Identity, enlightenment and political dissent in late colonial Spanish America

During the long crisis of the Spanish empire between 1810 and 1825, the Creole leaders of Spanish American independence asserted a new identity for the citizens of the states which they sought to establish, calling them 'Americanos'. This general title was paralleled and often supplanted by other political neologisms, as movements for independence and new polities took shape in the various territories of Spanish America. In New Spain, the insurgents who fought against royalist government during the decade after 181 o tried to rally fellow 'Mexicans' to a common cause; at independence in 1821, die Creole political leadership created a 'Mexican empire', the title of which, with its reference to the Aztec empire which had preceded Spain's conquest, was designed to evoke a 'national' history shared by all members of Mexican society. In South America, die leaders of the new republics also sought to promote patriotic feelings for territories which had been converted from administrative units of Spanish government into independent states. Thus, San Martin and O'Higgins convoked 'Chileans' to the cause of independence in the old Captaincy-General of Chile; shortly afterwards and with notably less success, San Martin called upon 'Peruvians' to throw off Spanish rule. Bolivar was, likewise, to call 'Colombians' to his banner in die erstwhile Viceroyalty of New Granada, before advancing south to liberate Peru in die name of 'Peruvians', and Upper Peru in die name of 'Bolivians', where die Republic which his military feats and political vision made possible was named after him

Amivantamab compared with real-world therapies in patients with advanced non-small cell lung cancer harboring EGFR exon 20 insertion mutations who progressed after platinum-based chemotherapy

BACKGROUND: In the single-arm CHRYSALIS study, amivantamab showed durable responses and manageable safety in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations (ex20ins) who progressed on prior platinum-based chemotherapy. External controls can provide context for interpreting amivantamab efficacy. METHODS: External controls were selected from three US-based databases (ConcertAI, COTA, and Flatiron). Key inclusion criteria were diagnosis of EGFR ex20ins advanced NSCLC, prior platinum-based chemotherapy, and performance status score ≤ 1. Duplicate external controls were identified using a tokenization procedure and removed, and adjustment for differences in baseline characteristics between amivantamab-treated and external control cohorts was achieved using propensity score weighting. RESULTS: Amivantamab-treated and pooled external control cohorts included 81 and 125 patients, respectively. Baseline characteristics were generally similar across cohorts, except more amivantamab-treated patients were Asian (56% vs 13%). Most common therapies received by external controls were non-platinum-based chemotherapy (25.1%), immuno-oncology therapies (24.2%), EGFR tyrosine kinase inhibitors (16.3%), and platinum-based chemotherapy (16.3%). Overall response rate was 40% among amivantamab-treated patients and 16% among external controls. Amivantamab-treated patients had longer progression-free survival (median 8.3 vs 2.9 months; hazard ratio [HR; 95% CI]: 0.47 [0.34-0.65]), time to next therapy (median 14.8 vs 4.8 months; HR [95% CI]: 0.40 [0.28-0.57]), and overall survival (median 22.8 vs 12.8 months; HR [95% CI]: 0.49 [0.31-0.77]) than external controls. Results were consistent in sensitivity analyses comparing each external control dataset against the amivantamab-treated group separately. CONCLUSION: Among post-platinum patients with EGFR ex20ins advanced NSCLC, those treated with amivantamab had improved outcomes, including 10-month longer overall survival, versus external controls

Systemic Blockade of Clever-1 Elicits Lymphocyte Activation Alongside Checkpoint Molecule Downregulation in Patients with Solid Tumors : Results from a Phase I/II Clinical Trial

Purpose: Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell-targeting therapies. Thus, agents able to reprogram macrophages toward a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of the macrophage scavenger receptor Clever-1 has shown benefit in inducing CD8 T-cell-mediated antitumor responses in mouse models of cancer, which supports the clinical development of Clever-1-targeting antibodies for cancer treatment. Patients and Methods: In this study, we analyzed the mode of action of a humanized IgG4 anti-Clever-1 antibody, FP-1305 (bexmarilimab), both in vitro and in patients with heavily pretreated metastatic cancer (n = 30) participating in part 1 (dose-finding) of a phase I/II open-label trial (NCT03733990). We studied the Clever-1 interactome in primary human macrophages in antibody pull-down assays and utilized mass cytometry, RNA sequencing, and cytokine profiling to evaluate FP-1305-induced systemic immune activation in patients with cancer. Results: Our pull-down assays and functional studies indicated that FP-1305 impaired multiprotein vacuolar ATPase-mediated endosomal acidification and improved the ability of macrophages to activate CD8(+)T-cells. In patients with cancer, FP-1305 administration led to suppression of nuclear lipid signaling pathways and a proinflammatory phenotypic switch in blood monocytes. These effects were accompanied by a significant increase and activation of peripheral T-cells with indications of antitumor responses in some patients. Conclusions: Our results reveal a nonredundant role played by the receptor Clever-1 in suppressing adaptive immune cells in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch, potentially leading to intratumoral proinflammatory responses in patients with metastatic cancer.Peer reviewe

