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OBJECTIVE: Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme, that has been implicated as a biomarker of cardiovascular risk in patients with rheumatoid arthritis (RA). We aimed to investigate how different biologic therapies affect levels of PON1 and oxylipins. METHODS: 1213 adult patients with RA in the Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory CoNditions cohort study with moderate-to-high disease activity (Clinical Disease Activity Index (CDAI) >10) who initiated a new biologic (tocilizumab (TCZ), n=296; abatacept, n=374; tumour necrosis factor inhibitors, n=427; rituximab, n=116) were followed prospectively with serum specimens analysed for PON1 activity by arylesterase (ARYL), lactonase (LAC) and PON assays at baseline and after 6 months of biologic therapy. A targeted panel of oxylipins was evaluated by liquid chromatography-mass spectrometry/mass spectrometry in a subset of patients with the lowest and highest 6-month Disease Activity Score 28 (DAS28)-C reactive protein (CRP) responses in each treatment group. RESULTS: PON1 activity generally increased in the entire cohort after 6 months of new biologic therapy, showing the greatest, most consistent increases in the TCZ group. Increases in all three PON1 domains associated with significant decreases in disease activity in DAS28-CRP/CDAI (p

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths, with adenosquamous carcinoma of the pancreas (ASCP), a rare variant, representing 1-10% of cases. Standard chemotherapy trials for pancreatic cancer exclude ASCP, leaving its optimal treatment uncertain. This report describes a 68-year-old male with metastatic ASCP and a KRAS G12C mutation, progressing through multiple lines of systemic therapy, including targeted inhibition of KRAS G12C. Notably, the patient exhibited a robust response to single-agent immune checkpoint inhibition (ICI) with pembrolizumab, despite intact mismatch repair proteins. The limited success of traditional therapies in pancreatic cancer, coupled with the rarity of ASCP, presents a challenge in establishing effective treatment strategies. While KRAS G12C inhibitors demonstrated modest benefits, this case highlights the remarkable response to ICI in a patient with squamous histology. The distinct tumor microenvironment of ASCP, characterized by squamous differentiation, may contribute to this exceptional response. This underscores the need for further research and clinical trials focused on ICI in ASCP, with an ongoing multi-center phase 2 trial investigating outcomes in this specific subset.

This post hoc analysis of the randomized, placebo-controlled N-MOmentum study (NCT02200770) of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD) evaluated relationships between circulating B-cell subsets and aquaporin-4 immunoglobulin G (AQP4-lgG) titers and attacks. Among participants receiving placebo, CD20+ and CD27+ B-cell counts were modestly increased from the pre-attack visit to attack; plasmablast/plasma cell gene signature was increased from baseline to the pre-attack visit (p = 0.016) and from baseline to attack (p = 0.009). With inebilizumab treatment, B-cell subset counts decreased and did not increase with attacks. No difference in change of AQP4-IgG titers from baseline to time of attack was observed.

Life-threatening thrombotic events and neurological symptoms are prevalent in COVID-19 and are persistent in patients with long COVID experiencing post-acute sequelae of SARS-CoV-2 infection1-4. Despite the clinical evidence1,5-7, the underlying mechanisms of coagulopathy in COVID-19 and its consequences in inflammation and neuropathology remain poorly understood and treatment options are insufficient. Fibrinogen, the central structural component of blood clots, is abundantly deposited in the lungs and brains of patients with COVID-19, correlates with disease severity and is a predictive biomarker for post-COVID-19 cognitive deficits1,5,8-10. Here we show that fibrin binds to the SARS-CoV-2 spike protein, forming proinflammatory blood clots that drive systemic thromboinflammation and neuropathology in COVID-19. Fibrin, acting through its inflammatory domain, is required for oxidative stress and macrophage activation in the lungs, whereas it suppresses natural killer cells, after SARS-CoV-2 infection. Fibrin promotes neuroinflammation and neuronal loss after infection, as well as innate immune activation in the brain and lungs independently of active infection. A monoclonal antibody targeting the inflammatory fibrin domain provides protection from microglial activation and neuronal injury, as well as from thromboinflammation in the lung after infection. Thus, fibrin drives inflammation and neuropathology in SARS-CoV-2 infection, and fibrin-targeting immunotherapy may represent a therapeutic intervention for patients with acute COVID-19 and long COVID.

BACKGROUND: The TROPiCS-02 study (NCT03901339) demonstrated that sacituzumab govitecan (SG) has superior clinical outcomes over treatment of physicians choice (TPC) chemotherapy in patients with hormone receptor-positive, human epidermal growth factor 2 receptor-negative (HR+/HER2-) metastatic breast cancer (mBC). Here, we present health-related quality of life (HRQoL) patient-reported outcome (PRO) findings from this study. PATIENTS AND METHODS: Eligible adults with HR+/HER2- mBC who previously received a taxane, endocrine-based therapy, a CDK4/6 inhibitor, and 2-4 lines of chemotherapy were randomized 1:1 to receive SG or TPC until progression or unacceptable toxicity. PROs were assessed at baseline and on day 1 of each cycle, using the European Organization for Research and Treatment of Cancer Quality-of-Life Core 30 (EORTC QLQ-C30), EQ-5D-5L, and PRO Common Terminology Criteria for Adverse Events (PRO-CTCAE). RESULTS: Compared to TPC, overall least square mean change from baseline was significantly better for SG for physical functioning and dyspnea, but worse for diarrhea. Time to first clinically meaningful worsening or death was significantly longer for SG in global health status/quality of life, physical functioning, fatigue, emotional functioning, dyspnea, insomnia, and financial difficulties of the EORTC QLQ-C30 and the EQ-VAS, but longer for TPC in diarrhea. Few patients in both arms reported experiencing any worsening to level 3 or 4 treatment-related symptomatic events during treatment, as assessed by 16 PRO-CTCAE items, except for diarrhea frequency and amount of hair loss, which favored TPC. CONCLUSIONS: SG was associated with an HRQoL benefit in most symptoms and functioning, compared with TPC. This supports the favorable profile of SG as a treatment option for patients with pretreated HR+/HER2- mBC.

