We are learning that the host response to SARS-CoV-2 infection is complex and highly dynamic. Effective initial host defense in the lung is associated with mild symptoms and disease resolution. Viral evasion of the immune response can lead to refractory alveolar damage, ineffective lung repair mechanisms, and systemic inflammation with associated organ dysfunction. The immune response in these patients is highly variable and can include moderate to severe systemic inflammation and/or marked systemic immune suppression. There is unlikely to be a “one size fits all” approach to immunomodulation in patients with COVID-19.  We believe that a personalized, immunophenotype-driven approach to immunomodulation that may include anti-cytokine therapy in carefully selected patients and immunostimulatory therapies in others is the shortest path to success in the study and treatment of patients with critical illness due to COVID-19.

Sepsis, a heterogeneous clinical syndrome, features a systemic inflammatory response to tissue injury or infection, followed by a state of reduced immune responsiveness. Measurable alterations occur in both the innate and adaptive immune systems. Immunoparalysis, an immunosuppressed state, associates with worsened outcomes, including multiple organ dysfunction syndrome, secondary infections, and increased mortality. Multiple immune markers to identify sepsis immunoparalysis have been proposed, and some might offer clinical utility. Sepsis immunoparalysis is characterized by reduced lymphocyte numbers and downregulation of class II human leukocyte antigens (HLA) on innate immune monocytes. Class II HLA proteins present peptide antigens for recognition by and activation of antigen-specific T lymphocytes. One monocyte class II protein, mHLA-DR, can be measured by flow cytometry. Downregulated mHLA-DR indicates reduced monocyte responsiveness, as measured by ex-vivo cytokine production in response to endotoxin stimulation. Our literature survey reveals low mHLA-DR expression on peripheral blood monocytes correlates with increased risks for infection and death. For mHLA-DR, 15,000 antibodies/cell appears clinically acceptable as the lower limit of immunocompetence. Values less than 15,000 antibodies/cell are correlated with sepsis severity; and values at or less than 8000 antibodies/cell are identified as severe immunoparalysis. Several experimental immunotherapies have been evaluated for reversal of sepsis immunoparalysis. In particular, sargramostim, a recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF), has demonstrated clinical benefit by reducing hospitalization duration and lowering secondary infection risk. Lowered infection risk correlates with increased mHLA-DR expression on peripheral blood monocytes in these patients. Although mHLA-DR has shown promising utility for identifying sepsis immunoparalysis, absence of a standardized, analytically validated method has thus far prevented widespread adoption. A clinically useful approach for patient inclusion and identification of clinically correlated output parameters could address the persistent high unmet medical need for effective targeted therapies in sepsis.

The use of immune checkpoint inhibitors in patients with metastatic melanoma generates clinical benefit, including improved survival. Yet disease resistance and immune-related adverse events persist as unmet needs. Sargramostim, a yeast-derived recombinant human GM-CSF, has shown clinical activity against diverse solid tumors, including metastatic melanoma. Here we review the use of sargramostim for treatment of advanced melanoma. Potential sargramostim applications in melanoma draw on the unique ability of GM-CSF to link innate and adaptive immune responses. We review preclinical and translational data describing the mechanism of action of sargramostim and synergy with immune checkpoint inhibitors to enhance efficacy and reduce treatment-related toxicity.