Document text
Principal Investigator: Parizad Torabi-Parizi
Organization: CLINICAL CENTER
Fiscal Year: 2022
Funding agency: NIH Clinical Center
Coronavirus disease 19 (COVID-19) is a rapidly growing health threat in the United States with a fatality rate ten times greater than with seasonal influenza. The virus is highly transmissible and has rapidly infected large numbers of people in China, in several European countries, and now in the US. From these recent clinical experiences and emerging preclinical studies, it is apparent that much of the morbidity and mortality related to this infection is due to excessive and maladaptive host innate and adaptive immune responses to the virus. These unchecked responses produce inflammatory lung injury leading to severe acute lung injury in 15 to 20% of patients and death in approximately 3%.
Patients at risk of severe COVID-19 infection are older and have underlying comorbid health conditions. Cancer is one such condition that increases infection risk related either to the immunosuppressive effects of the disease itself or the therapies it is treated with. However, a rapidly increasing number of patients with cancer are now being treated with checkpoint inhibitors (CPIs), which rather than being suppressive, actually stimulate the hosts immune response to cancer. Monoclonal antibodies (mAb) directed against the immune checkpoint molecules programmed death-1 (PD-1), its ligand programmed death-ligand 1 (PD-L1), or cytotoxic T-lymphocyte antigen-4 (CTLA-4) augment tumor-reactive cytotoxic T-cell function and have demonstrated great efficacy for several different cancers. However, the greatest adverse effect with the use of CPIs is the development of immune related adverse events, side effects associated with increased activity of the immune system. These adverse events can affect any organ system, including the lung. Checkpoint inhibitor pneumonitis can occur with a frequency of up to 10% and it can affect patients with any malignancy treated with CPIs. Given the large number of US cancer patients now receiving CPIs and who are at risk of developing COVID-19 infection, a critical question is whether patients on this treatment are going to experience increased inflammatory lung injury during pneumonia with the virus. Alternatively, it is possible that existing activation of host immunity related to CPI therapy might actually be protective during the onset of this pneumonia.
To address these two questions, we are going to develop a mouse hepatitis virus (MHV) model of acute lung injury which can be conducted at Biosafety Level 2 in Building 28. MHV is a coronavirus that primarily infects liver and central nervous tissue. However, several key viral proteins such as the nucleocapsid protein necessary for replication, have close homology between MHV and human and severe acute respiratory syndrome coronavirus (SARS). Furthermore, intranasal (IN) and intratracheal (IT) delivery of several strains of the virus has been shown to produce inflammatory lung injury and pneumonitis that simulates key aspects of the pathology of human coronavirus lung injury. One particular strain of MHV, MHV-1, used in the A/J inbred strain of mice produces lung findings most compatible with human coronavirus respiratory infection. Using this MHV-1 model of acute injury, we will examine whether a two or 4 week regimen of treatment with a murine PD-L1 mAb that has known anti-neoplastic effects in mice, increases or decreases lung injury and lethality during the development of MHV induced pneumonia. The model will employ the MHV-1 strain of virus and the A/J mouse strain.
Specific Aim 1: To develop a murine model of coronavirus-induced pneumonia.
Current status:
We have acquired the virus from a commercial entity. This virus along with the carrier control has been propagated and titered by an outside company. Experiments have been performed and we have completed the dose finding part of this study. A dose has been established that will yield the desired mortality rate of 50%.
Specific Aim 2: To determine the effects of 4 or 8 doses of checkpoint inhibitor therapy on the phenotype of lung immune cells.
Current status:
We have completed this part of the study. Four or 8 doses of checkpoint inhibitors block detection of PD-L1 on immune cells in the lung to a similar extent. Additionally, circulating levels of antibody are also similar in the two dosing regimen groups. The 4 dose regimen has been chosen for this protocol.
Specific Aim 3: To determine whether prior checkpoint inhibitor therapy has an effect on mortality in coronavirus-infected animals.
Current status:
These experiments have been completed. Prior checkpoint blockade has no effect on coronavirus mortality in this model.
Specific Aim 4: To examine the effect of checkpoint blockade on immune cell phenotypes under the same experimental conditions as #3 above.
Current status:
These experiments have been completed. By evaluating lung tissue cells by flow cytometry, lung tissue by histology, and total lung tissue by probing for total protein, we have shown that:
1- Prior checkpoint inhibitor therapy leads to lung immune cell phenotype changes. Additionally, prior checkpoint inhibitor treatment leads to circulating protein changes suggesting an inflammatory and anti-apoptotic phenotype.