IntroductionAmid recent approvals, early Alzheimer's disease (AD) remains an active area of treatment development.MethodsWe performed a conjoint experiment to compare preferences among 26 patients with mild cognitive impairment for four trial features including designs incorporating active aducanumab-control (vs. placebo), returning tau positron emission tomography (PET) results (vs. no disclosure), remote study partner participation (vs. in person), and increased risk of brain swelling (vs. lower risk). We used a generalized estimating equation to model the utility of factor levels.ResultsReturning tau PET results had the highest utility (est: 0.47; 95% confidence interval [CI]: 0.13, 0.81; P = 0.007); remote study partner participation showed a similar trend (est: 0.29; 95% CI: -0.05, 0.63; P = 0.097). Trials with active-controlled design (est: 0.01; 95% CI: -0.33, 0.35; P = 0.956) did not demonstrate utility and higher risk of brain swelling had negative utility (est: -0.64; 95% CI: -0.99, -0.30; P

BACKGROUND: In the phase 3 EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 study, cemiplimab significantly improved overall survival (OS) versus chemotherapy for patients with recurrent or metastatic cervical cancer who progressed after first-line platinum-based chemotherapy. We present a post hoc subgroup analysis of patients enrolled in Japan. METHODS: Patients were enrolled regardless of programmed cell death-ligand 1 status and randomized 1:1 to cemiplimab 350 mg intravenously every 3 weeks or investigators choice  single-agent chemotherapy for up to 96 weeks. Primary endpoint was OS. Key secondary endpoints were progression-free survival (PFS) and objective response rate (ORR). RESULTS: Overall, 608 patients were randomized, of whom 56 (9.2%) were in Japan (cemiplimab, n = 29; chemotherapy, n = 27). The median (range) duration of follow-up was 13.6 (6.0-25.3) versus 18.2 (6.0-38.2) months for patients in Japan and for the overall population, respectively. Median OS (95% confidence interval [CI]) was 8.4 (7.0-not evaluable) and 9.4 (5.4-14.9) months for cemiplimab versus chemotherapy (hazard ratio [HR]: 0.86; 95% CI: 0.43-1.68). Median PFS (95% CI) was 4.0 (1.4-8.2) versus 3.7 (1.8-4.2) months with cemiplimab and chemotherapy (HR: 0.90; 95% CI: 0.50-1.61), respectively. ORR was 17.2% for cemiplimab and 7.4% for chemotherapy (odds ratio, 2.47; 95% CI, 0.44-13.99). Incidence of treatment-emergent adverse events at any grade was 79.3% for cemiplimab and 100% for chemotherapy. Grade ≥3 adverse events were 37.9% versus 66.7% with cemiplimab and chemotherapy, respectively. DISCUSSION: While acknowledging limitations inherent to a small subgroup analysis, the HR of 0.86 observed in Japanese patients suggests an emerging survival benefit despite a 4.6-month shorter median duration of follow-up versus the overall study population.

BACKGROUND/OBJECTIVES: The phase 3 REGAIN study and its open-label extension demonstrated the efficacy of the complement C5 inhibitor eculizumab in patients with treatment-refractory, acetylcholine receptor antibody-positive generalized myasthenia gravis (gMG). The aim of the ELEVATE study was to assess the effectiveness of eculizumab in clinical practice in adults with MG in the United States. METHODS: A retrospective chart review was conducted in adults with MG who initiated eculizumab treatment between October 23, 2017 and December 31, 2019. Outcomes assessed before and during eculizumab treatment using a pre- versus post-treatment study design included Myasthenia Gravis-Activities of Daily Living (MG-ADL) total scores; minimal symptom expression (MSE); physician impression of clinical change; minimal manifestation status (MMS); and concomitant medication use. RESULTS: In total, 119 patients were included in the study. A significant reduction was observed in mean MG-ADL total score, from 8.0 before eculizumab initiation to 5.4 at 3 months and to 4.7 at 24 months after eculizumab initiation (both p

BackgroundGastric cancer poses a major diagnostic and therapeutic challenge as surgical resection provides the only opportunity for a cure. Specific labeling of gastric cancer could distinguish resectable and nonresectable disease and facilitate an R0 resection, which could improve survival.MethodsTwo patient-derived gastric cancer lines, KG8 and KG10, were established from surgical specimens of two patients who underwent gastrectomy for gastric adenocarcinoma. Harvested tumor fragments were implanted into the greater curvature of the stomach to establish patient-derived orthotopic xenograft (PDOX) models. M5A (humanized anti-CEA antibody) or IgG control antibodies were conjugated with the near-infrared dye IRDye800CW. Mice received 50 µg of M5A-IR800 or 50 µg of IgG-IR800 intravenously and were imaged after 72 hr. Fluorescence imaging was performed by using the LI-COR Pearl Imaging System. A tumor-to-background ratio (TBR) was calculated by dividing the mean fluorescence intensity of the tumor versus adjacent stomach tissue.ResultsM5A-IR800 administration resulted in bright labeling of both KG8 and K10 tumors. In the KG8 PDOX models, the TBR for M5A-IR800 was 5.85 (SE ± 1.64) compared with IgG-IR800 at 0.70 (SE ± 0.17). The K10 PDOX models had a TBR of 3.71 (SE ± 0.73) for M5A-IR800 compared with 0.66 (SE ± 0.12) for IgG-IR800.ConclusionsHumanized anti-CEA (M5A) antibodies conjugated to fluorescent dyes provide bright and specific labeling of gastric cancer PDOX models. This tumor-specific fluorescent antibody is a promising potential clinical tool to detect the extent of disease for the determination of resectability as well as to visualize tumor margins during gastric cancer resection.

Aggregation of protein-based therapeutics can occur during development, production, or storage and can lead to loss of efficacy and potential toxicity. Native mass spectrometry of a covalently linked pentameric monoclonal antibody complex with a mass of ∼800 kDa reveals several distinct conformations, smaller complexes, and abundant higher-order aggregates of the pentameric species. Charge detection mass spectrometry (CDMS) reveals individual oligomers up to the pentamer mAb trimer (15 individual mAb molecules; ∼2.4 MDa) whereas intermediate aggregates composed of 6-9 mAb molecules and aggregates larger than the pentameric dimer (1.6 MDa) were not detected/resolved by standard mass spectrometry, size exclusion chromatography (SEC), capillary electrophoresis (CE-SDS), or by mass photometry. Conventional quadrupole time-of-flight mass spectrometry (QTOF MS), mass photometry, SEC, and CE-SDS did not resolve partially or more fully unfolded conformations of each oligomer that were readily identified using CDMS by their significantly higher extents of charging. Trends in the charge-state distributions of individual oligomers provides detailed insight into how the structures of compact and elongated mAb aggregates change as a function of aggregate size. These results demonstrate the advantages of CDMS for obtaining accurate masses and information about the conformations of large antibody aggregates despite extensive overlapping m/z values. These results open up the ability to investigate structural changes that occur in small, soluble oligomers during the earliest stages of aggregation for antibodies or other proteins.

