Stratification of PD-1 blockade response in melanoma using pre- and post-treatment immunophenotyping of peripheral blood

Efficacy of checkpoint inhibitor therapies in cancer varies greatly, with some patients showing complete responses while others do not respond and experience progressive disease. We aimed to identify correlates of response and progression following PD-1-directed therapy by immunophenotyping peripheral blood samples from 20 patients with advanced malignant melanoma before and after treatment with the PD-1 blocking antibody pembrolizumab. Our data reveal that individuals responding to PD-1 blockade were characterised by increased CD8 T cell proliferation following treatment, while progression was associated with an increase in CTLA-4-expressing Treg. Remarkably, unsupervised clustering analysis of pre-treatment T cell subsets revealed differences in individuals that went on to respond to PD-1 blockade compared to individuals that did not. These differences mapped to expression of the proliferation marker Ki67 and the costimulatory receptor CD28 as well as the inhibitory molecules 2B4 and KLRG1. While these results require validation in larger patient cohorts, they suggest that flow cytometric analysis of a relatively small number of T cell markers in peripheral blood could potentially allow stratification of PD-1 blockade treatment response prior to therapy initiation

Safety of bendamustine for the treatment of indolent non-Hodgkin lymphoma: a UK real-world experience

Introduction: Bendamustine is among the most effective chemotherapeutics for indolent B-cell non-Hodgkin lymphomas (iNHL), but trial reports of significant toxicity, including opportunistic infections and excess deaths, led to prescriber warnings. We conducted a multicentre observational study evaluating bendamustine toxicity in real-world practice. Methods: Patients receiving at least one dose of bendamustine (B) +/- rituximab (R) for iNHL were included. Demographics, lymphoma and treatment details and grade 3-5 adverse events (AEs) were analysed. Results: 323 patients were enrolled from 9 NHS hospitals. Most patients (96%) received BR and 46% R maintenance. 21.7% experienced serious AEs (SAE) related to treatment, including infections in 12%, with absolute risk highest during induction (63%), maintenance (20%), and follow-up (17%), and the relative risk highest during maintenance (54%), induction (34%) and follow-up (28%). Toxicity led to permanent treatment discontinuation in 13% of patients, and 2.8% died of bendamustine-related infections (n=5), myelodysplastic syndrome (n=3), and cardiac disease (n=1). More SAEs per patient were reported in patients with mantle cell lymphoma, poor pre-induction PS, poor pre-maintenance PS, abnormal pre-induction total globulins and in those receiving growth factors. Use of antimicrobial prophylaxis was variable, and 3/10 opportunistic infections occurred despite prophylaxis. Conclusion: In this real-world analysis, bendamustine-related deaths and treatment discontinuation were similar to trial populations of younger, fitter patients. Poor PS, mantle cell histology and maintenance rituximab were potential risk factors. Infections, including late onset events, were the most common treatment-related SAE and cause of death warranting extended antimicrobial prophylaxis and infectious surveillance, especially in maintenance-treated patients

Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

https://deepblue.lib.umich.edu/bitstream/2027.42/138963/1/12987_2017_Article_71.pd

The efficacy of crizotinib in patients with -positive nonsmall cell lung cancer

Molecular profiling of nonsmall cell lung cancer (NSCLC) contributes to better understanding the different molecular subtypes of this heterogeneous group of diseases. The discovery of oncogenic ALK rearrangements in NSCLC and the subsequent success in their therapeutic targeting with crizotinib reinforces the benefits of a precision approach to systemic anticancer therapy. In addition, the rapid development of crizotinib from first discovery thorough accelerated US Food and Drug Administration approval, and late stage confirmatory clinical trials, exemplifies the success of the drug development strategy of close collaboration between clinicians, industry and regulatory authorities. In this review we describe the identification of ALK rearranged NSCLC, clinical characteristics of such patients, and clinical outcomes when treated with crizotinib

Tracking response of the freshwater copepod Hesperodiaptomus shoshone: Importance of hydrodynamic features

Using three-dimensional Schlieren-based videography, males of the freshwater alpine species Hesperodiaptomus shoshone (Wyoming) were found to follow both conspecific females and conspecific males, remaining 0.45 ± 0.13 cm (male) and 0.56 ± 0.13 cm (female) from the lead copepod for 0.91 ± 0.35 seconds (male) and 0.84 ± 0.46 seconds (female). Trail following is initiated when the male makes a rapid reorientation. Chemical pheromones either were not produced by the female or were not detected by the male because males would follow trail mimics composed of female-conditioned water. Using unconditioned water, males were found capable not only of following trail mimics but they showed a preference, quantified as a higher follow frequency, of trails running at speeds matching that of their female mate. Remarkably, the male copepods always followed upstream, micro-casting between the edges of the trail to remain on track. Trails flowing at speeds matching their mate’s swimming speed were followed for a longer period of time and at greater gross distance. As the flow speed of the trail mimic increased, the distance the copepod would advance would decrease until the threshold speed of 2.30 cm/sec at which it would not follow a trail and only station hold. Station holding has never been observed before for copepods and may represent an adaptive behavior to avoid being washed out of their resident alpine pond. At speeds greater than that evoking station holding, the stream seemed to push the copepod out of the flow even though the copepod would make repeated efforts to swim up the stream. This research revealed a behavior not documented before: instead of relying on discrete pulses of flow left by hopping copepods, this high alpine lake copepod followed smoothly swimming mates or continuously flowing thin streams, relying only on sensing hydrodynamic cues.M.S

