Engeneic (Australia)

Contact lenses (CLs) utilizing opaque, nonrefractive features may purposefully modulate retinal ganglion cell activity away from the baseline activity. This is a nonrefractive mechanism that may reduce myopia progression. However, the visual performance of CLs with opaque features is unknown. This study aimed to compare the visual performance and binocular/accommodative function of CLs with opaque features (test) against MiSight (control-1) and single-vision (control-2) CLs. This was a prospective, randomized, unmasked, cross-over study where 35 myopic CL wearers (18 to 39 years) wore each design for at least 5 days. Visual performance was subjectively assessed using 1 to 10 numeric ratings comprising clarity of vision, lack of ghosting, vision when driving, overall vision satisfaction, and willingness to purchase (yes/no: based on vision and myopia efficacy). Visual acuity measurements comprised monocular and binocular high and low contrast visual acuity at 6 m, and binocular high contrast visual acuity at 70 and 40 cm. Binocular function was assessed using heterophorias at 3 m and 40 cm. Accommodative function was assessed using monocular accommodative facility (MAF) at 40 cm and dynamic monocular accommodative response (AR: 6 m, 70 cm, and 40 cm). Test was rated higher than control-1 (p<0.001) and control-2 was rated higher than test (p≤0.0052) for all subjective ratings. More participants were willing to purchase test compared with control-1 for vision and myopia efficacy (p<0.001), while there was no difference between test and control-2 for either question (p>0.7). Both controls were better than test for all acuity-based measurements (p≤0.0013). MAF at 40 cm was better with test compared with control-1 (p=0.010) and not different to control-2 (p>0.99). AR was higher with test than both controls at 70 cm (p<0.0001), higher than control-1 at 40 cm (p<0.0001), and not different to control-2 at 40 cm (p=0.12). There were no differences between CLs for AR at 6 m or heterophorias at 3 m or 40 cm (p>0.1). Compared with control-1, the test offered better visual performance, a higher proportion of participants willing to purchase, and better MAF. Compared with control-2, the test offered worse visual performance, but the proportion of participants willing to purchase was not different, and accommodative function was comparable.

Multimodal temporal therapy orchestrated to leverage immunotherapy, tumor-targeted chemotherapy, and natural killer (NK) cell therapy may provide an opportunity to induce immunogenic cell death for tumor response and increased survival in patients with recurrent cancer. The interleukin-15 (IL-15) superagonist N-803, an enhancer of NK cells, CD4 + T cells, cytotoxic CD8 + T cells, and memory T-cell activity, combined with off-the-shelf PD-L1-targeted high-affinity NK (PD-L1 t-haNK) cells represent novel immunotherapies designed to overcome an immunosuppressive tumor microenvironment (TME). The epidermal growth factor receptor-targeted antibody-nanocell conjugate E-EDV-D682 provides tumor-targeted chemotherapy in the form of its anthracycline metabolite PNU159682 (nemorubicin) cargo and is currently being studied in combination with immunomodulatory EDVs delivering the adjuvant α-galactosyl ceramide (GC). Here, we report the compassionate use treatment of this combination in a patient with recurrent, metastatic pancreatic cancer (mPC) after 3 lines of therapy. Under the initial single-patient Investigational New Drug (spIND) protocol, the patient received N-803, PD-L1 t-haNK cells, and the albumin doxorubicin conjugate aldoxorubicin for ~27 months. The patient's disease became stable on this regimen, and a transient complete response was observed by ~14 months of therapy. Due to progression, a second spIND protocol was designed whereby the patient received E-EDV-D682 plus EDV-GC for more than 24 months, which resulted in stable disease and the patient's continued survival at the time this report was written. The patient's extended survival despite the dire prognosis associated with recurrent mPC points to the merits of this temporal combination regimen in overcoming immuno-chemo resistance with enhanced immune activity required for tumor response and extended survival.

BackgroundRecurrent or refractory solid and central nervous system (CNS) tumours in paediatric patients have limited treatment options and carry a poor prognosis. The EnGeneIC Dream Vector (EDV) is a novel nanocell designed to deliver cytotoxic medication directly to the tumour. The epidermal growth factor receptor is expressed in several CNS and solid tumours and is the target for bispecific antibodies attached to the EDV.ObjectiveTo assess the safety and tolerability of EGFR-Erbitux receptor EnGeneIC Dream Vector with mitoxantrone (EEDVsMit) in children with recurrent / refractory solid or CNS tumours expressing EGFR.Patients and methodsPatients aged 2–21 years with relapsed or refractory CNS and solid tumours, or radiologically diagnosed diffuse intrinsic pontine glioma (DIPG), were treated in this phase I open-label study of single agent EEDVsMit. Thirty-seven patients’ tumours were screened for EGFR expression. EEDVsMit was administered twice weekly in the first cycle and weekly thereafter. Standard dose escalation with a rolling 6 design was employed. Dosing commenced at 5 × 108 EEDVsMit per dose and escalated to 5 × 109 EEDVsMit per dose.ResultsEGFR expression was detected in 12 (32%) of the paediatric tumours tested. Nine patients were enrolled and treated on the trial, including three patients with diffuse midline glioma. Overall, EEDVsMit was well tolerated, with no dose-limiting toxicities observed. The most common drug-related adverse events were grade 1–2 fever, nausea and vomiting, rash, lymphopaenia, and mildly deranged liver function tests. All patients had disease progression, including one patient who achieved a mixed response as the best response.ConclusionsEGFR-Erbitux receptor targeted EnGeneIC Dream Vector with mitoxantrone can be safely delivered in paediatric patients aged 2–21 years with solid or CNS tumours harbouring EGFR expression. The discovery of EGFR expression in a high proportion of paediatric gliomas means that EGFR may be useful as a target for other treatment strategies. Targeted therapeutic-loaded EDVs may be worth exploring further for their role in stimulating an anti-tumour immune response.ClinicalTrials.gov IdentifierNCT02687386.