BACKGROUND: Most patients with metastatic gastroesophageal adenocarcinoma (mGEA) progress on immune checkpoint inhibitors (ICIs). Novel approaches to overcome resistance to ICI in mGEA are needed. Cabozantinib is a multi-tyrosine kinase inhibitor thought to enhance the immunomodulatory effects of ICI. This study evaluated the combination of cabozantinib and pembrolizumab in ICI refractory or resistant mGEA. METHODS: Investigator-initiated, single-arm, single institution, and phase II study in patients with mGEA. Patients had progressed on ICI and/or had PD-L1 CPS score ≤10%. Cabozantinib dose was 40 mg p.o. daily on days 1-21 of a 21-day cycle, with pembrolizumab 200 mg i.v. on day 1. The primary endpoint was progression-free survival at 6 months (PFS-6). RESULTS: Twenty-seven patients were enrolled. Median age 58 years (24-87), female (n = 14), ECOG 0/1 = 13/14, GC/GEJ = 16/11, and non-Hispanic White/Hispanic/Asian = 12/8/7. The primary endpoint was met. After a median follow-up of 31.4 months (range 3.3-42.5), PFS-6 was 22.2% (95% CI 9.0-39.0). The median PFS and OS are 2.3 months (95% CI 1.7-4.1) and 5.5 months (3.1-14.0), respectively. The most common mutations were TP53 (78.3%) and CDH1/PIK3CA/CTNNB1 (17.4% each). The most common grade (G) treatment-related adverse events (TRAE) were diarrhea (25.9%), fatigue (18.5%), hypertension, and muscle cramps (14.8% each). G3-4 TRAE were seen in n = 3 patients (hypertension, thromboembolic event, esophageal perforation; each n = 1). No G5 was observed. CONCLUSIONS: The addition of cabozantinib to pembrolizumab shows clinical benefit in ICI-resistant or refractory mGEA with a tolerable safety profile. (ClinicalTrials.gov Identifier: NCT04164979. IRB Approved: UCI 18-124, University of California Irvine IRB#20195426.).

BackgroundPulmonary ischaemia-reperfusion injury (IRI) is a major contributor to poor lung transplant outcomes. We recently demonstrated a central role of airway-centred natural killer (NK) cells in mediating IRI; however, there are no existing effective therapies for directly targeting NK cells in humans.MethodsWe hypothesised that a depleting anti-CD94 monoclonal antibody (mAb) would provide therapeutic benefit in mouse and human models of IRI based on high levels of KLRD1 (CD94) transcripts in bronchoalveolar lavage samples from lung transplant patients.ResultsWe found that CD94 is highly expressed on mouse and human NK cells, with increased expression during IRI. Anti-mouse and anti-human mAbs against CD94 showed effective NK cell depletion in mouse and human models and blunted lung damage and airway epithelial killing, respectively. In two different allogeneic orthotopic lung transplant mouse models, anti-CD94 treatment during induction reduced early lung injury and chronic inflammation relative to control therapies. Anti-CD94 did not increase donor antigen-presenting cells that could alter long-term graft acceptance.ConclusionsLung transplant induction regimens incorporating anti-CD94 treatment may safely improve early clinical outcomes.

BACKGROUND: Immunotherapy-based combinations have emerged as standard therapies for patients with metastatic renal cell carcinoma (mRCC). Pembrolizumab, a PD-1 inhibitor, combined with epacadostat, an indoleamine 2,3-deoxygenase 1 selective inhibitor, demonstrated promising antitumor activity in a phase 1 study in advanced solid tumors, including mRCC. METHODS: KEYNOTE-679/ECHO-302 was a randomized, open-label, parallel-group, multicenter, phase 3 study (NCT03260894) that compared pembrolizumab plus epacadostat with sunitinib or pazopanib as first-line treatment for mRCC. Eligible patients had histologically confirmed locally advanced or metastatic clear cell RCC and had not received systemic therapy. Patients were randomly assigned 1:1 to pembrolizumab 200 mg IV every 3 weeks plus epacadostat 100 mg orally twice daily versus sunitinib 50 mg orally once daily (4 weeks on treatment followed by 2 weeks off treatment) or pazopanib 800 mg orally once daily. Original dual primary end points were progression-free survival and overall survival. Enrollment was stopped when a phase 3 study in melanoma of pembrolizumab plus epacadostat compared with pembrolizumab monotherapy did not meet its primary end point. This protocol was amended, and primary end point was changed to investigator-assessed objective response rate (ORR) per RECIST 1.1. RESULTS: One-hundred-twenty-nine patients were randomly assigned to receive pembrolizumab plus epacadostat (n = 64) or sunitinib/pazopanib (n = 65). Median (range) follow-up, defined as time from randomization to data cutoff, was 10.3 months (2.2-14.3) and 10.3 months (2.7-13.8) in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. ORRs were similar between pembrolizumab plus epacadostat (31.3% [95% CI 20.2-44.1] and sunitinib/pazopanib (29.2% [18.6-41.8]). Grade 3-5 treatment-related adverse events occurred in 34.4% and 42.9% of patients in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. One patient in the sunitinib/pazopanib arm died of septic shock (not treatment-related). Circulating kynurenine levels decreased in the pembrolizumab plus epacadostat arm, but not to levels observed in healthy subjects. CONCLUSIONS: ORRs were similar between pembrolizumab plus epacadostat and sunitinib/pazopanib as first-line treatment in patients with mRCC. Safety and tolerability appeared similar between treatment arms; no new safety concerns were identified. Antitumor responses observed in patients with RCC receiving pembrolizumab plus epacadostat may be driven primarily by pembrolizumab. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; NCT03260894 .

