key: cord-0838973-uv978oxl authors: Silla, Lúcia title: Double‐bright (CD56bright/CD16bright) NK cell adoptive immunotherapy for SARS‐CoV‐2 date: 2020-07-09 journal: Br J Haematol DOI: 10.1111/bjh.17010 sha: 840f4759ed77b1dbc1deaafd2bec85211046e1a9 doc_id: 838973 cord_uid: uv978oxl SARS‐CoV‐2, affecting predominantly elderlies, was recognized as a global pandemic in March 11(th), 2020; clinical signs and laboratory alterations are similar to previous coronavirus epidemics with lymphocytopenia and neutrophilia observed in severe cases. described in humans in the present pandemic (1) and results in progressive hyper activation of inflammatory cells (macrophages and neutrophils) leading to SARS and cytokine storm in its final stages. Additionally, there are coagulopathies believed to be secondary to endothelial cells infection as virus elements within endothelial cells have been clearly shown (2) . In severe patients there are lower circulating B, T, and NK cells, endorsing the hypothesis that immune dysregulation plays a role in disease severity (1) . Pulmonary physiology is characterized and regulated by a unique mixture of alveolar epithelial cells -AEC (Type I and Type II) and resident immune cells. Type I AECs lined alveolar spaces, and through its thin cytoplasm, efficient gas exchange is accomplished; Type II AEC in addition to produce surfactant, regulates Type I regeneration and homeostasis. Inflammation interferes dangerously with gas exchange efficacy. Resident alveolar macrophages (rAM) appears to be central in maintaining pulmonary homeostasis through its anti-inflammatory phenotype, actively suppressing local cellular immune response (M2 phenotype) (3). New respiratory pathogens activate rAM that acquire an inflammatory phenotype (M1) activate resident dendritic cells (rDC). Pulmonary resident NK cells (rNK) with a peculiar quiescent phenotype, once activated, can also crosstalk with rDC which upon activation migrate to the lung draining lymph nodes to initiate T and B cell response (4, 5) . This article is protected by copyright. All rights reserved Aging has an adverse impact in pulmonary immunology, and its impact on NK cell function results in an increased susceptibility to tuberculosis re-activation, fungal and bacterial infections secondary to a decrease both in IFN-Gama production and expression of natural activating receptors such as NKp30 and NKp46; NK cell immune senescence contributes to the higher incidence of viral infections as well (6) . NK cells are innate large granular lymphocytes capable of lysing altered cells without previous exposition, its hallmark is the presence of KIRs able to either inhibit or activate NK cells activity. Self, normal cells are spared from NK cell lysis since KIR inhibitory receptors sense self- This article is protected by copyright. All rights reserved SARS-CoV-2 infected patients have a decrease number of circulating NK cells (1) , and in the predominant immune supressive lung microenvironment, senescent disfunctional NK cells probably are not properly activated (6) . In cancer, particularly in myeloid leukemias, the adoptive transfer of ex-vivo selected and activated NK cells is safe and display anti-leukemia activity (13) . We utilize an ex vivo expansion platform based on genetically modified feeder cells expressing membrane bound IL-21 (mbIL21) that gives rise to a highly activated, clinical grade Double-Bright (CD56 bright and CD16 bright ) NK cells. In a recent interim analysis of a Phase I/II clinical trial on DB-NK cells for R/R AML results were encouraging: 78.6% of overall response rate (ORR) (manuscript in preparation) without infusion related toxicity. In this study, we saw unexpected favorable activity in subgroups of patients with CNS leukemia and with severe infection; in two of the latter, unsuspected pulmonary tuberculosis and aspergillosis were diagnosed as a NK cell infusion emergent effect, with no hypoxia, and symptoms subsiding days after emergency (14) . In fact, none of Lessons learned from passive transfer of antibodies with convalescent plasma to treat infectious diseases, indicate better results when the transfer is done earlier in the course of the disease. Convalescent plasma appears effective for SAR-CoV-2 however, it is becoming clear that severe patients already in the overwhelming cytokine storm and coagulopathy phase, are less prone to have a benefit (15) . Since the idea is to stablish an adaptive immune response as early as possible, and to that end, attempt to overcome lung immune suppression by infusing highly activated DB-NK cells, it is our believe that NK cells should be infused early in the course of the disease since timing to develop a robust immune adaptive response is the key point of the proposed therapy. Dysregulation of immune response in patients with COVID-19 in Wuhan, China Endothelial cell infection and endotheliitis in COVID-19 Alveolar macrophage in the driver's seat Unique transcriptional and protein-expression signature in human lung tissue-resident NK cells Cross-talk between dendritic cells and natural killer cells in viral infection The impact of ageing on natural killer cell function and potential consequences for health in older adults Natural killer cells in HIV-1 infection and therapy Natural killer cell activation by respiratory syncytial virus-specific antibodies is decreased in infants with severe respiratory infections and correlates with Fc-glycosylation Natural killer p46High expression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis Immune memory: Inflammasomes drive NK cell memory Control of Acute Arboviral Infection by Natural Killer Cells Accepted Article This article is protected by copyright. All rights reserved 12 Severe herpesvirus infections in an adolescent without natural killer cells NK Cell-Based Immunotherapy for Hematological Malignancies Clinical and radiologic resolution of infections during treatment with mbIL-21-expanded FC21-NK cells in patients with relapsed or refractory acute myeloid leukemia (R/R AML) Convalescent plasma in Covid-19: Possible mechanisms of action Dean Antony Lee, MD, PhD shared his NK cell expansion platform enabling us to develop it. This article is protected by copyright. All rights reserved