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Esophageal Cancer><Esophagus Cancer><Evaluation><Event><Exhibits><Gene Expression><Generalized Growth><Genes><Genetic Alteration><Genetic Change><Genetic defect><Germ Lines><Goals><Growth><HDAC Agent><HDAC inhibitor><HDAC8><HDAC8 gene><Hawaii><Histone Deacetylase 8><Histone Deacetylase Inhibitor><Histone deacetylase inhibition><Histone-Lysine Methyltransferase><Histone-Lysine N-Methyltransferase><Histones><Human><IL-12><IL-15><IL12><IL15><IL15 Protein><Immune mediated therapy><Immune response><Immunocompetent><Immunological response><Immunologically Directed Therapy><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><In Vitro><Individual><Induction Therapy><Inhalation><Inhaling><Institution><Interleukin-12><Interleukin-15><Interleukin-15 Precursor><International><Intervention><Intervention Strategies><Keytruda><Life><Lung><Lung Respiratory System><MGC9721><Malignant><Malignant - descriptor><Malignant Cell><Malignant Esophageal Neoplasm><Malignant Esophageal Tumor><Malignant Mesothelioma of the Pleura><Malignant Neoplasms><Malignant Pleural Mesothelioma><Malignant Thoracic Neoplasm><Malignant Thoracic Tumor><Malignant Tumor><Malignant Tumor of the Esophagus><Malignant Tumor of the Lung><Malignant Tumor of the Thorax><Malignant neoplasm of esophagus><Malignant neoplasm of lung><Malignant neoplasm of thorax><Manuscripts><Mediating><Medication><Mesothelial Cell><Mesothelioma><Metastasis><Metastasis to the Lung><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to the Lung><Metastatic Tumor><Metastatic Tumor to the Lung><Mice><Mice Mammals><Modeling><Modern Man><Modification><Molecular><Murine><Mus><Mutation><NEOADJ><NKSF><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Natural Killer Cell Stimulatory Factor><Neoadjuvant><Neoadjuvant Therapy><Neoadjuvant Treatment><Neoplasm Metastasis><Neoplasms><Nivolumab><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Normal Cell><Nucleosomes><Onco-Suppressor Genes><Oncogenes-Tumor Suppressors><Oncoprotein p53><Opdivo><Operative Procedures><Operative Surgical Procedures><Oral><Oral Examination><P53><PSCTK2 Gene><PSCTK3 Gene><Participant><Pathway interactions><Patients><Peer Review><Perioperative><Pharmaceutical Preparations><Pharmacokinetics><Phase><Phase 1/2 Clinical Trial><Phase I/II Clinical Trial><Phosphoprotein P53><Phosphoprotein pp53><Position><Positioning Attribute><Programmed Cell Death><Protein Lysine Methyltransferase><Protein Methylase III><Protein Methyltransferase III><Protein TP53><Proteins><Protocol><Protocols documentation><Publications><Publishing><Pulmonary Cancer><Pulmonary malignant Neoplasm><Radiography><Recessive Oncogenes><Regimen><Roentgenography><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Scanning><Scientific Publication><Secondary Neoplasm><Secondary Tumor><Series><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Surgical><Surgical Interventions><Surgical Procedure><Syndrome><THU><TP53><TP53 gene><TRP53><Techniques><Testicles><Testis><Tetrahydrouridine><Thoracic Neoplasms><Thoracic Oncology><Thoracic Tumor><Thorax Tumor><Tissue Growth><Toxic effect><Toxicities><Translational Research><Translational Science><Treatment Protocols><Treatment Regimen><Treatment Schedule><Tumor Protein p53><Tumor Protein p53 Gene><Tumor Suppressing Genes><Tumor Suppressor Genes><Universities><Vaccines><Writing><adjuvant treatment><adoptive cell immunotherapy><aerosolized><cancer cell><cancer metastasis><cancer progenitor><cancer progenitor cells><cancer stem cell><cancer/testis antigen><cell sorting><check point blockade><checkpoint blockade><chromatin remodeling><conference><convention><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><cytokine><demethylation><derepression><drug/agent><early detection><epigenetic drug><epigenetic modifying drugs><epigenetic therapy><epigenetically><epigenomics><experience><first in man><first-in-human><genome mutation><host response><immune check point blockade><immune checkpoint blockade><immune competent><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunogenicity><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><in vivo Model><induction therapies><inhibitor><interventional strategy><lab assignment><lab experiment><laboratory activity><laboratory assignment><laboratory exercise><laboratory experiment><ladakamycin><liquid biopsy><lung cancer><lung metastasis><malignancy><malignant progenitor><malignant stem cell><metastasize to the lung><minimally invasive><neoplasia><neoplasm/cancer><neoplastic growth><oesophageal cancer><oncosuppressor gene><ontogeny><p53 Antigen><p53 Genes><p53 Tumor Suppressor><pathway><pembrolizumab><phase 2 trial><phase II trial><pre-clinical study><preclinical study><prevent><preventing><programs><protein p53><pulmonary><pulmonary metastasis><radiologic imaging><radiological imaging><response><response to therapy><response to treatment><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><summit><surgery><symposia><symposium><systemic toxicity><therapeutic response><therapy response><thoracic cancer><thoracic malignancies><thorax neoplasm><translation research><translational investigation><treatment response><treatment responsiveness><tumor><tumor cell metastasis><virtual>