The ODYSSEY OUTCOMES trial, comprising over 47 000 patient-years of placebo-controlled observation, demonstrated important reductions in the risk of recurrent ischaemic cardiovascular events with the monoclonal antibody to proprotein convertase subtilisin/kexin type 9 alirocumab, as well as lower all-cause death. These benefits were observed in the context of substantial and persistent lowering of low-density lipoprotein cholesterol with alirocumab compared with that achieved with placebo. The safety profile of alirocumab was indistinguishable from matching placebo except for a ∼1.7% absolute increase in local injection site reactions. Further, the safety of alirocumab compared with placebo was evident in vulnerable groups identified before randomization, such as the elderly and those with diabetes mellitus, previous ischaemic stroke, or chronic kidney disease. The frequency of adverse events and laboratory-based abnormalities was generally similar to that in placebo-treated patients. Thus, alirocumab appears to be a safe and effective lipid-modifying treatment over a duration of at least 5 years.

ObjectivePatients with relapsed or metastatic head and neck squamous cell carcinoma (HNSCC) after primary local therapy have low response rates with cetuximab, systemic chemotherapy or check point inhibitor therapy. Novel combination therapies with the potential to improve outcomes for patients with HNSCC is an area of high unmet need.MethodsThis is a phase II single-arm clinical trial of locally advanced or metastatic HNSCC patients treated with a combination of soluble EphB4-human serum albumin (sEphB4-HSA) fusion protein and pembrolizumab after platinum-based chemotherapy with up to 2 prior lines of treatment. The primary endpoints were safety and tolerability and the primary efficacy endpoint was overall response rate (ORR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). HPV status and EphrinB2 expression were evaluated for outcome.ResultsTwenty-five patients were enrolled. Median follow up was 40.4 months (range 9.8 - 40.4). There were 6 responders (ORR 24%). There were 5 responders in the 11 HPV-negative and EphrinB2 positive patients, (ORR 45%) with 2 of these patients achieving a complete response (CR). The median PFS in HPV-negative/EphrinB2 positive patients was 3.2 months (95% CI 1.1, 7.3). Median OS in HPV-negative/EphrinB2 positive patients was 10.9 months (95% CI 2.0, 13.7). Hypertension, transaminitis and fatigue were the most common toxicities.DiscussionThe combination of sEphB4-HSA and pembrolizumab has a favorable toxicity profile and favorable activity particularly among HPV-negative EphrinB2 positive patients with HNSCC.

The randomized, phase 2 GRIFFIN study (NCT02874742) evaluated daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM). We present final post hoc analyses (median follow-up, 49.6 months) of clinically relevant subgroups, including patients with high-risk cytogenetic abnormalities (HRCAs) per revised definition (del[17p], t[4;14], t[14;16], t[14;20], and/or gain/amp[1q21]). Patients received 4 induction cycles (D-RVd/RVd), high-dose therapy/transplant, 2 consolidation cycles (D-RVd/RVd), and lenalidomide±daratumumab maintenance (≤ 2 years). Minimal residual disease-negativity (10-5) rates were higher for D-RVd versus RVd in patients ≥ 65 years (67.9% vs 17.9%), with HRCAs (54.8% vs 32.4%), and with gain/amp(1q21) (61.8% vs 28.6%). D-RVd showed a trend toward improved progression-free survival versus RVd (hazard ratio [95% confidence interval]) in patients ≥ 65 years (0.29 [0.06-1.48]), with HRCAs (0.38 [0.14-1.01]), and with gain/amp(1q21) (0.42 [0.14-1.27]). In the functional high-risk subgroup (not MRD negative at the end of consolidation), the hazard ratio was 0.82 (0.35-1.89). Among patients ≥ 65 years, grade 3/4 treatment-emergent adverse event (TEAE) rates were higher for D-RVd versus RVd (88.9% vs 77.8%), as were TEAEs leading to discontinuation of ≥ 1 treatment component (37.0% vs 25.9%). One D-RVd patient died due to an unrelated TEAE. These results support the addition of daratumumab to RVd in transplant-eligible patients with high-risk NDMM. Video Abstract.

BACKGROUND: Novel noninvasive predictors of disease severity and prognosis in primary sclerosing cholangitis (PSC) are needed. This study evaluated the ability of extracellular matrix remodeling markers to diagnose fibrosis stage and predict PSC-related fibrosis progression and clinical events. METHODS: Liver histology and serum markers of collagen formation (propeptide of type III collagen [Pro-C3], propeptide of type IV collagen, propeptide of type V collagen), collagen degradation (type III collagen matrix metalloproteinase degradation product and type IV collagen matrix metalloproteinase degradation product), and fibrosis (enhanced liver fibrosis [ELF] score and its components [metalloproteinase-1, type III procollagen, hyaluronic acid]) were assessed in samples from baseline to week 96 in patients with PSC enrolled in a study evaluating simtuzumab (NCT01672853). Diagnostic performance for advanced fibrosis (Ishak stages 3-6) and cirrhosis (Ishak stages 5-6) was evaluated by logistic regression and AUROC. Prognostic performance for PSC-related clinical events and fibrosis progression was assessed by AUROC and Wilcoxon rank-sum test. RESULTS: Among 234 patients, 51% had advanced fibrosis and 11% had cirrhosis at baseline. Baseline Pro-C3 and ELF score and its components provided moderate diagnostic ability for discrimination of advanced fibrosis (AUROC 0.73-0.78) and cirrhosis (AUROC 0.73-0.81). Baseline Pro-C3, ELF score, and type III procollagen provided a moderate prognosis for PSC-related clinical events (AUROC 0.70-0.71). Among patients without cirrhosis at baseline, median changes in Pro-C3 and ELF score to week 96 were higher in those with than without progression to cirrhosis (both p < 0.001). CONCLUSIONS: Pro-C3 correlated with fibrosis stage, and Pro-C3 and ELF score provided discrimination of advanced fibrosis and cirrhosis and predicted PSC-related events and fibrosis progression. The results support the clinical utility of Pro-C3 and ELF score for staging and as prognostic markers in PSC.

