KSYOS TeleMedical Centre

Abstract Engagement of T cell or NK cells to harness a patient’s immune system is a promising approach in immuno-oncology. An immunocytokine, i.e. a tumor-targeting antibody (fragment) genetically fused to an immunostimulatory cytokine, is specifically designed for this purpose. Fusion antibody-IL-15 immunocytokines, based on a variety of molecular architectures, are currently finding their way to the clinic with promising results. Here we demonstrate how GlycoConnect™, a site-specific conjugation technology anchoring on the native antibody glycan, can be applied for attachment of IL-15 without prior antibody engineering. The molecular architecture of the resulting immune cell engagers (ICEs) can be readily tailored to 2:2 or 2:1 ratio (anti-TAA:IL-15) to mitigate cytokine release syndrome. Moreover, we show how immunostimulatory activity can be regulated via linker design, either by tailoring of IL-15-antibody spacing or by generation of a conditionally active IL-15 format. Structural and functional studies will be presented to corroborate the architecture of these GC™-ICEs and in vitro and in vivo activity in a syngeneic mouse model. Citation Format: Remon van Geel, Floris van Delft. GlycoConnect™ immune cell engagers (GC™-ICEs). A non-genetic approach to targeted IL-15 immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5606.

After several notable clinical failures in early generations, antibody-drug conjugates (ADC) have made significant gains with seven new FDA approvals within the last 3 years. These successes have been driven by a shift towards mechanistically informed ADC design, where the payload, linker, drug-to-antibody ratio, and conjugation are increasingly tailored to a specific target and clinical indication. However, fundamental aspects needed for design, such as payload distribution, remain incompletely understood. Payloads are often classified as "bystander" or "nonbystander" depending on their ability to diffuse out of targeted cells into adjacent cells that may be antigen-negative or more distant from tumor vessels, helping to overcome heterogeneous distribution. Seven of the 11 FDA-approved ADCs employ these bystander payloads, but the depth of penetration and cytotoxic effects as a function of physicochemical properties and mechanism of action have not been fully characterized. Here, we utilized tumor spheroids and pharmacodynamic marker staining to quantify tissue penetration of the three major classes of agents: microtubule inhibitors, DNA-damaging agents, and topoisomerase inhibitors. PAMPA data and coculture assays were performed to compare with the 3D tissue culture data. The results demonstrate a spectrum in bystander potential and tissue penetration depending on the physicochemical properties and potency of the payload. Generally, directly targeted cells show a greater response even with bystander payloads, consistent with the benefit of deeper ADC tissue penetration. These results are compared with computational simulations to help scale the data from in vitro and preclinical animal models to the clinic.

Introduction With wider adoption of store-and-forward telemedicine accelerating, particularly post-coronavirus disease 2019, it is essential to understand health care providers’ (HCPs) satisfaction with digital solutions offered by telemedicine organizations to (continuously) guarantee service quality. We developed the Store-and-Forward Telemedicine Service User-satisfaction Questionnaire to monitor and assess HCPs’ experiences with contracted telemedicine organizations. Methods Questionnaire construction (phase 1) consisted of exploratory literature search on validated telemedicine satisfaction questionnaires, a telemedicine domain and human factors expert focus group, stakeholder focus group (customer service employee and telemedicine account managers), and two pre-testing rounds among 18 HCPs. The pilot questionnaire (phase 2) was sent to 2179 HCPs for validity and reliability assessment. Results Phase 1: Two validated questionnaires (73 items overall) were used as input for Store-and-Forward Telemedicine Service User-satisfaction Questionnaire. Revisions resulted in 61 items. Phase 2: the pilot 61-item Store-and-Forward Telemedicine Service User-satisfaction Questionnaire instrument was completed by 181 of 2179 invited HCPs. Forty-one mandatory items of the pilot Store-and-Forward Telemedicine Service User-satisfaction Questionnaire rated on a 5-point Likert scale were included in psychometric analyses and resulted in six reliable scales: training, communication, organization policy and strategy, interaction platform, usage platform, and working conditions. Discussion The Store-and-Forward Telemedicine Service User-satisfaction Questionnaire is a reliable and valid questionnaire for measuring HCPs’ satisfaction with store-and-forward telemedicine services as part of a continuous quality improvement cycle. Reimbursement questions were excluded due to low response. As adoption of telemedicine may be impeded by financial compensation issues, this requires consideration in future telemedicine questionnaires. Store-and-Forward Telemedicine Service User-satisfaction Questionnaire including video consultation items is needed to monitor also synchronous services as these expanded in the coronavirus disease 2019 pandemic.

We developed an automatic system to identify and differentiate color fundus images containing no lesions, drusen or exudates. Drusen and exudates are lesions with a bright appearance, associated with age-related macular degeneration and diabetic retinopathy, respectively. The system consists of three lesion detectors operating at pixel-level, combining their outputs using spatial pooling and classification with a random forest classifier. System performance was compared with ratings of two independent human observers using human-expert annotations as reference. Kappa agreements of 0.89, 0.97 and 0.92 and accuracies of 0.93, 0.98 and 0.95 were obtained for the system and observers, respectively.

We carried out a pilot study on the feasibility and accuracy of store-and-forward teledermatology based on patient-provided images and history as a triage tool for outpatient consultation. Patients referred by their general practitioner provided a history and images via the Internet. The information was reviewed by one of 12 teledermatologists and the patient then visited a different dermatologist in person within two days. Three independent dermatologists compared the remote and in-person diagnoses in random order to determine diagnostic agreement. Broader agreement was also measured, by comparing the main disease groups into which the two diagnoses fell. The teledermatologists indicated whether an in-person consultation or further investigations were necessary. There were 105 eligible patients, aged four months to 72 years, who were willing to participate. For the 96 cases included in the analysis, complete diagnostic agreement was found in 41% (n=39), partial diagnostic agreement in 10% (n=10) and no agreement in 49% (n=47). There was disease group agreement in 66% of cases (n=63). Nearly a quarter (23%) of participating patients could have safely been managed without an in-person visit to a dermatologist.