BackgroundAnti-programmed cell death-1 (PD-1)/PD ligand 1 (PD-L1) checkpoint blockade has not been effective for all solid tumors and alternative therapies are needed for patients who do not respond ...to currently approved checkpoint inhibitors. Sialic acid binding immunoglobulin like lectin-15 (Siglec-15) is an immunomodulatory pathway independent of PD-1/PD-L1. Siglec-15 is expressed on tumor cells and macrophages and has been shown to play a role in the inhibition of T cells. Blocking Siglec-15 overcomes T cell inhibition and limits tumor growth.PYX-106 is an investigational, fully human, anti Siglec-15 immunoglobulin G1 kappa (IgG1k) monoclonal antibody that binds to human Siglec-15 with high affinity and cross-reacts to cynomolgus monkey, rat, and mouse Siglec-15. PYX-106 potently reverses Siglec-15-mediated suppression of CD4+ and CD8+ proliferation and induces IFN-gamma secretion in an ex vivo model. The PYX-106–101 clinical trial is in progress in participants with advanced cancers.MethodsPYX-106 is being evaluated in a first-in-human, open-label, non-randomized, Phase 1 dose-escalation (Part 1) study in participants with advanced solid tumors known to have expression of Siglec-15 (NCT05718557). The phase 1 study utilizes a Bayesian optimal interval design to explore ascending doses of PYX-106 administered as an intravenous infusion to identify the recommended phase 2 dose(s). The study is designed to characterize safety and pharmacokinetics and incorporates a robust translational biomarker plan. Upon completion of Part 1 and depending upon the data obtained, a Part 2 Dose Expansion part of the study may be initiated. The PYX-106–101 study began enrolling participants in February 2023 and will be conducted in the US and Europe. Adverse events are assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0. Tumor response is determined according to Response Evaluation Criteria in Solid Tumors 1.1 criteria and safety findings are reviewed by the dose escalation steering committee, which monitors the safety and recommends dose(s) for Part 2. The study population includes participants with histologically or cytologically confirmed solid tumors including non-small cell lung cancer (without driver mutations/translocations), breast cancer, endometrial cancer, thyroid cancer, kidney cancer, cholangiocarcinoma, bladder cancer, colorectal cancer, and head and neck squamous cell carcinoma. Clinical Trial Information: NCT05718557
The development of immune-related adverse events (irAEs) has been associated with improved efficacy of immune checkpoint inhibitors in patients with urothelial cancer, melanoma, and NSCLC. Whether ...this association exists in patients with SCLC is currently unknown.
We conducted a multicenter retrospective study to evaluate the relationship between irAEs and immunotherapy efficacy in SCLC. To account for the lead-time bias resulting from the time-dependent nature of irAEs, the development of irAEs was considered as a time-varying covariate in univariate and multivariate Cox proportional hazard models.
Of the 183 patients treated with immunotherapy, 73 (39.9%) experienced at least one irAE. A total of 42 patients (22.9%) had grade 1 to 2 irAEs, whereas 31 patients (16.9%) had grade 3 to 4 irAEs. The median time of onset to the first irAE was 24 days (interquartile range: 14–55). The baseline clinicopathologic features were well-balanced between patients with and without irAEs. At a median follow-up of 24 months (95% confidence interval CI: 17.0–31.6), the median progression-free survival was significantly longer in the irAE group than the non-irAE group (3.8 versus 1.3 mo, p < 0.0001). The median overall survival was also significantly longer among patients with irAEs than patients without irAEs (13.8 versus 2.9 mo, p < 0.0001). When analyzed as a time-varying covariate, the development of irAEs was associated with a significant improvement in progression-free survival (hazard ratio: 0.44 95% CI: 0.29–0.66, p < 0.001) and overall survival (hazard ratio: 0.47 95% CI: 0.32–0.71, p < 0.001) in multivariate models.
The development of irAEs is associated with improved clinical outcomes for immunotherapy in patients with advanced SCLC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ
Targeting the mutant p53 secretome Sehgal, Kartik; Barbie, David A
The Journal of clinical investigation,
01/2021, Volume:
131, Issue:
1
Journal Article
Peer reviewed
While p53 is the most highly mutated and perhaps best studied tumor suppressor protein related to cancer, it remains refractory to targeted therapeutic strategies. In this issue of theJCI, Tan and ...colleagues investigated the mechanistic basis of the mutant p53 secretome in preclinical models of lung adenocarcinoma. The authors uncovered miR-34a as a regulator of a conventional protein secretion axis, which is mediated by three proteins: the Golgi reassembly and stacking protein 55 kDa (GRASP55), basic leucine zipper nuclear factor 1, and myosin IIA. Inhibition of GRASP55 in TP53-deficient lung adenocarcinoma suppressed protumorigenic secretion of osteopontin/secreted phosphoprotein 1 and insulin-like growth factor binding protein 2 and reduced tumor growth and metastases in mice as well as in patient-derived xenografts. These results provide a therapeutic opportunity to target downstream effects of p53 loss.