BACKGROUND: Eculizumab and efgartigimod were approved to treat anti-acetylcholine receptor antibody-positive generalized myasthenia gravis (anti-AChR Ab-positive gMG). These relatively new biological treatments provide a more rapid onset of action and improved efficacy compared with conventional immunosuppressive treatments, but at a higher cost. OBJECTIVE: To assess the cost-effectiveness of eculizumab and, separately, efgartigimod, each added to conventional therapy vs conventional therapy alone, among patients with refractory anti-AChR Ab-positive gMG and those with anti-AChR Ab-positive gMG, respectively. METHODS: A Markov model with 4 health states was developed, evaluating costs and utility with a 4-week cycle length and lifetime time horizon from a health care system perspective and a modified societal perspective including productivity losses from patients and caregiver burden. Model inputs were informed by key clinical trials and relevant publications identified from targeted literature reviews, and drug costs were identified from Micromedex Red Book. Costs and outcomes were discounted at 3% per year. Incremental cost-effectiveness ratios (ICERs; cost per quality-adjusted life-year [QALY] gained) were calculated for each comparison. RESULTS: Among the corresponding populations, lifetime costs and QALYs, respectively, for eculizumab were $5,515,000 and 11.85, and for conventional therapy, $308,000 and 10.29, resulting in an ICER of $3,338,000/QALY gained. For efgartigimod, lifetime costs and QALYs, respectively, were $6,773,000 and 13.22, and for conventional therapy, $322,000 and 9.98, yielding an ICER of $1,987,000/QALY gained. After applying indirect costs in a modified societal perspective, the ICERs were reduced to $3,310,000/QALY gained for eculizumab and $1,959,000/QALY gained for efgartigimod. CONCLUSIONS: Eculizumab and efgartigimod are rapidly acting and effective treatments for myasthenia gravis. However, at their current price, both therapies greatly exceeded common cost-effectiveness thresholds, likely limiting patient access to these therapies.

Sarcospan (SSPN) is a 25-kDa transmembrane protein that is broadly expressed at the cell surface of many tissues, including, but not limited to, the myofibers from skeletal and smooth muscles, cardiomyocytes, adipocytes, kidney epithelial cells, and neurons. SSPN is a core component of the dystrophin-glycoprotein complex (DGC) that links the intracellular actin cytoskeleton with the extracellular matrix. It is also associated with integrin α7β1, the predominant integrin expressed in skeletal muscle. As a tetraspanin-like protein with four transmembrane spanning domains, SSPN functions as a scaffold to facilitate protein-protein interactions at the cell membrane. Duchenne muscular dystrophy, Becker muscular dystrophy, and X-linked dilated cardiomyopathy are caused by the loss of dystrophin at the muscle cell surface and a concomitant loss of the entire DGC, including SSPN. SSPN overexpression ameliorates Duchenne muscular dystrophy in the mdx murine model, which supports SSPN being a viable therapeutic target. Other rescue studies support SSPN as a biomarker for the proper assembly and membrane expression of the DGC. Highly specific and robust antibodies to SSPN are needed for basic research on the molecular mechanisms of SSPN rescue, pre-clinical studies, and biomarker evaluations in human samples. The development of SSPN antibodies is challenged by the presence of its four transmembrane domains and limited antigenic epitopes. To address the significant barrier presented by limited commercially available antibodies, we aimed to generate a panel of robust SSPN-specific antibodies that can serve as a resource for the research community. We created antibodies to three SSPN protein epitopes, including the intracellular N- and C-termini as well as the large extracellular loop (LEL) between transmembrane domains 3 and 4. We developed a panel of rabbit antibodies (poly- and monoclonal) against an N-terminal peptide fragment of SSPN. We used several assays to show that the rabbit antibodies recognize mouse SSPN with a high functional affinity and specificity. We developed mouse monoclonal antibodies against the C-terminal peptide and the large extracellular loop of human SSPN. These antibodies are superior to commercially available antibodies and outperform them in various applications, including immunoblotting, indirect immunofluorescence analysis, immunoprecipitation, and an ELISA. These newly developed antibodies will significantly improve the quality and ease of SSPN detection for basic and translational research.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Sacituzumab govitecan (SG), a first-in-class anti-trophoblast cell surface antigen 2 (Trop-2) antibody-drug conjugate, demonstrated superior efficacy over single-agent chemotherapy (treatment of physicians choice [TPC]) in patients with metastatic triple-negative breast cancer (mTNBC) in the international, multicenter, phase III ASCENT study.Patients were randomly assigned 1:1 to receive SG or TPC until unacceptable toxicity/progression. Final efficacy secondary end point analyses and post hoc analyses of outcomes stratified by Trop-2 expression and human epidermal growth factor receptor 2 status are reported. Updated safety analyses are provided.In this final analysis, SG (n = 267) improved median progression-free survival (PFS; 4.8 v 1.7 months; hazard ratio (HR), 0.41 [95% CI, 0.33 to 0.52]) and median overall survival (OS; 11.8 v 6.9 months; HR, 0.51 [95% CI, 0.42 to 0.63]) over TPC (n = 262). SG improved PFS over TPC in each Trop-2 expression quartile (n = 168); a trend was observed for improved OS across quartiles. Overall, SG had a manageable safety profile, with ≤5% of treatment-related discontinuations because of adverse events and no treatment-related deaths. The safety profile was consistent across all subgroups.These data confirm the clinical benefit of SG over chemotherapy, reinforcing SG as an effective treatment option in patients with mTNBC in the second line or later.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, hyperinflammatory syndrome. Emapalumab, a fully human monoclonal antibody that neutralizes the proinflammatory cytokine interferon gamma, is approved in the United States to treat primary HLH (pHLH) in patients with refractory, recurrent, or progressive disease, or intolerance with conventional HLH treatments. REAL-HLH, a retrospective study, conducted across 33 US hospitals, evaluated real-world treatment patterns and outcomes in patients treated with ≥1 dose of emapalumab between 20 November 2018 and 31 October 2021. In total, 46 patients met the pHLH classification criteria. Median age at diagnosis was 1.0 year (range, 0.3-21.0). Emapalumab was initiated for treating refractory (19/46), recurrent (14/46), or progressive (7/46) pHLH. At initiation, 15 of 46 patients were in the intensive care unit, and 35 of 46 had received prior HLH-related therapies. Emapalumab treatment resulted in normalization of key laboratory parameters, including chemokine ligand 9 (24/33, 72.7%), ferritin (20/45, 44.4%), fibrinogen (37/38, 97.4%), platelets (39/46, 84.8%), and absolute neutrophil count (40/45, 88.9%). Forty-two (91.3%) patients were considered eligible for transplant. Pretransplant survival was 38 of 42 (90.5%). Thirty-one (73.8%) transplant-eligible patients proceeded to transplant, and 23 of 31 (74.2%) of those who received transplant were alive at the end of the follow-up period. Twelve-month survival probability from emapalumab initiation for the entire cohort (N = 46) was 73.1%. There were no discontinuations because of adverse events. In conclusion, results from the REAL-HLH study, which describes treatment patterns, effectiveness, and outcomes in patients with pHLH treated with emapalumab in real-world settings, are consistent with the emapalumab pivotal phase 2/3 pHLH trial.