Routing pipelines, cables and umbilicals in offshore locations represents a key activity with potential impacts for design, installation and operation. Deficient routing may result in (a) increased offshore construction durations (b) requirements for engineered mitigations from geophysical/geotechnical constraints and (c) unforeseen requirements for intervention during operations. Despite this, offshore route selection is restricted to repetitive, inefficient, and iterative processes between draughters, engineers and asset owners. Now, digital technologies enable optimised solutions for cables and pipelines. This paper presents the development and application of a complex routing algorithm using modern software code frameworks. The algorithm serves as an artificial intelligence platform by replicating engineering expertise. This identifies commonly encountered routing constraints such as geophysical features, seabed gradients, existing offshore facilities. Ideal geometric parameters are then determined to minimise route costs. The algorithm structure will be presented in pseudocode, which will define/describe the digital simulation of route selection within the algorithm. This includes sequences such as (a) processing of offshore geotechnical survey data, (b) recreating offshore locales and routes in a data environment, (c) implementation of geospatial intersection detection, (d) 3-dimensional route length optimisation and (e) automated route selection criteria. This replicates the sequence of manual processes undertaken by engineering experts into a digital realm, thus eliminating time-consumption, repetition and human error. Finally, the algorithm will be demonstrated in offshore case studies with challenging conditions such as highly disturbed seabeds and routing obstacles. Thus, engineers in the future developments can better answer the question ‘What is the best route?’.

4632 Background: Targeted EDV nanocells loaded with doxorubicin and microRNA16a have shown excellent safety profiles in Phase I trials in recurrent glioma and mesothelioma. This planned safety analysis of an ongoing first-in-human, open label Phase I/IIa study in patients with treatment-refractory metastatic pancreatic cancer, assesses safety, biologic and clinical activity of EGFR-targeted EDV nanocells carrying cytotoxic drug PNU-159682, designed to overcome drug resistance, combined with EDV nanocells carrying immunomodulatory adjuvant α-galactosyl ceramide, designed to stimulate anti-tumour immune response. Methods: 9 patients with advanced pancreatic cancer enrolled in the dose escalation phase to evaluate safety of the EDV combination. Doses gradually escalated from 2 x 109 EDVs/dose to a maximum of 7 x 109 EDVs/dose in Week 7, with subsequent dosing at the maximum dose achieved in Cycle 1. iRECIST criteria was used to assess tumour response after each cycle, and blood was collected each cycle for cytokine and PBMC analysis. Results: Combination EDVs were well tolerated with no DLTs, and no drug related SAEs. A minority of patients experienced G1 infusion reactions, which responded promptly to supportive treatment. PR or SD was achieved at 8 weeks in 8/9 patients (CBR 89%), with responses confirmed at 4 months in 4/5 evaluable patients (80%), with 2 durable responses seen beyond 6 months. Exploratory analyses have revealed elevation of IFN-α and IFN-γ in almost all evaluable patients (6/8). In addition, we observed elevated CD8+ T cells (2/8), iNKT, dendritic and NK cells (3/8), and a reduction in exhausted CD8+ T cells (3/8), suggesting activation of both innate and adaptive immune responses. Conclusions: EDVs carrying the cytotoxic drug and immune adjuvant are safe and well tolerated. Early signals point to durable responses, possibly related to the development of an innate and adaptive immune response along with cytotoxic effects on drug resistant tumour cells. The Phase IIa study plans to enrol an additional 35 patients to further evaluate safety and anti-tumour efficacy. Clinical trial information: ACTRN12619000385145 .

Ceri Probert explains, with two case examples, how eye care is being delivered efficiently under the Welsh government funded Eye Health Examinations Wales service.

miRNAs are responsible for post-transcriptional control of gene expression, and are frequently downregulated in cancer. It has become well established that restoring miRNA levels can inhibit tumor growth, and many studies have demonstrated this in preclinical models. This in turn has led to the first clinical trials of miRNA replacement therapy. This special report focuses on the development of TargomiRs - miRNA mimics delivered by targeted bacterial minicells - and the very first clinical experience of a miRNA replacement therapy in thoracic cancer patients in the Phase I MesomiR-1 trial.