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 can...