GEN-1 immunotherapy for the treatment of ovarian cancer

GEN-1 is a gene-based immunotherapy, comprising a human IL-12 gene expression plasmid and a synthetic plasmid delivery system, delivered intraperitoneally (ip.) to produce local and persistent levels of a pleiotropic immunocytokine, IL-12, at the tumor site in patients with advanced ovarian cancer. The goal of local and persistent IL-12 delivery is to remodel the highly immunosuppressive tumor microenvironment to favor immune stimulation while avoiding serious systemic toxicities, a major limitation of recombinant IL-12 therapy. Safe and sustained local production of IL-12 and related immunocytokines at the tumor site could produce potentially more favorable immunological changes in the tumor microenvironment and antitumor responses than a bolus systemic delivery of recombinant IL-12. Treatment safety, clinical benefits and biological activity of GEN-1 ip. in patients with ovarian cancer and in representative animal models are described

Historic clinical trial external control arm provides actionable GEN-1 efficacy estimate before a randomized trial

PURPOSE: To inform continued development of the novel immune agent GEN-1, we compared ovarian cancer patients\u27 end points from a neoadjuvant single-arm phase IB study with those of similar historic clinical trial (HCT) patients who received standard neoadjuvant chemotherapy. METHODS: Applying OVATION-1 trial (ClinicalTrials.gov identifier: NCT02480374) inclusion and exclusion criteria to Medidata HCT data, we identified historical trial patients for comparison. Integrating patient-level Medidata historic trial data (N = 41) from distinct neoadjuvant ovarian phase I-III trials with patient-level OVATION-1 data (N = 18), we selected Medidata patients with similar baseline characteristics as OVATION-1 patients using propensity score methods to create an external control arm (ECA). RESULTS: Fifteen OVATION-1 patients (15 of 18, 83%) were matched to 15 (37%, 15 of 41) Medidata historical trial control patients. Matching attenuated preexisting differences in attributes between the groups. The median progression-free survival time was not reached by the OVATION-1 group and was 15.8 months (interquartile range, 11.40 months to nonestimable) for the ECA. The hazard of progression was 0.53 (95% CI, 0.16 to 1.73), favoring GEN-1 patients. Compared with ECA patients, OVATION-1 patients had more nausea, fatigue, chills, and infusion-related reactions. CONCLUSION: Comparing results of a single-arm early-phase trial to those of a rigorously matched HCT ECA yielded insights regarding comparative efficacy prior to a randomized controlled trial. The effect size estimate itself informed both the decision to continue development and the randomized phase II trial (ClinicalTrials.gov identifier: NCT03393884) sample size. The work illustrates the potential of HCT data to inform drug development

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Synergistic Effect of Formulated Plasmid and Needle-Free Injection for Genetic Vaccines

Purpose. A plasmid-based gene expression system was complexed with protective, interactive, and non-condensing (PINC™) polymer system and administered with Medi-Jector™, a needle-free injection device (NFID), to achieve high and sustained levels of antigen-specific antibodies in blood circulation. Methods. Human growth hormone (hGH) or bacterial β-galactosidase gene expression plasmids driven by a cytomegalovirus (CMV) promoter were formulated in saline or complexed with a PINC polymer, polyvinylpyrrolidone (PVP), and intramuscularly or subcutaneously administered into dogs and pigs using a 22-gauge needle or a NFID. The hGH-specific IgG titers in serum were measured by an ELISA. β-galactosidase expression was measured in injected muscles by an enzymatic assay or immunohistochemistry. The effect of NFID on DNA stability and topology was assessed by gel electrophoresis. Results. Intramuscular (i.m.) or subcutaneous (s.c.) injection of a hGH expression plasmid pCMV-hGH (0.05-0.5 mg/kg) in dogs and pigs elicited antigen-specific IgG antibody titers to expressed hGH. With both routes of injection, pDNA delivery by a NFID was superior to pDNA injection by needle. The magnitude of hGH-specific IgG titers with NFID was 15−20-fold higher than needle injection when pDNA was complexed with PVP, and only 3−4-fold higher with pDNA in saline. The transfection efficiency in the injected muscle, as measured by β-galaclosidase expression, following i.m. injection of pCMV-β-galaclosidase/PVP, was not significantly different between needle and NFID-injected groups. Conclusions. These data demonstrate that the combination of pDNA/ PVP complexes and a NFID act synergistically to achieve high and sustained levels of antigen-specific IgG response to expressed antigen. This gene delivery approach may offer advantage over needle injection of naked DNA for the development of genetic vaccines

Perception, attitude, and preference of trainees towards workplace-based assessment in dental education at a tertiary care institute in Multan, Pakistan

Background: Modern medical education has flourished with an emergent interest in a variety of assessment approaches that entails direct observation of performance and provision of feedback. Workplace-based assessment (WPBA) has been embraced into specialty training in the United Kingdom (UK) within National Health Service (NHS). In Pakistan, this educational framework is incorporated to gauge the clinical proficiency of trainees at the postgraduate and undergraduate levels. The present study was done to identify how WPBA is perceived by dental field postgraduate trainees in Pakistan. Objective: The study explored and ascertained trainees\u27 perceptions, attitudes, and preferences considering their experiences with the systematic organization and execution of WPBA in dental educational settings. Method: This cross-sectional study design involved the clinical trainees of various cadres in a tertiary care hospital in Multan. A structured and validated questionnaire previously used for another analysis was administered among 90 trainees at the institute. The results were analyzed and tabulated using SPSS-21. Influential statistics (Pearson\u27s Chi-Square Test) was performed and the confidence interval was set at 95% (P≤0.05). Results: The response rate was 88%. Opinions were more positive compared to the former surveys. The majority of the respondents (65.8%) have shown a positive attitude towards WPBA and preferred it to be a valuable assessment system as it fosters reflective practices in educational settings. In addition, it was shown that WPBA has the potential to improve clinical training (72.2%) and aid in the effective implementation of clinical practice (68.4%). As the system of digital education has been introduced ever since the pandemic, the highest percentage of participants (56%) preferred a combination of on-paper and online assessment systems. Conclusion: The study reported that WPBA proposes the opportunity to associate teaching, learning, and assessment. The faculty training program is a significant input to upholding the quality of WPBA. Empirical research on WPBA is essential to be carried out to overcome the inadequacies thus endorsing its application universall