Bexmarilimab-induced macrophage activation leads to treatment benefit in solid tumors:The phase I/II first-in-human MATINS trial

Macrophage Clever-1 contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial investigates the safety and tolerability of Clever-1 blockade with bexmarilimab in patients with treatment-refractory solid tumors and assesses preliminary anti-tumor efficacy, pharmacodynamics, and immunologic correlates. Bexmarilimab shows no dose-limiting toxicities in part I (n = 30) and no additional safety signals in part II (n = 108). Disease control (DC) rates of 25%–40% are observed in cutaneous melanoma, gastric, hepatocellular, estrogen receptor-positive breast, and biliary tract cancers. DC associates with improved survival in a landmark analysis and correlates with high pre-treatment intratumoral Clever-1 positivity and increasing on-treatment serum interferon γ (IFNγ) levels. Spatial transcriptomics profiling of DC and non-DC tumors demonstrates bexmarilimab-induced macrophage activation and stimulation of IFNγ and T cell receptor signaling selectively in DC patients. These data suggest that bexmarilimab therapy is well tolerated and show that macrophage targeting can promote immune activation and tumor control in late-stage cancer

Systemic Blockade of Clever-1 Elicits Lymphocyte Activation Alongside Checkpoint Molecule Downregulation in Patients with Solid Tumors: Results from a Phase I/II Clinical Trial

Purpose:Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell–targeting therapies. Thus, agents able to reprogram macrophages toward a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of the macrophage scavenger receptor Clever-1 has shown benefit in inducing CD8+ T-cell–mediated antitumor responses in mouse models of cancer, which supports the clinical development of Clever-1–targeting antibodies for cancer treatment.Patients and Methods:In this study, we analyzed the mode of action of a humanized IgG4 anti–Clever-1 antibody, FP-1305 (bexmarilimab), both in vitro and in patients with heavily pretreated metastatic cancer (n = 30) participating in part 1 (dose-finding) of a phase I/II open-label trial (NCT03733990). We studied the Clever-1 interactome in primary human macrophages in antibody pull-down assays and utilized mass cytometry, RNA sequencing, and cytokine profiling to evaluate FP-1305–induced systemic immune activation in patients with cancer.Results:Our pull-down assays and functional studies indicated that FP-1305 impaired multiprotein vacuolar ATPase–mediated endosomal acidification and improved the ability of macrophages to activate CD8+ T-cells. In patients with cancer, FP-1305 administration led to suppression of nuclear lipid signaling pathways and a proinflammatory phenotypic switch in blood monocytes. These effects were accompanied by a significant increase and activation of peripheral T-cells with indications of antitumor responses in some patients.Conclusions:Our results reveal a nonredundant role played by the receptor Clever-1 in suppressing adaptive immune cells in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch, potentially leading to intratumoral</p

Tackling Immunotherapy Resistance: Developing Rational Combinations of Immunotherapy and Targeted Drugs

Mechanisms of resistance to immunotherapies are multiple and complex with components intrinsic to the tumor cell and within the immune microenvironment. We review evidence of the interaction of tumor cell signaling pathways with immune pathways and the role this plays in de novo and acquired resistance. The mitogen-activated protein kinase (MAPK) pathway activation and effects on T-cell function are discussed. Phosphoinositide 3-kinase (PI3K) pathway activation (including PTEN loss of function) correlates with T-cell inhibition and immunotherapy resistance. Wnt signaling has been implicated in T-cell function suppression. Key evidence from preclinical models exists for the role of these signaling pathways and is described. Clinical evidence is less advanced though correlation of mutations in key nodes with immune resistance provides a limited clinical correlation. Serial biomarker analysis in patients receiving targeted drugs has been attempted with notable examples including BRAF inhibition in melanoma patients resulting in dynamic changes in programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes. Drug combinations aim to overcome mechanisms of resistance, and recent years have seen numerous combinations of targeted therapies and immune checkpoint inhibitors proposed. However, clear biological rationale and thoughtful trial designs with a translational focus are required to allow such combinations to achieve their full potential

Trends in Patient-Reported Outcome (PRO) use in Early Phase Dose-finding Oncology Trials (DFOT)- an Analysis of ClinicalTrials.gov

