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Principal Investigator: CANDACE S JOHNSON
Organization: ROSWELL PARK CANCER INSTITUTE CORP
Fiscal Year: 2020
Award: $420,500
Funding agency: National Cancer Institute
Following infection with the novel coronavirus SARS-CoV-, immunocompromised and older individuals are at higher risk of severe illness and fatality. Patients with cancer exhibit multiple factors associated with elevated morbidity and mortality from COVID-19, including older age, pre-existing cardiac and lung disease, and immune impairment from the underlying malignancy and chemotherapy. While the innate immune response is the first line of antiviral defense against SARS-CoV-2, coronavirus infection is accompanied by suppression of type I interferon (IFN), thereby limiting activation of innate immune pathways required for immediate control of infection and adaptive immunity. Coronavirus-mediated inhibition of innate immunity via the type I IFN pathway allows the virus to replicate in epithelial cells, and particularly in high-risk patients, progress to pneumonia and respiratory failure. The mechanisms include inhibition of intracellular signaling driven by pattern recognition receptors (e.g. RIG-I and MDA5) and suppression of IRF-3, a transcriptional factor that induces the expression of type 1 interferons. Consequently, we hypothesize that augmentation of innate immunity during early mild or moderately severe infection might avert progression to respiratory failure and mortality. Rintatolimod, a selective dsRNA ligand of TLR3, has strong antiviral activity against multiple viruses including the coronavirus SARS-CoV-1 in vitro and in animal models. The combination of recombinant IFN (Intron-A) and rintatolimod is currently being evaluated in clinical trials developed by our group at Roswell Park (NCT03403634, NCT03599453, NCT03899987) for patients with multiple solid tumors. In this proposal, we will re-purpose these agents to test whether the synergistic combination therapy will overcome the defective ability to induce type I IFN and stimulate TLR-mediated immune activation to provide protection from viral infection. Patients with cancer and mild or moderate COVID-19 within the Roswell Park catchment area will be enrolled over 6 months. Roswell Park has been selected by New York State as a regional testing area for COVID-19. The principal endpoint is safety of rintatolimod and Intron-A. Secondary endpoints are: (i) progression of infection requiring hospitalization; (ii) respiratory failure requiring mechanical ventilation; and (iii) death within 30 days Biospecimens collected from all patients will be used for translational assays, including kinetics of 1) viral clearance from nasal swabs and serum; 2) circulating inflammatory mediators; and 3) immunophenotype of lymphocyte subsets. Overall significance: We will repurpose the combination of two antiviral agents, which showed safety and promising results in patients with advanced cancer, to stop viral replication and mitigate the risk of progression to severe COVID19 in patients with cancer and SARS-CoV-2 infection. We expect to establish the safety of rIFNα and Rintatolimod in patients with cancer and COVID-19 and create the foundation for a larger multi-center randomized trial to test efficacy.
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disease rate><Multimodal Therapy><Multimodal Treatment><NCI Organization><NIH RFA><Nasal><Nasal Passages Nose><National Cancer Institute><Native Immunity><Natural Immunity><New York><Non-Specific Immunity><Nonspecific Immunity><Nose><Oncology><Oncology Cancer><Pathway interactions><Patients><Pattern recognition receptor><Phase><Play><Pneumonia><Population><Population Sciences><Preventative strategy><Prevention education><Prevention strategy><Preventive strategy><Pulmonary Diseases><Pulmonary Disorder><Randomization trial><Recombinants><Recording of previous events><Regimen><Request for Applications><Research><Research Personnel><Research Resources><Researchers><Resource Sharing><Resources><Respiratory Disease><Respiratory Failure><Respiratory System Disease><Respiratory System Disorder><Respiratory System, Nose, Nasal Passages><Risk><Role><SARS Virus><SARS corona virus><SARS coronavirus><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV-2><SARS-CoV2><SARS-Related Coronavirus><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Safety><Science><Scientist><Serum><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe acute respiratory syndrome coronavirus 2><Signal Transduction><Signal Transduction Systems><Signaling><Solid Neoplasm><Solid Tumor><Swab><TLR3><TLR3 gene><Testing><Therapeutic><Tissue Growth><Toll-Like Receptor 3><Training><Transcription Factor Proto-Oncogene><Transcription factor genes><Viral><Viral Diseases><Virus><Virus Diseases><Virus Replication><Wuhan coronavirus><adaptive immunity><ages><anti-cancer research><anti-cancer therapy><anti-tumor immune therapy><anti-tumor immunotherapy><anti-viral agents><anti-viral drugs><anti-virals><anticancer research><anticancer therapy><antitumor immune therapy><antitumor immunotherapy><biological signal transduction><cancer care><cancer education><cancer immunology><cancer prevention><cancer research><cancer therapy><chemotherapy><combination therapy><combined modality treatment><combined treatment><corona virus><corona virus disease 2019><coronavirus disease 2019><coronavirus emergence><developmental><disease of the lung><disorder of the lung><dsRNA><efficacy testing><emergent CoV><emergent coronavirus><emerging CoV><emerging coronavirus><enroll><experience><heart disorder><high risk><immune activation><immunosuppressed patient><inflammatory mediator><innate immune pathways><innovate><innovation><innovative><interventional strategy><investigator-initiated trial><lung disorder><malignancy><mechanical respiratory assist><member><model of animal><model organism><mortality><multi-modal therapy><multi-modal treatment><nCoV><neoplasm immunology><neoplasm immunotherapy><neoplasm/cancer><new CoV><new coronavirus><next generation><novel CoV><novel coronavirus><ontogeny><outreach><pathway><peer><personnel><population based><prevent><preventing><programs><pulmonary failure><randomized trial><recruit><recruit teachers><respiratory insufficiency/failure><secondary end point><secondary endpoint><severe acute respiratory syndrome-CoV><social role><survivorship><teacher recruitment><transcription factor><treatment trial><tumor immune therapy><tumor immunology><tumor immunotherapy><viral infection><viral multiplication><viral replication><virus infection><virus multiplication><virus-induced disease>