Coronavirus disease 2019: investigational therapies in the prevention and treatment of hyperinflammation

Human coronaviruses (hCoVs) can be divided into low pathogenic and highly pathogenic coronaviruses. The low pathogenic CoVs infect the upper respiratory tract and cause mild, cold-like respiratory illness. In contrast, highly pathogenic hCoVs such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) predominantly infect lower airways and cause fatal pneumonia. Severe pneumonia caused by pathogenic hCoVs is often associated with rapid virus replication, massive inflammatory cell infiltration and elevated pro-inflammatory cytokine/chemokine responses resulting in acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Recent studies in experimentally infected animal strongly suggest a crucial role for virus-induced immunopathological events in causing fatal pneumonia after hCoV infections. Here we review the current understanding of how a dysregulated immune response may cause lung immunopathology leading to deleterious clinical manifestations after pathogenic hCoV infections.

Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment ofpatients up to age 25years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation, ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.

Chimeric antigen receptor (CAR)-T-cell therapies are showing great promise in the treatment of cancer, particularly B-cell malignancies, but are associated with characteristic, potentially fatal toxicities, principally cytokine-release syndrome, CAR-T-cell-related encephalopathy syndrome, and haemophagocytic lymphohistiocytosis/macrophage-activation syndrome. Herein, the CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group, comprising multidisciplinary investigators from various institutions with clinical experience in the use of a range of CAR-T-cell platforms, review these acute toxicities and provide monitoring, grading, and management recommendations.