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Principal Investigator: Adolfo Garcia-Sastre
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2024
Award: $119,920
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 corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV vaccine><ACE2><Ab-dependent cellular cytotoxicity><Address><Age><Anti-viral Agents><Antibodies><Antisera><Assay><Bio-Informatics><Bioassay><Bioinformatics><Biological Assay><Body Tissues><COVID crisis><COVID detection><COVID epidemic><COVID pandemic><COVID-19><COVID-19 antibody><COVID-19 crisis><COVID-19 detection><COVID-19 epidemic><COVID-19 era><COVID-19 exposure><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 immunity><COVID-19 infection><COVID-19 pandemic><COVID-19 period><COVID-19 predisposition><COVID-19 public health crisis><COVID-19 related risk><COVID-19 risk><COVID-19 risk factor><COVID-19 susceptibility><COVID-19 therapy><COVID-19 treatment><COVID-19 vaccine><COVID-19 virus><COVID-19 virus infection><COVID-19 vulnerability><COVID-19 years><COVID19 detection><COVID19 infection><COVID19 virus><CV-19><Cancer Patient><Cancers><Cell Body><Cells><Clinical><Clinical Sciences><Clinical Trials><CoV-2><CoV2><Collaborations><Collection><Coronavirus Infectious Disease 2019><Coronavirus disease 2019 predisposition><Coronavirus disease 2019 susceptibility><Coronavirus disease 2019 vulnerability><Data><Data Science Core><Data Science Resource Core><Data Set><Death Rate><Defect><Development><Disease><Disorder><Drugs><Emergencies><Emergency Situation><Epithelial Cells><Epithelium><Evaluation><Exhibits><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 Diseases><Lung Neoplasms><Lung Respiratory System><Lung Tumor><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><Pharmaceutical Preparations><Population><Predisposed to COVID-19><Predisposed to SARS-CoV-2><Predisposed to Severe acute respiratory syndrome coronavirus 2><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 Epithelium><Risk><Risk Reduction><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 antibody><SARS-CoV-2 detection><SARS-CoV-2 epidemic><SARS-CoV-2 exposure><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 immunity><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 predisposition><SARS-CoV-2 susceptibility><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV-2 vaccine><SARS-CoV-2 vulnerability><SARS-CoV2><SARS-CoV2 exposure><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sample Size><Sampling><Serology><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 exposure><Severe acute respiratory syndrome coronavirus 2 immunity><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 predisposition><Severe acute respiratory syndrome coronavirus 2 susceptibility><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome coronavirus 2 vulnerability><Severe acute respiratory syndrome related corona virus 2><Smoking><Smoking Status><Specificity><Structure of respiratory epithelium><Susceptibility><Tissues><Tobacco smoking><Tobacco smoking behavior><Transcription><Tumor Cell><Type A Influenza><Vaccination><Vaccines><Veklury><Viral><Viral Activity><Viral Diseases><Viral 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