2- We additionally show an increase in inflammatory proteins that have also been shown to have a role in COVID-19.
Manuscript is currently in preparation:
Anti-PD-L1 therapy altered inflammation but not survival in a lethal coronavirus pneumonia model.
Colleen S. Curran, Xizhong Cui, Yan Li, Mark Jaekle, Junfeng Sun, Cumhur Yusuf Demirkale, Rhea Dhamapurkar, Samuel Minkove, Victoria Hoffman, Peter Q. Eichacker, Parizad Torabi-Parizi
Terms: <A/J Mouse><Acute><Acute Lung Injury><Acute Pulmonary Injury><Address><Adverse Experience><Adverse effects><Adverse event><Affect><Airway infections><Animals><Anti-Cancer Agents><Antibodies><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Apoptotic><B7-H1><B7H1><CD152><CD152 Antigen><CD152 Gene><CD274><COVID-19><COVID19><CTLA 4><CTLA-4 Gene><CTLA4><CTLA4 gene><CTLA4-TM><CV-19><CV19><Cancer Drug><Cancer Patient><Cancers><Cell Body><Cell Function><Cell Process><Cell physiology><Cell-Mediated Lympholytic Cells><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cessation of life><Checkpoint inhibitor><China><Clinical><Clinical Treatment Moab><Coronaviridae><Coronavirus><Country><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocyte Protein 4><Cytotoxic T-Lymphocyte-Associated Antigen 4><Cytotoxic T-Lymphocyte-Associated Protein 4><Cytotoxic T-Lymphocyte-Associated Serine Esterase-4><Cytotoxic T-Lymphocytes><Death><Detection><Development><Disease><Disorder><Dose><European><Fatality rate><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Frequencies><Goals><HCoV><Health><Hepatitis><Histology><Human><Human Pathology><Immune><Immune checkpoint inhibitor><Immune response><Immune system><Immunes><Immunity><Immunological response><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Inbred Strains Mice><Infection><Inflammation><Inflammatory><Injury><Ligands><Liver><Lung><Lung Inflammation><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung damage><Mainland China><Malignant Neoplasms><Malignant Tumor><Manuscripts><Mice><Mice Mammals><Modeling><Modern Man><Monoclonal Antibodies><Morbidity><Morbidity - disease rate><Mouse Hepatitis Virus><Mouse Strains><Murine><Murine Gastroenteritis Virus><Murine hepatitis virus><Mus><Neoplastic Disease Chemotherapeutic Agents><Nerve Tissue><Nervous Tissue><Nucleocapsid Proteins><Organ System><PD 1><PD-1><PD-L1><PD1><PDL-1><PDL1><Patients><Persons><Phenotype><Pneumonia><Pneumonitis><Preparation><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Proteins><Protocol><Protocols documentation><Pulmonary Inflammation><Regimen><Respiratory Infections><Respiratory Tract Infections><Rhea><Risk><Role><SARS Virus><SARS corona virus><SARS coronavirus><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV-1><SARS-Related Coronavirus><Severe Acute Respiratory Coronavirus><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Structure of parenchyma of lung><Subcellular Process><The Sun><Time><Treatment Protocols><Treatment Regimen><Treatment Schedule><Tumor-Specific Treatment Agents><United States><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><adaptive immune response><allergic/immunologic body system><allergic/immunologic organ system><anti-cancer drug><anticancer agent><anticancer drug><body system><check point blockade><check point immunotherapy><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint blockade><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><co-morbid><co-morbidity><comorbidity><corona virus><corona virus disease 2019><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cytotoxic T-lymphocyte antigen 4><developmental><experience><experiment><experimental research><experimental study><flow cytophotometry><hepatic body system><hepatic organ system><host response><human CoV><human corona virus><human coronavirus><immune check point><immune check point blockade><immune check point inhibitor><immune check point therapy><immune checkpoint><immune checkpoint blockade><immune checkpoint therapy><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immune-mediated adverse events><immune-related adverse events><immunecheckpoint><immunoresponse><immunosuppressive activity><immunosuppressive function><infection risk><injuries><killer T cell><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lung injury><mAbs><malignancy><mortality><mouse development><mouse model><murine model><neoplasm/cancer><pneumonia model><pneumonia models><pre-clinical study><preclinical study><programmed cell death 1><programmed cell death ligand 1><programmed cell death protein 1><programmed cell death protein ligand 1><programmed death 1><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><response><seasonal flu><seasonal influenza><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome-CoV><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><side effect><sle2><social role><sun><systemic lupus erythematosus susceptibility 2><tumor><virus protein>