Targeting the mutant p53 secretome Sehgal, Kartik; Barbie, David A
The Journal of clinical investigation,
01/2021, Volume:
131, Issue:
1
Journal Article
Peer reviewed
Open access
While p53 is the most highly mutated and perhaps best studied tumor suppressor protein related to cancer, it remains refractory to targeted therapeutic strategies. In this issue of the JCI, Tan and ...colleagues investigated the mechanistic basis of the mutant p53 secretome in preclinical models of lung adenocarcinoma. The authors uncovered miR-34a as a regulator of a conventional protein secretion axis, which is mediated by three proteins: the Golgi reassembly and stacking protein 55 kDa (GRASP55), basic leucine zipper nuclear factor 1, and myosin IIA. Inhibition of GRASP55 in TP53-deficient lung adenocarcinoma suppressed protumorigenic secretion of osteopontin/secreted phosphoprotein 1 and insulin-like growth factor binding protein 2 and reduced tumor growth and metastases in mice as well as in patient-derived xenografts. These results provide a therapeutic opportunity to target downstream effects of p53 loss.
Aim
The objective was to assess respiratory efficacy of hydrochlorothiazide and spironolactone and ascertain any adverse effects.
Methods
Data from 2014 to 2018 was analysed for infants <28 weeks' ...gestational age (GA) administered oral diuretics. Impact on respiratory support, weight gain and electrolyte status was assessed as a pre‐post intervention study.
Results
Of 491 infants, 117 (24%) were administered diuretics for evolving or established bronchopulmonary dysplasia. GA and birthweight of the cohort were 25.7 ± 1.1 weeks and 779 ± 172 g, respectively. Median (interquartile range) chronological age and GA at the start of diuretics was 45 (22, 62) days and 32.1 (30.1, 35.1) weeks, respectively. In 71/117 (61%) infants, diuretics were started at <36 weeks GA. Of them 63 (88.7%) went on to develop bronchopulmonary dysplasia. Median duration of diuretics was 38 (18–52) days. Modest improvement was noted in respiratory parameters (ventilator pressure (cm of H2O), 8.8 ± 0.4 vs. 8.8 ± 0.5, P = 0.39, oxygen requirement (%), 32 ± 1 vs. 30 ± 1, P = 0.07 and pO2 (mm Hg) 34.5 ± 1.3 vs. 36.6 ± 1, P = 0.04. Ninety‐eight (84%) infants developed hyponatraemia (<135 mmol/L); sodium supplements were administered in 58/98 (59%) infants. In one third infants, phosphate levels dropped below 1.8 mmol/L, needing supplementation. Weight gain (g/kg/day) slowed down significantly (18.2 ± 2.1 to 10 ± 2.9, P = <0.001).
Conclusions
Use of diuretics was associated with modest improvements in respiratory support requirements but was associated with significant electrolyte abnormalities and slowdown in weight gain (or weight loss).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Cancer genomic profiling has improved our understanding of the key drivers of tumor development, clonal evolution, and recurrence, and aided precision medicine efforts to eradicate therapy-resistant ...cancer cell clones. In this issue, You and colleagues report these results for recurrent nasopharyngeal carcinoma, an aggressive malignancy associated with poor outcomes with recurrent disease. They identify a crucial contributory role of clonal NF-κB activating mutations in pathogenesis of recurrence in this cancer and provide a promising target for combinatorial therapeutic approaches.
