ABSTRACT
How immune dysregulation affects recovery from COVID-19 infection in patients with cancer remains unclear. We analyzed cellular and humoral immune responses in 103 patients with prior COVID-19 infection, more than 20% of whom had delayed viral clearance. Delayed clearance was associated with loss of antibodies to nucleocapsid and spike proteins with a compensatory increase in functional T cell responses. High-dimensional analysis of peripheral blood samples demonstrated increased CD8+ effector T cell differentiation and a broad but poorly converged COVID-specific T cell receptor (TCR) repertoire in patients with prolonged disease. Conversely, patients with a CD4+ dominant immunophenotype had a lower incidence of prolonged disease and exhibited a deep and highly select COVID-associated TCR repertoire, consistent with effective viral clearance and development of T cell memory. These results highlight the importance of B cells and CD4+ T cells in promoting durable SARS-CoV-2 clearance and the significance of coordinated cellular and humoral immunity for long-term disease control.
Subject(s)
COVID-19 , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Humans , Immunity, Cellular , Immunity, Humoral , Immunologic Memory , Receptors, Antigen, T-Cell , SARS-CoV-2ABSTRACT
PURPOSE: Immune checkpoint inhibition (ICI) alone is not active in mismatch repair-proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy alone result in objective systemic benefit. However, combined radiotherapy plus ICI can induce systemic antitumor immunity in preclinical and clinical models. PATIENTS AND METHODS: In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1,500 mg plus tremelimumab 75 mg every 4 weeks plus radiotherapy. The primary endpoint was objective response rate (ORR) in nonirradiated lesions. Treatment and efficacy were correlated with peripheral immune cell profiles. RESULTS: We enrolled 24 patients, and report outcomes after a median follow-up of 21.8 (range: 15.9-26.3) months. The ORR was 8.3% (2 patients) [95% confidence interval (CI), 1.0-27.0]. The median progression-free survival was 1.8 (95% CI, 1.7-1.9) months, median overall survival was 11.4 (95% CI, 10.1-17.4) months. Twenty five percent of patients (n = 6) had treatment-related grade 3-4 adverse events. We observed increased circulating CD8+ T lymphocyte activation, differentiation, and proliferation in patients with objective response. CONCLUSIONS: This combination of radiotherapy plus ICI study did not meet the prespecified endpoint criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in nonirradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus radiotherapy is feasible in MMR-P mCRC with a manageable safety profile. Further studies of novel immunotherapy combinations, and identification of biomarkers predictive of abscopal response are warranted.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Chemoradiotherapy/methods , Colorectal Neoplasms/therapy , Immune Checkpoint Inhibitors/administration & dosage , Adult , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , CD8-Positive T-Lymphocytes/immunology , Chemoradiotherapy/adverse effects , Colorectal Neoplasms/immunology , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , DNA Mismatch Repair/immunology , Feasibility Studies , Female , Follow-Up Studies , Humans , Immune Checkpoint Inhibitors/adverse effects , Male , Middle Aged , Progression-Free Survival , Response Evaluation Criteria in Solid TumorsABSTRACT
A chemical free, nanotechnology-based, antimicrobial platform using Engineered Water Nanostructures (EWNS) was recently developed. EWNS have high surface charge, are loaded with reactive oxygen species (ROS), and can interact-with, and inactivate an array of microorganisms, including foodborne pathogens. Here, it was demonstrated that their properties during synthesis can be fine tuned and optimized to further enhance their antimicrobial potential. A lab based EWNS platform was developed to enable fine-tuning of EWNS properties by modifying synthesis parameters. Characterization of EWNS properties (charge, size and ROS content) was performed using state-of-the art analytical methods. Further their microbial inactivation potential was evaluated with food related microorganisms such as Escherichia coli, Salmonella enterica, Listeria innocua, Mycobacterium parafortuitum, and Saccharomyces cerevisiae inoculated onto the surface of organic grape tomatoes. The results presented here indicate that EWNS properties can be fine-tuned during synthesis resulting in a multifold increase of the inactivation efficacy. More specifically, the surface charge quadrupled and the ROS content increased. Microbial removal rates were microorganism dependent and ranged between 1.0 to 3.8 logs after 45 mins of exposure to an EWNS aerosol dose of 40,000 #/cm(3).
Subject(s)
Anti-Infective Agents/pharmacology , Nanotechnology , Reactive Oxygen Species/metabolism , Solanum lycopersicum/microbiology , Anti-Infective Agents/chemistry , Food Microbiology , Listeria/drug effects , Listeria/pathogenicity , Solanum lycopersicum/growth & development , Microbial Viability , Mycobacterium/drug effects , Mycobacterium/pathogenicity , Nanostructures/chemistry , Saccharomyces cerevisiae , Salmonella enterica/drug effects , Salmonella enterica/pathogenicity , Surface PropertiesABSTRACT
Urinary tract infection (UTI) is a predominant condition in prostate cancer patients. Escherichia coli ORN178 (EC-178) is the uropathogen that causes recurrent infection by binding specifically to adhesins of prostate cancer cells (DU-145 cells). Gold nanoparticles (GNPs) have been used in biodiagnosis of pathogens. In this study, we have investigated the binding time of EC-178 to DU-145 cells, the cytotoxicity and uptake of plain and mannose functionalized and 20 and 200 nm GNPs (d-mannan (Mn)-GNPs). We also investigated the protein corona of GNPs when incubated with fetal bovine serum to study the protein corona which decides the biological fate of the GNPs. It was seen that EC-178 binds and is inside the DU-145 cells by 3 h of incubation period. Plain 20 nm GNPs decrease the percentage of viable cells in 48 and 72 h in log and lag phase of DU-145 cells. It was also observed that the Mn-GNPs were taken up by the DU-145 cells significantly more than the plain GNPs. Protein corona was observed when GNPs were incubated with fetal bovine serum which was confirmed by dynamic light scattering measurements and SDS-PAGE gel.
ABSTRACT
Separating live and dead cells is critical to the diagnosis of early stage diseases and to the efficacy test of drug screening, etc. This work demonstrates a novel microfluidic approach to dielectrophoretic separation of yeast cells by viability. It exploits the cell dielectrophoresis that is induced by the inherent electric field gradient at the reservoir-microchannel junction to selectively trap dead yeast cells and continuously separate them from live ones right inside the reservoir. This approach is therefore termed reservoir-based dielectrophoresis (rDEP). It has unique advantages as compared to existing dielectrophoretic approaches such as the occupation of zero channel space and the elimination of any mechanical or electrical parts inside microchannels. Such an rDEP cell sorter can be readily integrated with other components into lab-on-a-chip devices for applications to biomedical diagnostics and therapeutics.