PURPOSE: To report the results of OPAL (ClinicalTrials.gov identifier: NCT03574779) cohort A, a single-arm substudy of niraparib plus dostarlimab and bevacizumab for the treatment of advanced, platinum-resistant ovarian cancer (PROC). METHODS: Participants with PROC who received 1-2 previous lines of therapy were treated with niraparib (200 or 300 mg once daily), dostarlimab (500 mg once every 3 weeks for four 21-day cycles, followed by 1,000 mg once every 6 weeks), and bevacizumab (15 mg/kg once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1. Safety was also assessed. Exploratory biomarker end points included evaluation of changes in the tumor molecular profile and microenvironment using baseline and on-treatment tumor samples. RESULTS: Of 41 enrolled participants (median age, 66.0 years [range, 37-83 years]), 9.8% had tumors that were BRCA-mutated, 19.5% were homologous recombination (HR)-deficient, and 17.1% were HR repair (HRR)-mutated. As of the cutoff date, all participants discontinued treatment. The ORR was 17.1% (80% CI, 9.8 to 27.0), including one complete response (2.4%); the disease control rate was 73.2% (80% CI, 62.3 to 82.2). Two participants withdrew before first postbaseline scan because of adverse events (AEs). Grade ≥3 treatment-emergent AEs were reported in 92.7% of participants, with the most common being hypertension (26.8%). Response was not correlated with BRCA, HRR, HR deficiency (HRD), or PD-L1 status. Changes suggesting immune activation were observed in on-treatment samples after triplet therapy. CONCLUSION: Results demonstrated modest activity of niraparib, dostarlimab, and bevacizumab in participants with PROC, many of whom had prognostic factors for poor treatment response. Most participants with response were bevacizumab-naïve. No association was found with HRD, BRCA, or PD-L1 status. AEs were consistent with previous monotherapy reports, except that hypertension was reported more frequently.

The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs1-3 and revealed how quickly viral escape can curtail effective options4,5. When the SARS-CoV-2 Omicron variant emerged in 2021, many antibody drug products lost potency, including Evusheld and its constituent, cilgavimab4-6. Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination4 and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign and renew the efficacy of COV2-2130 against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and subsequent variants of concern, and provides protection in vivo against the strains tested: WA1/2020, BA.1.1 and BA.5. Deep mutational scanning of tens of thousands of pseudovirus variants reveals that 2130-1-0114-112 improves broad potency without increasing escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Our computational approach does not require experimental iterations or pre-existing binding data, thus enabling rapid response strategies to address escape variants or lessen escape vulnerabilities.

OBJECTIVE: This study aims to evaluate published clinical trials of ramucirumab to assess the risk/benefit profile and burden over time for patients. BACKGROUND: The burden of oncologic drug development on patients paired with increasing clinical trial failure rates emphasizes the need for reform of drug development. Identifying and addressing patterns of excess burden can guide policy, ensure evidence-based protections for trial participants, and improve medical decision-making. METHODS: On May 25, 2023 a literature search was performed on Pubmed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov for clinical trials using ramucirumab as monotherapy or in combination with other interventions for cancer treatment. Authors screened titles and abstracts for potential inclusion in a masked, duplicate fashion. Following data screening, data was extracted in a masked, duplicate fashion. Trials were classified as positive when meeting their primary endpoint and safety, negative or indeterminate. RESULTS: Ramucirumab was initially approved for gastric cancer but has since been tested in 20 cancers outside of its FDA approved indications. In our analysis of ramucirumab trials, there were a total of 10,936 participants and 10,303 adverse events reported. Gains in overall survival and progression-free survival for patients were 1.5 and 1.2 months, respectively. FDA-approved indications have reported more positive outcomes in comparison to off-label indications. CONCLUSION: We found that FDA-approved indications for ramucirumab had better efficacy outcomes than non-approved indications. However, a concerning number of adverse events were observed across all trials assessed. Participants in ramucirumab randomized controlled trials saw meager gains in overall survival when evaluated against a comparison group. Clinicians should carefully weigh the risks associated with ramucirumab therapy given its toxicity burden and poor survival gains.

BACKGROUND: We report the final results of the randomized phase 2 FIGHT trial that evaluated bemarituzumab, a humanized monoclonal antibody selective for fibroblast growth factor receptor 2b (FGFR2b), plus mFOLFOX6 in patients with FGFR2b-positive (2 + /3 + membranous staining by immunohistochemistry), HER-2-negative gastric or gastroesophageal junction cancer (GC). METHODS: Patients received bemarituzumab (15 mg/kg) or placebo once every 2 weeks with an additional bemarituzumab (7.5 mg/kg) or placebo dose on cycle 1 day 8. All patients received mFOLFOX6. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, and safety. Efficacy was evaluated after a minimum follow-up of 24 months. RESULTS: In the bemarituzumab-mFOLFOX6 (N = 77) and placebo-mFOLFOX6 (N = 78) arms, respectively, 59.7% and 66.7% of patients were FGFR2b-positive in ≥ 10% of tumor cells. The median PFS (95% confidence interval [CI]) was 9.5 months (7.3-13.7) with bemarituzumab-mFOLFOX6 and 7.4 months (5.7-8.4) with placebo-mFOLFOX6 (hazard ratio [HR], 0.72; 95% CI 0.49-1.08); median OS (95% CI) was 19.2 (13.6-24.2) and 13.5 (9.3-15.9) months, respectively (HR 0.77; 95% CI 0.52-1.14). Observed efficacy in FGFR2b-positive GC in ≥ 10% of tumor cells was: PFS: HR 0.43 (95% CI 0.26-0.73); OS: HR 0.52 (95% CI 0.31-0.85). No new safety findings were reported. CONCLUSIONS: In FGFR2b-positive advanced GC, the combination of bemarituzumab-mFOLFOX6 led to numerically longer median PFS and OS compared with mFOLFOX6 alone. Efficacy was more pronounced with FGFR2b overexpression in ≥ 10% of tumor cells. Confirmatory phase 3 trials are ongoing (NCT05052801, NCT05111626). CLINICAL TRIAL REGISTRATION: NCT03694522.