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Highlights • The specialized antigen-presentation capability of dendritic cells and the plasticity of different DC subsets make them valuable targets for immunotherapy. • The success of recently ...reported phase I trial of NY-ESO1-anti-DEC205 antibody vaccine has set the stage for further clinical testing of in-situ DC-targeted vaccines. • Nanoparticles also represent an attractive strategy for targeting DCs in situ.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract
Coronavirus disease 2019 (COVID-19), currently a worldwide pandemic, is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The suspected contribution ...of thrombotic events to morbidity and mortality in COVID-19 patients has prompted a search for novel potential options for preventing COVID-19-associated thrombotic disease. In this article by the Global COVID-19 Thrombosis Collaborative Group, we describe novel dosing approaches for commonly used antithrombotic agents (especially heparin-based regimens) and the potential use of less widely used antithrombotic drugs in the absence of confirmed thrombosis. Although these therapies may have direct antithrombotic effects, other mechanisms of action, including anti-inflammatory or antiviral effects, have been postulated. Based on survey results from this group of authors, we suggest research priorities for specific agents and subgroups of patients with COVID-19. Further, we review other agents, including immunomodulators, that may have antithrombotic properties. It is our hope that the present document will encourage and stimulate future prospective studies and randomized trials to study the safety, efficacy, and optimal use of these agents for prevention or management of thrombosis in COVID-19.
Background: Fetal growth restriction (FGR) affects 5–10% term gestational age pregnancies. When accompanied by prematurity, FGR infants have significantly greater risk of perinatal morbidity and/or ...mortality compared to non-growth restricted preterm infants. Aim: Current study aimed to ascertain the incidence FGR among premature infants and its association with respiratory morbidity. Methods: Institution database for preterm infants of 23–31+6 weeks of gestation was accessed. FGR infants were compared with gestation/sex matched appropriately grown infants. Results: During the period 2016–2018, 973 infants between 23 and 31+6 weeks gestation were admitted amongst whom, 206 (27%) were FGR. Between 28 and 31+6 weeks gestation, approximately 1/3rd were FGR. Gestation and birth weight of the FGR and appropriately grown cohorts were 30.2±0.2 versus 30.1±0.2 weeks (p=0.8) and 1132±43 versus 1499±54 g (p<0.0001), respectively. While antenatal steroids, surfactant, mechanical ventilation, sepsis, and ductal therapy were comparable, respiratory outcomes were significantly worse in the FGR cohort (duration of respiratory support: 37±10 vs. 23±5 days p=0.016, home oxygen: 24 11.6% vs. 8 3.8%; p=0.005 and chronic lung disease CLD: 53 25.7% vs. 28 13.6%, p=0.002, respectively). The odds ratio (95% confidence intervals) for developing CLD and for home oxygen when born FGR were 2.2 (1.3–3.6) and 3.2 (1.4–7.4), respectively. Conclusions: In spite of comparable postnatal variables, FGR infants had significantly greater respiratory morbidity.
The optimal management of advanced non‐small cell lung cancer (NSCLC) with noncanonical epidermal growth factor receptor (EGFR) mutations (i.e., exon 19 deletion and exon 21 L858R) is constrained by ...the heterogeneous behavior of individual uncommon mutations and limited prospective clinical data in this setting. Despite encouraging results with osimertinib from a recently published phase II trial from South Korea, afatinib remains the only currently approved drug for patients with tumors harboring uncommon EGFR mutations (i.e., S768I, L861Q, and/or G719X). When used at the standard dose of 40 mg daily, afatinib is associated with significant rates of treatment‐related adverse events, leading to frequent dose reductions and treatment discontinuations. We report a case of a woman with advanced NSCLC harboring EGFR‐G719A mutation treated with afatinib (at an off‐label pulse dose strategy that merits further evaluation in prospective studies) with sustained partial response for 20 months with manageable expected toxicities. Subsequent disease progression was mediated by off‐target pan‐EGFR inhibitor (including osimertinib)–resistant KRAS mutation and not by acquisition of EGFR‐T790M. We further present the current state of evidence in the literature behind use of first‐, second‐, and third‐generation tyrosine kinase inhibitors and summarize the evolving spectrum of activity ascribed to osimertinib (and newer EGFR inhibitors with a more favorable therapeutic window and intracranial penetration) in this population of patients with advanced NSCLC and uncommon EGFR mutations.
Key Points
Uncommon EGFR mutations characterize a heterogeneous group of patients with advanced non‐small cell lung cancer (NSCLC).
Afatinib is the only currently U.S. Food and Drug Administration–approved drug for management of advanced NSCLC with uncommon EGFR mutations (S768I, L861Q, and/or G719X).
Afatinib treatment at 40 mg daily is associated with high rates of adverse events and dose reductions; alternative strategies including pulse intermittent dosing should be evaluated prospectively.
Osimertinib (with favorable safety profile and intracranial penetration) has shown promising results in this population in a phase II trial from South Korea; additional trials are ongoing.
This article presents the case of patient with advanced non‐small cell lung cancer harboring an EGFR‐G719A mutation treated with afatinib and reviews the literature regarding the use of first‐, second‐, and third‐generation tyrosine kinase inhibitors in this patient population.
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