Purpose: Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a firstin-class small activating RNA oligonucleotide drug which up-regulates C/EBP-α. Experimental Design:We conducted a phase I, open label, dose escalation trial of MTL-CEBPA in adults with advanced HCC with cirrhosis, or resulting from non-alcoholic steatohepatitis (NASH) or with liver metastases. Patients received intravenous MTL-CEBPA once a week for 3 weeks followed by a rest period of 1 week per treatment cycle in the dose escalation phase (3+3 design).Results: 38 participants have been treated across 6 dose levels (28-160 mg/m2) and 3 dosing schedules. 34 patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatmentrelated adverse events were not associated with dose and no maximum dose was reached across the 3 schedules evaluated. Grade 3 treatment related adverse events occurred in 9 (24%) patients. In 24 HCC patients evaluable for efficacy, an objective tumour response was achieved in 1 patient [4%; partial response (PR) for over 2 years] and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven patients were treated with tyrosine kinase inhibitors (TKI); 3 patients had a complete response with one further PR and two with SD.Conclusions: MTL-CEBPA is the first saRNA in clinical trials and demonstrates an acceptable safety profile and potential synergistic efficacy with TKIs in HCC. These encouraging Phase I data validate targeting of C/EBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC.Funding: This study was funded by MiNA Therapeutics. ClinicalTrials.gov ID: NCT02716012 Statement of translational relevancePreclinical data have emerged suggesting C/EBP-a effects on the tumour microenvironment through myeloid derived suppressor cells could enhance response to sorafenib. The data from this trial provide preliminary validation for targeting C/EBP-a in patients with advanced HCC, particularly in context of sequential administration with TKIs and provide a rationale for combining MTL-CEBPA with TKIs.

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Lymphatic filariasis is a chronic disease characterized by a pronounced Th2 bias in the immune response and impaired antigen (Ag)-specific Th1 responses. We have used a mouse model of filariasis to investigate the role of the infective form (the third-stage larvae [L3]) in modulating the immune response. Subcutaneous infection of BALB/c mice with L3 of Brugia pahangi has a profound effect on Th cell function. By day 12 postinfection, spleen cells from these mice exhibited a dramatic reduction in concanavalin A-driven proliferation and interleukin-2 (IL-2) and gamma interferon (IFN-␥) secretion in comparison with uninfected controls. However, exposure to L3 did not render the mice completely unresponsive; these animals mounted a strong Th2 response to the parasite, characterized by elevated levels of IL-4, IL-5, and IL-10 and parasite-specific serum immunoglobulin G (IgG), IgG1, and IgE. Treatment of spleen cells from L3-infected mice with neutralizing anti-IL-4 or recombinant IL-2 resulted in a dramatic increase in concanavalin A-induced proliferation and IL-2 and IFN-␥ production. Despite their defective polyclonal Th1 response, cells from L3 infected mice proliferated when stimulated with Ag, and this response was blocked by anti-IL-4. However, anti-IL-4 treatment failed to induce Ag-specific IL-2 or IFN-␥ production, indicating that B. pahangi-primed Th1 cells do not appear to be present or are still unable to respond even in the absence of IL-4.

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11015 Background: Burnout is a syndrome defined by emotional exhaustion, depersonalisation and loss of personal accomplishment. It is a growing concern amongst doctors, particularly in oncology, who face the added stress of delivering life changing results to patients and managing end of life care. This has potential for negatively impacting mental health, job satisfaction and ultimately patient care. This has been compounded by the COVID-19 pandemic and the uncertainty around complex oncological treatment decisions, longer working hours, redeployment, and constant changes to working patterns to meet the evolving clinical need. In response to this, a novel wellbeing intervention was designed by the educational lead consultant and psychologists to prevent burnout during the pandemic. Methods: Junior doctors working at a single UK cancer centre during the COVID-19 pandemic were invited to attend weekly 30 minute wellbeing sessions facilitated by a clinical psychologist throughout their oncology placement (average 4-6 months). Sessions had an average attendance of 3-6 doctors and began with a 5 minute breathing and relaxation exercise followed by a mixture of clinical debriefing, reflective practice, and mindfulness strategies. Trainees were invited to have individual sessions if required. Surveys based on the 14 point Warwick Edinburgh Well Being Scale (WEMWBS) were conducted at the start and end of placement. Additional qualitative feedback was collated. Results: Throughout a 6 month period, 10 doctors participated in this study. Baseline WEMWBS scores revealed average mental wellbeing (n = 8), high mental wellbeing (n = 1) and probable depression (n = 1). Median baseline WEMWBS score was 52(41-62). Median number of sessions attended was 11(3-14). Post intervention, there was no significant deterioration in baseline WEMWBS score (mean change +2.2; p= 0.34). When doctors were asked about their optimism for the future, there was a significant increase by +0.4 points ( p= 0.037). With respect to participant feedback, 100% were either ‘satisfied’ (n = 1) or ’very satisfied’ (n = 9) with the group facilitation and 100% found the group sessions either ‘helpful’ (n = 7) or ‘very helpful’ (n = 3). Trainee feedback described the benefits of reflecting in a structured and safe environment, breathing exercises, and learning mindfulness strategies. Conclusions: Burnout is a serious concern amongst junior oncologists and is rising as a result of COVID-19. We present a novel intervention that promoted psychological flexibility and importantly maintained mental wellbeing throughout the pandemic. Further studies are planned to develop evidence based interventions to tackle this important issue.