Rintatolimod and IFN Alpha-2b for the Treatment of COVID-19 in Cancer Patients

Inclusion Criteria: * INCLUSION CRITERIA (MAIN COHORT): * Patients with cancer, with the exception of patients with active acute leukemia and allogeneic hematopoietic stem cell transplant recipients. Patients may be on active therapy or received therapy (e.g., chemotherapy, radiation or surgery) within 7 years. Patients with active cancer who have not yet been treated (e.g. newly diagnosed cancer or early stage myelodysplastic syndrome \[MDS\] or chronic lymphocytic leukemia \[CLL\]) are eligible. Basal cell cancer and carcinoma in situ treated with local excision alone do not qualify for inclusion * Presence of symptomatic infection, defined by fever (temperature \[T\] \>= 38 degrees Celsius \[C\]) OR respiratory symptoms (cough, nasal congestion, or shortness of breath) OR lung infilitrates on chest X-ray or CT imaging. Diagnosis of COVID-19 is based on polymerase chain reaction (PCR) testing of respiratory samples. * Age equal to \>= 18 years or older (children are excluded because COVID-19 typically has a milder course in children, and lack of safety data of this regimen in children) * Platelet \>= 75,000/uL * Hemoglobin \>= 9 g/dL * Hematocrit \>= 27% * Absolute neutrophil count (ANC) \>= 1000/uL * Creatinine clearance \>= 50 mL/min (Cockcroft-Gault Equation-note: plasma creatine instead of serum is used at Roswell Park) * Total bilirubin =\< 2 X institutional upper limit of normal (ULN) * Aspartate transaminase (AST) (plasma) and alanine transferase (ALT) (plasma) =\< 2 X institutional ULN * Plasma amylase and lipase =\< 2 X institutional ULN * In the absence of COVID-19, a life expectancy of 6 months is expected * Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure * NOTE: For blood chemistry labs, Roswell Park clinical blood chemistries are performed on plasma unless otherwise indicated * EXPANSION COHORT: Patients with cancer or allogeneic stem cell transplant recipients with and without a cancer diagnosis * Patients with cancer may be on active therapy or received therapy (e.g., chemotherapy, radiation or surgery) within 7 years * Patients with active cancer who have not yet been treated (e.g. newly diagnosed cancer or early stage MDS or CLL) are eligible * Basal cell cancer and carcinoma in situ treated with local excision alone do not qualify for inclusion * Presence of symptomatic infection, defined by fever (T \>= 38.0 degrees C ) OR respiratory symptoms (cough, nasal congestion, or shortness of breath) OR lung infiltrates by chest X-ray or CT imaging. Diagnosis of COVID-19 is based on PCR testing of respiratory samples. Severe infection is excluded * Age equal to \>= 18 years or older (children are excluded because COVID-19 typically has a milder course in children, and lack of safety data of this regimen in children). In the absence of COVID-19, a life expectancy of 6 months is expected * Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure. There may be specific instances when the patient can't provide informed consent, e.g. they require mechanical ventilation and are sedated, in which case a health care proxy will be able to provide informed consent. Patients with temporary cognitive impairment will be consented once their capacity has returned. Patients with chronic cognitive impairment, e.g. dementia, that precludes informed consent will not be enrolled. Exclusion Criteria: * EXCLUSION CRITERIA (MAIN COHORT): * Patients with severe COVID-19 infection defined by pulmonary infiltrates on chest x-ray or computed tomography (CT) imaging plus one of the following: room air oxygen saturation (SaO2) =\< 92%, room air partial pressure of oxygen (PaO2) \< 70 mm Hg, or partial pressure of oxygen in arterial blood (PaO2)-PaO2 (alveolar gas) \>= 35 mm Hg * Contraindication to recombinant (r)-INFalpha based on prior hypersensitivity, autoimmune hepatitis, decompensated liver disease * Patients who have active acute myeloid leukemia or acute lymphoid leukemia or are allogeneic hematopoietic stem transplant recipients. Acute leukemia in remission and chronic leukemias are not exclusion criteria * Cardiac events: * Acute coronary syndrome, myocardial infarction, or ischemia within past 3 months * New York Heart Association classification of III or IV congestive heart failure * Unwilling or unable to follow protocol requirements * Patients with known serious mood disorders * Any additional condition, such as pre-existing inflammatory lung disease, which in the investigator's opinion deems the participant an unsuitable candidate to receive the study drugs * Concurrent infections, e.g. bacterial pneumonia or sepsis, that would make it difficult to evaluate clinical response to therapy or study drug toxicities * Therapies known to cause cytokine release syndrome (CRS), e.g. engineered T cells, within 30 days * Patients at high risk for tumor lysis syndrome * Concurrent active pneumonitis predating COVID-19, such as from checkpoint inhibitor therapy, chemotherapy-associated toxicity, or radiation pneumonitis * Autoimmune disease that requires systemic immunosuppression * Protocol-defined baseline abnormalities in cell counts, renal, or hepatic function * Any additional condition which in the investigator's opinion deems the participant an unsuitable candidate to receive the study drugs * EXCLUSION CRITERIA: EXPANSION COHORT: * Patients with respiratory failure requiring mechanical ventilation with FIO2 of \> 60%. * Allogeneic hematopoietic stem cell transplant recipients with active pulmonary graft versus host disease (GvHD) (any grade) * Cardiac events: * Acute coronary syndrome, myocardial infarction, or ischemia within past 3 months, * New York Heart Association classification of III or IV congestive heart failure * Unwilling or unable to follow protocol requirements * Any additional condition which in the investigator's opinion deems the participant an unsuitable candidate to receive the study drugs * Cognitively impaired adults/adults with impaired decision-making capacity * Individuals who are not yet adults (infants, children, teenagers) * Pregnant women * Prisoners