Open Access

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its ‘Minimal Information for Studies of Extracellular Vesicles’, which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly.

Background This phase 3 trial assessed daromun, a combination of two fibronectin-targeting immunocytokines (L19IL2 and L19TNF), as a neoadjuvant treatment for patients with clinically detectable stage IIIB/C melanoma (AJCC version 7). Methods Patients were randomized to 4 weekly intralesional daromun administrations (13 Mio IU of L19IL2 and 400 μg of L19TNF) followed by surgery, or upfront surgery. Pretreatment with approved adjuvant agents was allowed. The primary endpoint was recurrence-free survival (RFS): events were disease recurrence or death from any cause after complete surgical tumor resection. Key findings 246 patients were randomized and included in the intention-to-treat analysis: 74% had undergone ≥ 2 prior surgical resections and 35% had received prior systemic therapy. At a median follow-up of 21 months, the neoadjuvant group (N=122) had a significantly longer RFS than the upfront surgery group (N=124), with a median RFS of 16.7 and 6.8 months, respectively (HR 0.59; 95% CI 0.41 to 0.86, p=0.005, log-rank test). The risk of distant recurrence was reduced by 40% in the neoadjuvant arm (HR=0.60; 95% CI [0.37; 0.95]; p=0.029). Grade ≥ 3 treatment-related adverse events (TRAEs) were 6.7% in the surgery alone arm and 27.1% in the daromun arm, mostly injection site reactions. Conclusions Neoadjuvant daromun resulted in a significantly longer RFS than upfront surgery in patients with locally advanced melanoma. TRAEs were transient and manageable. Neoadjuvant daromun is a new therapeutic option for patients with stage III melanoma, including those with locoregional recurrence after surgery and previous adjuvant therapy.