ObjectivesVedolizumab (VDZ) and ustekinumab (UST) are second-line treatments in pediatric patients with ulcerative colitis (UC) refractory to antitumor necrosis factor (anti-TNF) therapy. Pediatric studies comparing the effectiveness of these medications are lacking. Using a registry from ImproveCareNow (ICN), a global research network in pediatric inflammatory bowel disease, we compared the effectiveness of UST and VDZ in anti-TNF refractory UC.MethodsWe performed a propensity-score weighted regression analysis to compare corticosteroid-free clinical remission (CFCR) at 6 months from starting second-line therapy. Sensitivity analyses tested the robustness of our findings to different ways of handling missing outcome data. Secondary analyses evaluated alternative proxies of response and infection risk.ResultsOur cohort included 262 patients on VDZ and 74 patients on UST. At baseline, the two groups differed on their mean pediatric UC activity index (PUCAI) (p = 0.03) but were otherwise similar. At Month 6, 28.3% of patients on VDZ and 25.8% of those on UST achieved CFCR (p = 0.76). Our primary model showed no difference in CFCR (odds ratio: 0.81; 95% confidence interval [CI]: 0.41-1.59) (p = 0.54). The time to biologic discontinuation was similar in both groups (hazard ratio: 1.26; 95% CI: 0.76-2.08) (p = 0.36), with the reference group being VDZ, and we found no differences in clinical response, growth parameters, hospitalizations, surgeries, infections, or malignancy risk. Sensitivity analyses supported these findings of similar effectiveness.ConclusionsUST and VDZ are similarly effective for inducing clinical remission in anti-TNF refractory UC in pediatric patients. Providers should consider safety, tolerability, cost, and comorbidities when deciding between these therapies.

In the MASTER study (NCT03224507), daratumumab+carfilzomib/lenalidomide/dexamethasone (D-KRd) demonstrated promising efficacy in transplant-eligible newly diagnosed multiple myeloma (NDMM). In GRIFFIN (NCT02874742), daratumumab+lenalidomide/bortezomib/dexamethasone (D-RVd) improved outcomes for transplant-eligible NDMM. Here, we present a post hoc analysis of patients with high-risk cytogenetic abnormalities (HRCAs; del[17p], t[4;14], t[14;16], t[14;20], or gain/amp[1q21]). Among 123 D-KRd patients, 43.1%, 37.4%, and 19.5% had 0, 1, or ≥2 HRCAs. Among 120 D-RVd patients, 55.8%, 28.3%, and 10.8% had 0, 1, or ≥2 HRCAs. Rates of complete response or better (best on study) for 0, 1, or ≥2 HRCAs were 90.6%, 89.1%, and 70.8% for D-KRd, and 90.9%, 78.8%, and 61.5% for D-RVd. At median follow-up (MASTER, 31.1 months; GRIFFIN, 49.6 months for randomized patients/59.5 months for safety run-in patients), MRD-negativity rates as assessed by next-generation sequencing (10-5) were 80.0%, 86.4%, and 83.3% for 0, 1, or ≥2 HRCAs for D-KRd, and 76.1%, 55.9%, and 61.5% for D-RVd. PFS was similar between studies and superior for 0 or 1 versus ≥2 HRCAs: 36-month PFS rates for D-KRd were 89.9%, 86.2%, and 52.4%, and 96.7%, 90.5%, and 53.5% for D-RVd. These data support the use of daratumumab-containing regimens for transplant-eligible NDMM with HCRAs; however, additional strategies are needed for ultra-high-risk disease (≥2 HRCAs). Video Abstract.

PURPOSE: Locally advanced/metastatic urothelial cancer (la/mUC) affects patients quality of life (QOL) and functioning. We describe the impact of first-line (1L) enfortumab vedotin (EV) alone or with pembrolizumab (P) on QOL/functioning/symptoms in patients with la/mUC who were cisplatin-ineligible from EV-103 Cohort K. METHODS: In this phase Ib/II trial, patients were randomly assigned 1:1 to EV + P or EV monotherapy (mono). Exploratory patient-reported outcomes (PROs) were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire (EORTC QLQ-C30) and Brief Pain Inventory Short Form (BPI-SF) at baseline, once per week for cycles 1-3, and then in every cycle through the end of treatment. Changes in scores from baseline to week 24, reported as least squares mean (standard error), were assessed by mixed models for repeated measures. There were no formal statistical comparisons between treatment arms. RESULTS: Of 149 patients treated, 65 (EV + P) and 63 (EV mono) comprised the PRO analysis set. For EV + P, EORTC QLQ-C30 QOL was maintained through week 24 with improvements in emotional functioning, pain, and insomnia. Clinically meaningful improvements were seen in EORTC QLQ-C30 pain after EV + P at weeks 12 (-14.41 [3.14]) and 24 (-14.99 [3.56]) and BPI-SF worst pain at week 24 (-2.07 [0.37]). For EV mono, EORTC QLQ-C30 QOL remained stable with clinically meaningful improvements in EORTC QLQ-C30 pain (-12.55 [4.27]), insomnia (-14.46 [4.69]), and constipation (-10.09 [4.35]) at week 24. There were small-to-moderate improvements in BPI-SF worst pain at week 24. CONCLUSION: EV + P in patients with la/mUC who were cisplatin-ineligible was associated with preservation or improvement of QOL/functioning/symptoms. Improvement in pain was seen in both PRO instruments and treatment arms. These data complement clinical outcomes of 1L EV + P.