ABSTRACT Background Patient‐reported adverse events (AEs) may be a useful adjunct to clinician‐assessed AEs for assessing tolerability in early phase, dose‐finding oncology trials (DFOTs). We reviewed DFOTs on ClinicalTrials.gov to describe trends in patient‐reported outcome (PRO) use. Methods DFOTs commencing 01 January 2007 – 20 January 2020 with ‘PROs’ or ‘quality of life’ as an outcome were extracted and inclusion criteria confirmed. Study and PRO characteristics were extracted. Completed trials that reported PRO outcomes and published manuscripts on ClinicalTrials.gov were identified, and PRO reporting details were extracted. Results 5.3% (548/10 372) DFOTs included PROs as an outcome. 231 (42.2%) were eligible: adult (224, 97%), solid tumour (175, 75.8%), and seamless phase 1/2 (108, 46.8%). PRO endpoints were identified in more trials (2.3 increase/year, 95% CI: 1.6–2.9) from an increasing variety of countries (0.7/year) (95% CI: 0.4–0.9) over time. PROs were typically secondary endpoints (207, 89.6%). 15/77 (19.5%) completed trials reported results on the ClinicalTrials.gov results database, and of those eight included their PRO results. Eighteen trials had published manuscripts available on ClinicalTrials.gov. Three (16.7%) used PROs to confirm the maximum tolerated dose. No trials identified who completed the PROs or how PROs were collected. Conclusions PRO use in DFOT has increased but remains limited. Future work should explore the role of PROs in DFOT and determine what guidelines are needed to standardise PRO use

Statistical methods and data visualisation of patient-reported outcomes in early phase dose-finding oncology trials: A systematic review

BACKGROUND: Traditionally, within dose-finding clinical trials, treatment toxicity and tolerability are assessed by clinicians. Research has shown that clinician reporting may have inadequate inter-rater reliability, poor correlation with patient reported outcomes, and under capture the true toxicity burden. The introduction of patient-reported outcomes (PROs), where the patient can assess their own symptomatic adverse events or quality of life, has potential to complement current practice to aid dose optimisation. There are no international recommendations offering guidance for the inclusion of PROs in dose-finding trial design and analysis. Our review aimed to identify and describe current statistical methods and data visualisation techniques employed to analyse and visualise PRO data in published early phase dose-finding oncology trials (DFOTs). METHODS: DFOTs published from June 2016-December 2022, which presented PRO analysis methods, were included in this methodological review. We extracted 35 eligible papers indexed in PubMed. Study characteristics extracted included: PRO objectives, PRO measures, statistical analysis and visualisation techniques, and whether the PRO was involved in interim and final dose selection decisions. FINDINGS: Most papers (30, 85.7%) did not include clear PRO objectives. 20 (57.1%) papers used inferential statistical techniques to analyse PROs, including survival analysis and mixed-effect models. One trial used PROs to classify a clinicians' assessed dose-limiting toxicities (DLTs). Three (8.6%) trials used PROs to confirm the tolerability of the recommended dose. 25 trial reports visually presented PRO data within a figure or table within their publication, of which 12 papers presented PRO score longitudinally. INTERPRETATION: This review highlighted that the statistical methods and reporting of PRO analysis in DFOTs are often poorly described and inconsistent. Many trials had PRO objectives which were not clearly described, making it challenging to evaluate the appropriateness of the statistical techniques used. Drawing conclusions based on DFOTs which are not powered for PROs may be misleading. With no guidance and standardisation of analysis methods for PROs in early phase DFOTs, it is challenging to compare study findings across trials. Therefore, there is a crucial need to establish international guidance to enhance statistical methods and graphical presentation for PRO analysis in the dose-finding setting. FUNDING: EA has been supported to undertake this work as part of a PhD studentship from the Institute of Cancer Research within the MRC/NIHR Trials Methodology Research Partnership. AM is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust, the Institute of Cancer Research and Imperial College

Assessing cognitive toxicity in early Phase Trials ‐ what are we missing?

Objectives: novel therapies, such as, small protein molecule inhibitors and immunotherapies are first tested clinically in Phase I trials. Moving on to later phase trials and ultimately standard practice. A key aim of these early clinical trials is to define a toxicity profile; however, the emphasis is often on safety. The concern is cognitive toxicity is poorly studied in this context and may be under-reported. The aim of this review is to map evidence of cognitive assessment, toxicity, and confounding factors within reports from Phase I trials and consider putative mechanisms of impairment aligned with mechanisms of novel therapies. Methods: a scoping review methodology was applied to the search of databases, including Embase, MEDLINE, Clinicaltrials.gov. A [keyword search was conducted, results screened for duplication then inclusion/exclusion criteria applied. Articles were further screened for relevance; data organised into categories and charted in a tabular format]. Evidence was collated and summarised into a narrative synthesis. Results: despite the availability of robust ways to assess cognitive function, these are not routinely included in the conduct of early clinical trials. Reports of cognitive toxicity in early Phase I trials are limited and available evidence on this shows that a proportion of patients experience impaired cognitive function over the course of participating in a Phase I trial. Links are identified between the targeted action of some novel therapies and putative mechanisms of cognitive impairment. Conclusion: the review provides rationale for research investigating cognitive function in this context. A study exploring the cognitive function of patients on Phase I trials and the feasibility of formally assessing this within early clinical trials is currently underway at the Royal Marsden.</p