ABSTRACT
Despite good results in the treatment of hematological malignancies, Natural killer (NK) cells have shown limited effectiveness in solid tumors, such as ovarian cancer (OvCa). Here, we assessed the potential of an oncolytic adenovirus expressing a variant interleukin-2 (vIL-2) cytokine, Ad5/3-E2F-d24-vIL2 (vIL-2 virus), also known as TILT-452, to enhance NK cell therapy efficacy in human OvCa ex vivo. Human OvCa surgical specimens were processed into single-cell suspensions and NK cells were expanded from healthy blood donors. OvCa sample digests were co-cultured ex vivo with NK cells and vIL-2 virus and cancer cell killing potential assessed in real time through cell impedance measurement. Proposed therapeutic combination was evaluated in vivo with an OvCa patient-derived xenograft (PDX) in mice. Addition of vIL-2 virus significantly enhanced NK cell therapy killing potential in treated OvCa co-cultures. Similarly, vIL-2 virus in combination with NK cell therapy promoted the best in vivo OvCa tumor control. Mechanistically, vIL-2 virus induced higher percentages of granzyme B in NK cells, and CD8+ T cells, while T regulatory cell proportions remained comparable to NK cell monotherapy in vivo. Ad5/3-E2F-d24-vIL2 virus treatment represents a promising strategy to boost adoptive NK cell therapeutic effect in human OvCa.
Subject(s)
Hematopoietic Stem Cell Transplantation , Ovarian Neoplasms , Humans , Animals , Mice , Female , Cytokines , Adenoviridae/genetics , Cell Line, Tumor , Ovarian Neoplasms/genetics , Ovarian Neoplasms/therapy , Cell- and Tissue-Based TherapyABSTRACT
While the presence of tumor-infiltrating lymphocytes (TILs) associates with improved survival prognosis in ovarian cancer (OvCa) patients, TIL therapy benefit is limited. Here, we evaluated an oncolytic adenovirus coding for a human variant IL-2 (vIL-2) cytokine, Ad5/3-E2F-d24-vIL2 (vIL-2 virus), also known as TILT-452, as an immunotherapeutic strategy to enhance TIL responsiveness towards advanced stage OvCa tumors. Fragments of resected human OvCa tumors were processed into single-cell suspensions, and autologous TILs were expanded from said samples. OvCa tumor specimens were co-cultured with TILs plus vIL-2 virus, and cell killing was assessed in real time through cell impedance measurement. Combination therapy was further evaluated in vivo through a patient-derived xenograft (PDX) ovarian cancer murine model. The combination of vIL-2 virus plus TILs had best cancer cell killing ex vivo compared to TILs monotherapy. These results were supported by an in vivo experiment, where the best OvCa tumor control was obtained when vIL-2 virus was added to TIL therapy. Furthermore, the proposed therapy induced a highly cytotoxic phenotype demonstrated by increased granzyme B intensity in NK cells, CD4+ T, and CD8+ T cells in treated tumors. Our results demonstrate that Ad5/3-E2F-d24-vIL2 therapy consistently improved TILs therapy cytotoxicity in treated human OvCa tumors.
Subject(s)
Adenoviridae Infections , Antineoplastic Agents , Ovarian Neoplasms , Humans , Animals , Female , Mice , Lymphocytes, Tumor-Infiltrating , Cytokines , Interleukin-2/genetics , Interleukin-2/pharmacology , Adenoviridae/genetics , Carcinoma, Ovarian Epithelial/genetics , Carcinoma, Ovarian Epithelial/therapy , Ovarian Neoplasms/genetics , Ovarian Neoplasms/therapySubject(s)
Athletic Injuries , Coronavirus Infections , Pandemics , Pneumonia, Viral , Sports , Athletes , Betacoronavirus , COVID-19 , Humans , SARS-CoV-2ABSTRACT
Methane is an essential component of the global carbon cycle and one of the most powerful greenhouse gases, yet it is also a promising alternative source of carbon for the biological production of value-added chemicals. Aerobic methane-consuming bacteria (methanotrophs) represent a potential biological platform for methane-based biocatalysis. Here we use a multi-pronged systems-level approach to reassess the metabolic functions for methane utilization in a promising bacterial biocatalyst. We demonstrate that methane assimilation is coupled with a highly efficient pyrophosphate-mediated glycolytic pathway, which under oxygen limitation participates in a novel form of fermentation-based methanotrophy. This surprising discovery suggests a novel mode of methane utilization in oxygen-limited environments, and opens new opportunities for a modular approach towards producing a variety of excreted chemical products using methane as a feedstock.
Subject(s)
Methane/metabolism , Methylococcaceae/physiology , Catalysis , Formaldehyde/metabolism , Gene Expression Regulation, Bacterial/physiology , Genome, Bacterial , Oxidation-Reduction , TranscriptomeABSTRACT
A family is described in which four members of a sibship of seven suffered from a hematologic and systemic disorder whcih has been fatal in three and has been proved at autopsy to have been fatal in three and has been proved at autopsy to have been thrombotic purpura. The fourth member has probably suffered the same disorder. The clinical laboratory and genetic features of the family are discussed at length. No cause of the disorder has been determined.
Subject(s)
Anemia, Hemolytic/genetics , Purpura, Thrombotic Thrombocytopenic/genetics , Adrenal Glands/pathology , Anemia, Hemolytic/blood , Child , Child, Preschool , Erythrocytes, Abnormal/pathology , Female , Humans , Infant , Intracranial Embolism and Thrombosis/genetics , Male , Myocardium/pathology , Pedigree , Purpura, Thrombotic Thrombocytopenic/blood , Purpura, Thrombotic Thrombocytopenic/pathology , SyndromeABSTRACT
The results of a two-year prospective study of myocardial infarction in a rural city is reported. In the under 70 years age group there was a 10 per cent mortality of patients whilst being nursed in the coronary care area. Later deaths after transfer to the general wards raised the overall hospital mortality rate to 15 per cent. These figures compare favourably with other series.
