A djuvant immune checkpoint inhibition (CPI) and BRAF/ MEK-targeted therapies after therapeutic lymph node dissection (TLND) have improved relapse-free survival (RFS) in patients with clinical stage III nodal melanoma. Despite these improvements, approximately 40-50% of patients have a relapse within 3-5 years after TLND 1-3 . Preclinical and early clinical trial data suggest that neoadjuvant CPI leads to superior anti-tumor immunity and survival benefit compared to adjuvant CPI 4,5 . Similarly to stage IV melanoma, the combination of anti-CLTA-4 and anti-PD-1 appears to be superior to anti-PD-1 monotherapy in the neoadjuvant setting 6,7 . Previous clinical trials (OpACIN (NCT02437279) and OpACIN-neo (NCT02977052)) testing neoadjuvant ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1) in stage III melanoma demonstrated high pathologic response rates (pRRs; 74-78%) and a strong association between pathologic response and RFS, with 94-100% of responding patients remaining free of relapse at 2 years 5,7-9 . Similarly, long-term benefit was observed upon complete response to CPI in stage IV melanoma, even after cessation of CPI [10][11][12] .The association between response and survival; the observed ongoing responses after cessation of therapy in stage IV melanoma; and the substantial morbidity from TLND [13][14][15][16] that impairs

TPS9605 Background: Adjuvant treatment with anti-PD1 therapy improves the recurrence free survival (RFS) in resectable stage III melanoma. The Checkmate-238 and KEYNOTE-054 trials respectively reported a 4-year RFS of 52.5% for adjuvant nivolumab and a 3-year RFS of 63.7% for adjuvant pembrolizumab. Despite these improved outcomes, a considerable proportion of patients have a relapse in the years after therapeutic lymph node dissection (TLND). The OpACIN trial showed that neoadjuvant treatment with nivolumab (NIVO) plus ipilimumab (IPI) is feasible and induces a stronger and broader T-cell response. The subsequent OpACIN-neo trial identified 2 cycles of NIVO 3mg/kg + IPI 1mg/kg as a neoadjuvant dosing scheme with decreased toxicity and preserved high pathologic response rates (77%), which was confirmed in the PRADO trial. A favorable 2-year RFS (83,6%) was achieved in the overall OpACIN-neo population, although patients with a pathological partial or non-response have a worse prognosis and may therefore benefit from additional adjuvant therapy. The efficacy of neoadjuvant checkpoint inhibition versus the current standard of adjuvant therapy needs to be confirmed in a phase III trial, before neoadjuvant therapy can be considered as a standard option for this patient population. Methods: This international, randomized phase 3 trial aims to compare the efficacy of neoadjuvant IPI + NIVO with adjuvant NIVO in macroscopic stage III melanoma. In total 420 patients diagnosed with recurrent or de novo melanoma, with at least one pathologically proven, clinically detectable lymph node (up to 3 in-transit metastases (ITMs) allowed), will be randomized to neoadjuvant or adjuvant treatment. The population will be stratified by BRAF mutation, continent and the presence of ITMs. Patients in arm A will receive 2 cycles of IPI 80mg + NIVO 240mg and will undergo TLND at week 6. In the case of pathological partial response or non-response, surgery will be followed by adjuvant NIVO (11 cycles) or adjuvant dabrafenib + trametinib (46 weeks) if BRAFV600-mutation is present. Patients in arm B will undergo upfront TLND followed by 12 cycles of NIVO 480mg. The primary endpoint will be the event free survival (EFS) defined as the time from randomization until progression to unresectable stage III or stage IV melanoma, recurrent melanoma, a new primary melanoma or death due to melanoma or treatment. Final analysis will be performed after 132 events have been observed, or at latest 2 years after the last patient is included. Baseline biopsies and blood samples (screening, week 0, 3, 6, 9 and 12) will be collected for translational research. Quality of Life questionnaires and electronic Patient Reported Outcomes will be collected using the Kaiku application. The first patient was enrolled on the 23rd of July 2021. Clinical trial information: NCT04949113.

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) has been responsible for the largest pandemic in recent decades. After seemingly being in control due to consequent lock-downs and social distancing, the majority of countries faces currently a second wave of exponentially increasing infections, hospital referrals and deaths due to SARS-CoV-2-mediated disease (COVID-19). To date, no effective vaccination has been found, and wearing masks and social distancing are the only effective approaches to reduce further spreading.However, unwillingness in the societies to distance again and consequently wear masks might be reasons for the second SARS-CoV-2 infection wave. User-friendly chemicals interfering at the host site with viral entry might be an approach to contain the pandemic. In addition, such an approach would work synergistic with vaccinations that miss new virus mutants.Nafamostat (NM) has been shown in vitro to interfere with cellular virus entry by inhibition of the host transmembrane protease serine 2 (TMPRSS2), an enzyme required for SARS-CoV-2 spike protein cleavage, a prerequisite for cell entry.We hypothesized that nasal application of NM in a liposomal layer (as additional mechanical barrier) could lower the nasal viral load and subsequently reduce the severity of COVID-19. We found, indeed, that nasal viral load one day post single NM application, was lowered in a hamster SARS-CoV-2 infection model. However, severity of subsequent local tissue destruction and weight loss due to pneumonitis was not favorably altered.In conclusion, a single NM application reduced nasal viral load, but did not favorably improve the outcome of COVID-19, likely due to the short half-time of NM. Improvement of NM stability or repetitive application (which was not permitted in this animal model according to Dutch law) might circumvent these challenges.

No abstract

No abstract