Optimising Cancer Vaccine Design in Sarcoma

Immunotherapeutics are increasingly recognized as a key tool in the armamentarium against malignancy. The success of immune checkpoint-targeting drugs and adoptive cell therapy has refocused attention on the potential anti-cancer effect of eliciting a tumour-specific immunological response. Sarcomas are a rare and diverse group of tumours with a limited prognosis in advanced disease despite systemic therapeutics. Various vaccine strategies including peptide vaccines against cancer testis antigens, dendritic cell vaccines, and viral vectors have been trialled in sarcoma with growing evidence of efficacy. Here, we review the principles of successful vaccine development and how these have been applied thus far to the treatment of sarcoma

Real-World Outcomes of Stage IV NSCLC with PD-L1 ≥ 50% Treated with First-Line Pembrolizumab: Uptake of Second-Line Systemic Therapy

Introduction: Platinum-based chemotherapy was compared to single-agent pembrolizumab in advanced non-small cell lung cancer (NSCLC) with PDL1 > 50% in KEYNOTE-024. In this trial, it was found that patients who received single-agent pembrolizumab had improved progression-free survival in addition to overall survival (OS). Based on KEYNOTE-024, only 53% of patients treated originally with pembrolizumab received second-line anticancer systemic therapy with an OS of 26.3 months. Based on these results, the objective of this study was to characterize real-world NSCLC patients who received second-line therapy after single-agent pembrolizumab. Methods: This was a retrospective cohort study considering stage IV NSCLC patients diagnosed with BC Cancer between 2018 and 2021 with PD-L1 ≥ 50% who received first-line single agent pembrolizumab. Patient demographics, cancer history, treatment administered, and survival were collected retrospectively. Descriptive statistics were produced. OS was calculated using Kaplan–Meier curves and compared using the log rank test. A multivariate model evaluated characteristics associated with the receipt of second-line therapy. Results: A total of 718 patients were diagnosed with Stage IV NSCLC and received at least one cycle of pembrolizumab. The median duration of treatment was 4.4 months, and the follow-up duration was 16.0 months. There were 567 (79%) patients who had disease progression, of whom 21% received second-line systemic therapy. Within the subset of patients with disease progression, the median duration of treatment was 3.0 months. It would be found that patients who received second-line therapy had better baseline ECOG performance status, were younger at diagnosis, and had a longer duration of pembrolizumab. Within the full population, the OS from the treatment initiation date was 14.0 months. OS was 5.6 months in patients who did not receive additional therapy after progression and 22.2 months in patients who received subsequent therapy. Baseline ECOG performance status was associated with improved OS in multivariate analysis. Conclusion: Based on this real-world Canadian population, 21% of patients received second-line systemic therapy, despite second-line therapy being associated with prolonged survival. In this real-world population, we found that 60% fewer patients received second-line systemic therapy when compared to KEYNOTE-024. Although differences always exist when comparing a clinical and non-clinical trial population, our findings suggest undertreating stage IV NSCLC patients

Alternate Pembrolizumab Dosing Interval in Advanced NSCLC with PD-L1 TPS ≥ 50%: 3 Weekly Compared to 6 Weekly Dosing

