A phase I trial of cyclosporine for hospitalized patients with COVID-19.

BACKGROUNDCOVID-19 remains a global health emergency with limited treatment options, lagging vaccine rates, and inadequate healthcare resources in the face of an ongoing calamity. The disease is characterized by immune dysregulation and cytokine storm. Cyclosporine A (CSA) is a calcineurin inhibitor that modulates cytokine production and may have direct antiviral properties against coronaviruses.METHODSTo test whether a short course of CSA was safe in patients with COVID-19, we treated 10 hospitalized, oxygen-requiring, noncritically ill patients with CSA (starting at a dose of 9 mg/kg/d). We evaluated patients for clinical response and adverse events, measured serum cytokines and chemokines associated with COVID-19 hyperinflammation, and conducted gene-expression analyses.RESULTSFive participants experienced adverse events, none of which were serious; transaminitis was most common. No participant required intensive care unit-level care, and all patients were discharged alive. CSA treatment was associated with significant reductions in serum cytokines and chemokines important in COVID-19 hyperinflammation, including CXCL10. Following CSA administration, we also observed a significant reduction in type I IFN gene expression signatures and other transcriptional profiles associated with exacerbated hyperinflammation in the peripheral blood cells of these patients.CONCLUSIONShort courses of CSA appear safe and feasible in patients with COVID-19 who require oxygen and may be a useful adjunct in resource-limited health care settings.TRIAL REGISTRATIONThis trial was registered on ClinicalTrials.gov (Investigational New Drug Application no. 149997; ClinicalTrials.gov NCT04412785).FUNDINGThis study was internally funded by the Center for Cellular Immunotherapies.

Autologous CD4 T Lymphocytes Modified with a Tat-Dependent, Virus-Specific Endoribonuclease Gene in HIV-Infected Individuals.

MazF is an Escherichia coli-derived endoribonuclease that selectively cleaves ACA sequences of mRNA prevalent in HIV. We administered a single infusion of autologous CD4 T lymphocytes modified to express a Tat-dependent MazF transgene to 10 HIV-infected individuals (six remaining on antiretroviral therapy [ART]; four undergoing treatment interruption post-infusion) in order to provide a population of HIV-resistant immune cells. In participants who remained on ART, increases in CD4 and CD8 T cell counts of ~200 cells/mm3 each occurred within 2 weeks of infusion and persisted for at least 6 months. Modified cells were detectable for several months in the blood and trafficked to gastrointestinal lymph tissue. HIV-1 Tat introduced ex vivo to the modified CD4+ T cells induced MazF expression in both pre- and post-infusion samples, and MazF expression was detected in vivo post-viral-rebound during ATI. One participant experienced mild cytokine release syndrome. In sum, this study of a single infusion of MazF-modified CD4 T lymphocytes demonstrated safety of these cells, distribution to lymph tissue and maintenance of Tat-inducible MazF endoribonuclease activity, as well as sustained elevation of blood CD4 and CD8 T cell counts. Future studies to assess effects on viremia and latent proviral reservoir are warranted.

Transfer of influenza vaccine-primed costimulated autologous T cells after stem cell transplantation for multiple myeloma leads to reconstitution of influenza immunity: results of a randomized clinical trial.

Severe immune deficiency follows autologous stem cell transplantation for multiple myeloma and is associated with significant infectious morbidity. This study was designed to evaluate the utility of a pretransplantation vaccine and infusion of a primed autologous T-cell product in stimulating specific immunity to influenza. Twenty-one patients with multiple myeloma were enrolled from 2007 to 2009. Patients were randomly assigned to receive an influenza-primed autologous T-cell product or a nonspecifically primed autologous T-cell product. The study endpoint was the development of hemagglutination inhibition titers to the strain-specific serotypes in the influenza vaccine. Enzyme-linked immunospot assays were performed to confirm the development of influenza-specific B-cell and T-cell immunity. Patients who received the influenza-primed autologous T-cell product were significantly more likely to seroconvert in response to the influenza vaccine (P = .001). Seroconversion was accompanied by a significant B-cell response. No differences were observed in the global quantitative recovery of T-cell and B-cell subsets or in global T-cell and B-cell function. The provision of a primed autologous T-cell product significantly improved subsequent influenza vaccine responses. This trial was registered at www.clinicaltrials.gov as #NCT00499577.