ABSTRACT
BackgroundPatients with immunodeficiency-associated antibody disorders are at a higher risk of prolonged/persistent COVID-19 infection, having no viable treatment options. MethodsThis is a retrospective analysis of patients with primary and/or secondary immunodeficiency-associated antibody disorders who received casirivimab and imdevimab (REGEN-COV(R)) under emergency compassionate use. The objectives were to describe safety and response to REGEN-COV, with a focus on the subset of patients who had COVID-19 duration [≥]21 days prior to treatment. Quantitative (change in oxygenation status and/or viral load) and/or qualitative (physician-reported clinical status) patient outcomes data are reported. ResultsOutcome data are available from 64 patients who received REGEN-COV. Improvement in [≥]1 outcome measure was observed in 90.6% of the overall patient group. Thirty-seven of these patients had COVID-19 duration [≥]21 days prior to treatment, with a median time from RT-PCR diagnosis to REGEN-COV administration of 60.5 days. Of the 29 patients with COVID-19 duration [≥]21 days prior to treatment who had available outcome data, 96.6% showed improvement in [≥]1 outcome measure evaluated following use of REGEN-COV. In the 14 patients who had post-treatment RT-PCR results available, 11 (78.6%) reported a negative RT-PCR following treatment with REGEN-COV, with 5 patients (45.5%) reporting a negative RT-PCR within 5 days of treatment and 8 (72.7%) reporting a negative RT-PCR within 21 days of treatment. ConclusionsIn this retrospective analysis of immunodeficient patients who were granted REGEN-COV under the compassionate use program, REGEN-COV treatment was associated with rapid viral clearance and clinical improvement in the evaluable patients with long-standing COVID-19. SummaryPatients with immunodeficiency-associated antibody disorders are at a higher risk of prolonged/persistent COVID-19 infection. In this retrospective analysis, compassionate use of REGEN-COV in such patients was associated with rapid viral clearance and/or clinical improvement in the evaluable patients.
ABSTRACT
OBJECTIVE: The BCL2 family proteins are critical mediators of cellular apoptosis and, as such, have been implicated as determinants of cancer cell chemo-sensitivity. Recently, it has been demonstrated that the phosphorylation status of the BCL2 antagonist of cell death (BAD) protein may influence ovarian cancer (OVCA) cell sensitivity to cisplatin. Here, we sought to evaluate how kinase and phosphatase components of the BAD apoptosis pathway influence OVCA chemo-sensitivity. METHODS: Protein levels of cyclin-dependent kinase 1 (CDK1) and protein phosphatase 2C (PP2C) were measured by immunofluorescence in a series of 64 primary advanced-stage serous OVCA patient samples. In parallel, levels of cAMP-dependent protein kinase (PKA), AKT, and PP2C were quantified by Western blot analysis in paired mother/daughter platinum-sensitive/resistant OVCA cell lines (A2008/C13, A2780S/A2780CP, Chi/ChiR). BAD pathway kinase CDK1 was depleted using siRNA transfection, and the influence on BAD phosphorylation and cisplatin-induced apoptosis was evaluated. RESULTS: OVCA patient samples that demonstrated complete responses to primary platinum-based therapy demonstrated 4-fold higher CDK1 (p<0.0001) and 2-fold lower PP2C (p=0.14) protein levels than samples that demonstrated incomplete responses. Protein levels of PP2C were lower in the platinum-resistant versus that shown in the platinum-sensitive OVCA cell line sub-clones. Levels of PKA were higher in all platinum-resistant than in platinum-sensitive OVCA cell line sub-clones. Selective siRNA depletion of CDK1 increased sensitivity to cisplatin-induced apoptosis (p<0.002). CONCLUSION: BAD pathway kinases and phosphatases, including CDK1 and PP2C, are associated with OVCA sensitivity to platinum and may represent therapeutic opportunities to enhance cytotoxic efficacy.