Background: A fixed dose of 200 mg of pembrolizumab every 3 weeks (Q3W) is the standard of care for patients with stage IV non-small cell lung cancer (NSCLC) and PDL1 ≥50%. In April 2020, based on pharmacokinetic modeling without formal comparative studies, the FDA approved 400 mg every 6 weeks (Q6W). Pharmacokinetic studies also suggested comparable target engagement with weight-based and flat dosing for the respective schedules. The objective of this study was to determine if overall survival (OS) differs based on the Q3W vs. Q6W dosing schedule of pembrolizumab. Methods: BC Cancer patients with stage IV NSCLC and PDL1 ≥50% treated with pembrolizumab were retrospectively reviewed. Patients were treated with weight-based dosing, per institution standard, of pembrolizumab 2 mg/kg Q3W or 4 mg/kg Q6W. Patient demographics, treatment and outcome were recorded. Patients were assigned to Q3W or Q6W according to the schedule that was used for the majority of treatment (greater than 50%). Results: 718 patients with NSCLC and PDL1 ≥50% received first-line pembrolizumab between 2017 and2021, Q3W/Q6W dosing 677/41 patients. Baseline characteristics with respect to age, sex, smoking status, histology and performance status (PS) were similar between groups. In the multivariate model, including age, sex, PS and dosing schedule, the hazard ratio for death (HR) for OS Q3W vs. Q6W was 0.759 (p = 0.230). A 2:1 case-matched analysis for OS was performed, controlling for sex, age ± 5 years, PS and duration on pembrolizumab ± 2 months for Q3W vs. Q6W (n = 113) with a HR 0.834 (p = 0.500). Conclusions: There was no OS difference demonstrated with pembrolizumab dosing Q3W compared to Q6W in a multivariate analysis that included age, sex and PS. A case-matched analysis that controlled for these variables and for duration of treatment confirmed these findings. This study supports the use of Q6W pembrolizumab dosing, allowing for less frequent interactions with the medical system

Salona I. Recherches archéologiques franco-croates à Salone. Catalogue de la sculpture architecturale paléochrétienne de Salone.

Ce volume I, fruit d'une coopération entre la France et la Croatie, présente le catalogue du matériel des églises, et autres monuments de l'Antiquité Tardive, recueilli sur le territoire de Salone - capitale de la Dalmatie antique et centre mondialement connu pour l'archéologie chrétienne - et dans son voisinage. C'est le premier catalogue raisonné de sculpture architecturale de cette période pour l'ensemble du site - après deux inventaires de fouilles dressés par E. Dyggve entre les deux guerres - comme d'ailleurs pour la Dalmatie tout entière. Il a été rédigé sous la direction de C. Metzger, conservateur en chef au Louvre, et comporte une présentation du site par E. Marin, directeur du Musée archéologique de Split, des introductions pour chaque catégorie de matériel par différents spécialistes (outre C. Metzger : Ν. Duval, P. Chevalier et M.-P. Flèche-Mourgues) ; un chapitre important donne la liste du matériel comparable repéré en Dalmatie (par P. Chevalier et C. Metzger), et deux appendices traitent de problèmes particuliers. Chaque pièce conservée a été dessinée en axonométrie (sous la direction de Br. Pender, chef des services techniques du Musée de Split) - avec une restitution quand elle est possible - et quelques photographies illustrent les plus spectaculaires. Des tables de concordance avec les inventaires du musée archéologique de Split en font aussi un instrument muséographique conforme aux normes modernes. Le matériel, souvent fragmentaire malheureusement, est fait essentiellement d'éléments en pierre dure de Brač (qui peut se polir facilement), avec un décor sommaire (surtout fait de croix et autres symboles chrétiens) et répétitif, mais assez soigné dans la présentation : linteaux de portes, « meneaux » de fenêtre bifores et trifores, poteaux de « chancels » (soit de barrières basses, soit de barrières avec superstructure annonçant l'iconostase), plaques de chancels pleines ou ajourées, colonnes de ciborium et colonnettes d'autel. La typologie était déjà bien établie, mais la masse du catalogue permet de se faire une idée claire d'une production provinciale de série, à partir d'une pierre locale dont la qualité est encore prisée de nos jours. Le destin du territoire de Salone, bouleversé depuis les invasions du VIIe siècle, fait que le matériel de marbre importé a été en grande partie soit réemployé et retaillé depuis le Moyen- Âge, soit brûlé dans les fours à chaux. Les fragments subsistant montrent cependant qu'il a été abondant et parfois original : on a réservé un traitement particulier aux chancels « à colonnettes » de l'église de Manastirine et aux panneaux en marbre de Proconnese portant le monogramme de l'évêque Honorius, contemporains - au VIe siècle - des chancels encore conservées en série dans l'église de San Clemente à Rome. Une partie importante du volume est aussi consacrée aux tables (mensae) de différents types et de différents usages (autels, tables profanes, tables funéraires ou consacrées aux saints locaux - martyrs et évêques), particulièrement nombreuses sur le site et qui ont déjà suscité bien des discussions depuis un siècle, puisque leurs inscriptions sont le seul témoignage fiable pour l'hagiographie de Salone. Ν. Duval traite notamment de l'usage cimétérial de ces tables, des témoignages de survivance de rites de libation et de repas funéraires, du sens qu'il attribue au mot piscina désignant localement la tombe et le plateau creux qui la surmonte. E. Marin, à partir d'une découverte récente, propose une autre interprétation.Duval Noël, Marin Emilio, Metzger Catherine et al. Salona I. Recherches archéologiques franco-croates à Salone. Catalogue de la sculpture architecturale paléochrétienne de Salone. Rome : École Française de Rome, 1994. 472 p. (Publications de l'École française de Rome, 194