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Principal Investigator: Adolfo Garcia-Sastre
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2020
Award: $878,495
Funding agency: National Cancer Institute
PROJECT 2: ABSTRACT
Project 2 is based on evidence that lung cancer patients have higher susceptibility to SARS-CoV-2 infection and
increased risk of severe disease and mortality. This increased vulnerability is likely due to a combination of
factors, including immune-suppressing effects of the cancer itself or its treatment, age, pre-existing
comorbidities, or smoking. Moreover, the potential elevated levels of the receptor for SARS-CoV-2, ACE2
protein, in tumor and tumor-adjacent normal tissues observed in cancer patients and in lungs of tobacco smoking
individuals likely contributes to the susceptibility of these patients to SARS-CoV-2. Tumor cells are also known
to be more permissive to viral replication due to defects in innate antiviral immunity. The potential for increased
SARS-CoV-2 amplification in lung cancer cells might be a major factor contributing to enhanced COVID-19
disease in lung cancer patients. An increased susceptibility to viral infection and replication in lung cells in these
patients might also impact the ability of neutralizing antibodies to block viral replication, making lung cancer
patients more susceptible to SARS-CoV-2 infection and less able to become immune. Thus, a better
understanding of the factors that impact SARS-CoV-2 replication in lung cancer and normal lung cells is needed
for devising strategies to reduce the risk of lung cancer patients for severe COVID-19 disease, and for evaluation
of the protective efficacy of future SARS-CoV-2 vaccines in these patients. To address these knowledge gaps,
in Aim 1 we will identify factors associated with the inter-individual variation in susceptibility to infection by SARS-
CoV-2 using an existing unique panel of human lung derived cancer and normal epithelial cells, and relate these
factors to key clinical, demographic, and molecular features. We will use a combination of virological and
genomics approaches, transcriptomics, and scRNAseq assays. The specificity of the susceptibility to SARS-
CoV-2 infection will be evaluated by comparison to other respiratory viruses, such as influenza viruses. In Aim
2, we will characterize the functional activity of antibodies and antivirals in susceptible lung cancer and normal
lung epithelial cells. Together with Project 1, we will determine the neutralizing potency of various antisera in
susceptible lung cancer cells versus non-cancer respiratory tissue, and antibody dependent cellular cytotoxicity
activities of antibodies in lung cancer versus normal lung epithelial cells. Lastly, we will determine the preclinical
activity of drugs under clinical trial consideration in lung cancer cells vs. non-cancer respiratory tissue. Successful
completion of these aims depend on our multi-disciplinary team, the clinical cohorts, biospecimens and resources
provided by the Clinical and Data Sciences Cores and coordinated with overall U54 activities by the
Administrative Core. In sum, these studies will provide new information on the determinants of the susceptibility
of lung cancer patients to SARS-CoV-2 infection and uncover potential new therapeutic strategies.
Terms: <2019 novel coronavirus><2019-nCoV><Ab-dependent cellular cytotoxicity><Address><Age><Antibodies><Antisera><Antiviral Agents><Antiviral Drugs><Antivirals><Assay><Bio-Informatics><Bioassay><Bioinformatics><Biologic Assays><Biological Assay><Body Tissues><COVID-19><COVID-19 epidemic><COVID-19 pandemic><COVID19><COVID19 epidemic><COVID19 pandemic><Cancer Patient><Cancers><Cell Body><Cells><Clinical><Clinical Sciences><Clinical Trials><Collaborations><Collection><Data><Data Science Core><Data Science Resource Core><Data Set><Dataset><Defect><Development><Disease><Disorder><Drugs><Emergencies><Emergency Situation><Epithelial><Epithelial Cells><Epithelium><Epithelium Part><Evaluation><Exhibits><Exposure to><Future><GS-5734><Gene Transcription><Genetic Transcription><Genomic approach><Histology><Human><IFN><Immune><Immune Sera><Immune response><Immunes><Immunological response><Individual><Infection><Influenza A><Influenza A virus><Influenza Virus><Influenza Viruses Type A><Influenzavirus A><Innate Immunity><Interferons><Kidney><Kidney Urinary System><Knowledge><Lung><Lung Neoplasms><Lung Respiratory System><Lung Tumor><Lung diseases><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Mediating><Medication><Methods><Modern Man><Molecular><Monitor><Monkeys><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Normal Cell><Normal Tissue><Normal tissue morphology><Orthomyxovirus Type A><Patients><Pharmaceutic Preparations><Pharmaceutical Preparations><Population><Predisposition><Preparation><Preventative strategy><Prevention strategy><Preventive strategy><Production><Proteins><Pulmonary Cancer><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Neoplasms><Pulmonary malignant Neoplasm><RNA Expression><Receptor Protein><Research Resources><Resistance><Resources><Respiratory Disease><Respiratory Epithelium><Respiratory System Disease><Respiratory System Disorder><Risk><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Sample Size><Sampling><Serologic><Serological><Severe acute respiratory syndrome coronavirus 2><Smoking><Smoking Status><Specificity><Structure of respiratory epithelium><Sum><Susceptibility><Tissues><Tobacco smoking><Tobacco smoking behavior><Transcription><Tumor Cell><Type A Influenza><Vaccination><Vaccines><Viral><Viral Diseases><Viral Receptor><Virus Diseases><Virus Receptors><Virus Replication><Wuhan coronavirus><acquired immunity><adaptive immunity><ages><anti-viral agents><anti-viral drugs><anti-viral immunity><anti-virals><antibody dependent cell mediated cytotoxicity><antibody dependent cytotoxicity><antibody-dependent cell cytotoxicity><antibody-dependent cellular cytotoxicity><antibody-mediated cytotoxicity><antiviral immunity><base><cancer cell><co-morbid><co-morbidity><cohort><comorbidity><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 epidemic><coronavirus disease 2019 pandemic><cytokine><demographics><developmental><disease of the lung><disorder of the lung><drug/agent><experiment><experimental research><experimental study><expression subtypes><gender diversity><genomic effort><genomic strategy><host response><immune serum><immunoresponse><individual heterogeneity><individual patient><individual variability><individual variation><influenzavirus><insight><inter-individual variability><inter-individual variation><interindividual variation><lung cancer><lung disorder><malignancy><molecular sub-types><molecular subsets><molecular subtypes><mortality><multidisciplinary><neoplasm/cancer><neoplastic cell><neutralizing antibody><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><novel therapeutic approach><novel therapeutic intervention><novel therapy approach><pandemic flu><pandemic influenza><pandemic strain of influenza><patient population><permissiveness><pre-clinical><preclinical><prevent><preventing><protective efficacy><protein expression><pulmonary><receptor><remdesivir><renal><resistant><respiratory><respiratory virus><response><scRNA-seq><screening panel><single cell RNA-seq><single cell RNAseq><single-cell RNA sequencing><transcriptomics><tumor><viral infection><viral multiplication><viral replication><virology><virus infection><virus multiplication><virus-induced disease>