The Last Aid course aims to teach public palliative care by increasing public awareness and empowering people about the role of the individual in the death of loved ones. The Covid-19 pandemic, however, has altered educational methods prohibiting classroom settings. Therefore, an online course was created to enable continued and safe public palliative care education. A mixed-methods study was performed to examine the feasibility of delivering the Last Aid course online. Data collection included participant questionnaires with qualitative and quantitative data, observations and a focus group discussion. Data were analyzed using descriptive analysis and qualitative description. In total, 15 online Last Aid courses were held, 174 participants took part in the study and 92 completed questionnaires were included. Findings revealed overall course satisfaction for the online courses in line with previous findings for classroom teaching. The online platform enabled course participation from people previously unable or unwilling to attend, namely caregivers to dying relatives and younger people. Instructors displayed an ability to teach online. However, some instructors expressed frustration over reduced interaction and technical challenges, which was echoed by participant ratings showing that many lacked social networking with fellow participants. Nonetheless, this pilot study demonstrates the feasibility of the online Last Aid course. Attention must be given to increasing both participant-to-participant and instructor-to-participant interaction. More research on the long-term effects of Last Aid courses is needed.
BackgroundIn pediatric sarcomas, outcomes of established therapies still remain poor, especially due to high-grade resistances to chemotherapeutic compounds. Taking novel biological approaches into account, virotherapy was found to be efficient in many pediatric sarcoma types. Also NK cell therapy was denoted to represent a promising upcoming strategy for pediatric sarcoma patients. We here investigated a combinatorial approach employing oncolytic measles vaccine virotherapeutics (MeV) together with activated human NK cells (or PBMCs).MethodsThe human sarcoma cell lines A673 and HT1080 were used to evaluate the efficacy of this combinatorial treatment modality. Oncolysis was determined by measuring real-time cell proliferation using the xCELLigence RTCA SP system. Furthermore, expression of receptors on NK cells and the respective ligands on A673 cells was analyzed by flow cytometry. To measure the protein release of activated NK cells a LEGENDplex™ assay was performed.ResultsMonotherapy with MeV led to a time- and dose-dependent oncolytic reduction of A673 and HT1080 sarcoma tumor cell masses. Concurrently, such MeV infections did not change the expression of NK cell ligands MICA/B, ULBP1, 2, and 3, CD112, and CD155. As shown by real-time proliferation assays, infections of A673 and HT1080 sarcoma cells with MeV followed by co-culture with activated NK cells or PBMCs led to enhanced sarcoma cell destruction when compared to the respective monotherapies. In parallel, this dual therapy resulted in an increased release of granzymes, perforin, and granulysin from NK cells. In contrast, expression of activation and ontogenesis receptors on NK cells was not found to be altered after co-culture with MeV-infected A673 sarcoma cells.ConclusionsTaken together, the combined treatment strategy comprising oncolytic MeV and activated NK cells resulted in enhanced oncolysis of A673 and HT1080 cells when compared to the respective monotherapies. In parallel, we observed an increased release of NK cell activation markers upon co-culture with MeV-infected A673 human sarcoma cells. These results support the onset of clinical trials combining oncolytic virotherapy with NK cell based immunotherapies.
ImportanceAutoimmune disorders can affect various organs and if refractory, can be life threatening. Recently, CD19-targeting–chimeric antigen receptor (CAR) T cells were efficacious as an immune suppressive agent in 6 patients with refractory systemic lupus erythematosus and in 1 patient with antisynthetase syndrome.ObjectiveTo test the safety and efficacy of CD19-targeting CAR T cells in a patient with severe antisynthetase syndrome, a complex autoimmune disorder with evidence for B- and T-cell involvement.Design, Setting, and ParticipantsThis case report describes a patient with antisynthetase syndrome with progressive myositis and interstitial lung disease refractory to available therapies (including rituximab and azathioprine), who was treated with CD19-targeting CAR T cells in June 2022 at University Hospital Tübingen in Tübingen, Germany, with the last follow-up in February 2023. Mycophenolate mofetil was added to the treatment to cotarget CD8+ T cells, hypothesized to contribute to disease activity.ExposurePrior to treatment with CD19-targeting CAR T cells, the patient received conditioning therapy with fludarabine (25 mg/m2 [5 days before until 3 days before]) and cyclophosphamide (1000 mg/m2 [3 days before]) followed by infusion of CAR T cells (1.23×106/kg [manufactured by transduction of autologous T cells with a CD19 lentiviral vector and amplification in the CliniMACS Prodigy system]) and mycophenolate mofetil (2 g/d) 35 days after CD19-targeting CAR T-cell infusion.Main Outcomes and MeasuresThe patient’s response to therapy was followed by magnetic resonance imaging of the thigh muscle, Physician Global Assessment, functional muscle and pulmonary tests, and peripheral blood quantification of anti-Jo-1 antibody levels, lymphocyte subsets, immunoglobulins, and serological muscle enzymes.ResultsRapid clinical improvement was observed after CD19-targeting CAR T-cell infusion. Eight months after treatment, the patient’s scores on the Physician Global Assessment and muscle and pulmonary function tests improved, and there were no detectable signs of myositis on magnetic resonance imaging. Serological muscle enzymes (alanine aminotransferase, aspartate aminotransferase, creatinine kinase, and lactate dehydrogenase), CD8+ T-cell subsets, and inflammatory cytokine secretion in the peripheral blood mononuclear cells (interferon gamma, interleukin 1 [IL-1], IL-6, and IL-13) were all normalized. Further, there was a reduction in anti-Jo-1 antibody levels and a partial recovery of IgA (to 67% of normal value), IgG (to 87%), and IgM (to 58%).Conclusions and RelevanceCD19-targeting CAR T cells directed against B cells and plasmablasts deeply reset B-cell immunity. Together with mycophenolate mofetil, CD19-targeting CAR T cells may break pathologic B-cell, as well as T-cell responses, inducing remission in refractory antisynthetase syndrome.
The exploitation of natural killer (NK) cell-mediated antileukemic responses in its various facets (emergence of alloreactive NK cells early posttransplantation, cotransfer of mature NK cells during graft manipulation, and adoptive transfer of mature NK cells) has recently come into the focus (reviewed by Handgretinger et al 1 ). Recent publications indicate that NK cells-although belonging per definition to the innate immune system-may acquire under certain conditions (such as high concentrations of cytokines or viral and presumably also tumor antigens) features of adaptive immune cells. 2 Depending on the initiating stimulus, we distinguish these memory NK cells as cytomegalovirus-induced, cytokine-induced, or tumor-induced memory NK cells. Theoretically, these memory NK cells should entail a higher clinical efficacy 1 as they are long-lived, vividly expand, Abstract Natural killer (NK) cells belong to innate lymphoid immune cells that contribute to antitumor responses without requiring prior sensitization. There is strong evidence that NK cells may induce graft-vs-leukemia (GvL) effect without causing graft-vs-host disease (GvHD), and significant efforts are currently undertaken to design and optimize NK cell-based immunotherapeutic strategies against human cancers, particularly against leukemias. However, the results of a number of adoptive NK cell transfer How to cite this article: Schmidt M, André MC. From bench to bedside: Exploiting memory NK cell responses to leukemia.Adv Cell Gene Ther. 2019;2:e28. https://doi.
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