BACKGROUND: Autologous stem cell transplantation (ASCT) after induction therapy improves disease-free survival for patients with multiple myeloma (MM). While the goal of ASCT is to render a minimal disease state, it is also associated with eradication of immunosuppressive cells, and we hypothesize that early introduction of immunotherapy post-ASCT may provide a window of opportunity to boost treatment efficacy. METHODS: We conducted a phase 1 clinical trial to investigate the application of autologous lymphocyte infusion and anti-SLAMF7 monoclonal antibody, elotuzumab, after ASCT in patients with newly diagnosed MM previously treated with induction therapy. In addition to CD34+ stem cells, peripheral blood mononuclear cells were harvested prior to transplant and infused on day 3 after stem cell infusion to accelerate immune reconstitution and provide autologous natural killer (NK) cells that are essential to the mechanism of elotuzumab. Elotuzumab was administered starting on day 4 and then every 28 days after until 1 year post-ASCT. Cycles 4-12 were administered with standard-of-care lenalidomide maintenance. RESULTS: All subjects were evaluated for safety, and 13 of 15 subjects completed the treatment protocol. At 1 year post-ASCT, the disease status of enrolled subjects was as follows: five stringent complete responses, one complete response, six very good partial responses, one partial response, and two progressive diseases. The treatment plan was well tolerated, with most grade 3 and 4 AEs being expected hematologic toxicities associated with ASCT. Correlative analysis of the immune microenvironment demonstrated a trend toward reduced regulatory T cells during the first 3 months post-transplant followed by an increase in NK cells and monocytes in patients achieving a complete remission. CONCLUSIONS: This phase 1 clinical trial demonstrates that early introduction of immunotherapy after ASCT is well tolerated and shows promising disease control in patients with MM, accompanied by favorable changes in the immune microenvironment. TRIAL REGISTRATION NUMBER: NCT02655458.

BACKGROUND: Pembrolizumab has a manageable safety profile as described in its label, which was primarily based on 2799 patients who participated in clinical trials for melanoma or non-small cell lung cancer. Here, we evaluated the safety of pembrolizumab in a broader population of patients from 31 advanced cancer clinical trials across 19 cancer types. METHODS: Safety was analyzed in patients who received at least one dose of pembrolizumab (200 mg every 3 weeks [Q3W], 10 mg/kg Q2W or Q3W, or 2 mg/kg Q3W). Adverse events (AEs) and immune-mediated AEs and infusion reactions were evaluated. RESULTS: Safety data from 8937 patients in 31 trials of pembrolizumab monotherapy were pooled (median, seven administrations; range, 1-59). Median duration on treatment was 4.1 months (range, 0.03-40.1). AEs occurred in 96.6% of patients. Grade 3-5 AEs occurred in 50.6% of patients. AEs led to pembrolizumab discontinuation in 12.7% of patients and death in 5.9%. Immune-mediated AEs and infusion reactions occurred in 23.7% of patients (4.6% experienced multiple immune-mediated AEs/infusion reactions) and led to pembrolizumab discontinuation in 3.6% and death in 0.2%. Grade 3-5 immune-mediated AEs occurred in 6.3% of patients. Serious immune-mediated AEs and infusion reactions occurred in 6.0% of patients. Median time to immune-mediated AE onset was 85 days (range, 13-163). Of 2657 immune-mediated AEs, 22.3% were initially treated with prednisone ≥ 40 mg/day or equivalent, and 8.3% were initially treated with lower steroid doses. CONCLUSIONS: This pooled analysis of 31 clinical trials showed that pembrolizumab has a consistent safety profile across indications.

WHAT IS THIS SUMMARY ABOUT?: This summary provides the results of a study of two treatments for cancer, enfortumab vedotin and pembrolizumab, that were studied together against locally advanced or metastatic urothelial cancer (la/mUC), a cancer that occurs most commonly in the bladder. WHAT WERE THE RESULTS?: In the 45 patients studied, around 16% did have serious side effects, but most side effects were manageable. Twenty-four percent of patients, however, stopped the study treatment because of their side effects. Within about 2 months of starting treatment, most patients (73%) tumors were smaller and stayed smaller, on average, for more than 2 years. WHAT DO THE RESULTS MEAN?: The combination of enfortumab vedotin plus pembrolizumab is a new treatment option for patients with locally advanced or metastatic urothelial cancer when they cannot receive the typical treatment, cisplatin. Advanced or metastatic urothelial cancer is a type of cancer where the cancer has already spread outside of the bladder or urinary tract.

BACKGROUND: Patients with atopic dermatitis (AD), particularly infants and young children, are at greater risk of developing skin infections. In this study, we assessed infection rates in AD patients aged 6 months to 5 years treated with dupilumab. METHODS: In LIBERTY AD PRESCHOOL, a double-blind, placebo-controlled, phase III clinical trial, children aged 6 months to 5 years with moderate-to-severe AD were randomized 1:1 to subcutaneous dupilumab or placebo, with concomitant low-potency topical corticosteroids, every 4 weeks for 16 weeks. Exposure-adjusted infection rates were used to compare treatment groups. RESULTS: The analysis included 162 patients, of whom 83 received dupilumab and 79 received placebo. Total infection rates were not significantly different between the dupilumab and placebo groups (rate ratio [RR] 0.75, 95% CI 0.48-1.19; p = 0.223). Non-herpetic adjudicated skin infections and bacterial infections were significantly less frequent with dupilumab versus placebo (non-herpetic skin infections: RR 0.46, 95% CI 0.21-0.99; p = 0.047; bacterial infections: RR 0.09, 95% CI 0.01-0.67; p = 0.019), and the number of patients using systemic anti-infective medication was significantly lower in the dupilumab group (RR 0.52, 95% CI 0.30-0.89; p = 0.019). There were no significant differences in the number of herpetic infections between the dupilumab and placebo groups (RR 1.17, 95% CI 0.31-4.35; p = 0.817). The number of patients with two or more infection events was significantly higher in the placebo group (RR 0.29, 95% CI 0.12-0.68; p = 0.004), and no severe or serious infections (including eczema herpeticum) were observed among patients receiving dupilumab. CONCLUSIONS: These data suggest that dupilumab treatment in infants and children younger than 6 years with AD does not increase overall risk of infections and is associated with a reduced risk of bacterial and non-herpetic skin infections compared with placebo, resulting in a reduced need for anti-infective medication. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov with ID number NCT03346434 on November 17, 2017. INFOGRAPHIC.

BackgroundCentral nervous system (CNS) WHO grade 2 low-grade glioma (LGG) patients are at high risk for recurrence and with unfavorable long-term prognosis due to the treatment resistance and malignant transformation to high-grade glioma. Considering the relatively intact systemic immunity and slow-growing nature, immunotherapy may offer an effective treatment option for LGG patients.MethodsWe conducted a prospective, randomized pilot study to evaluate the safety and immunological response of the multipeptide IMA950 vaccine with agonistic anti-CD27 antibody, varlilumab, in CNS WHO grade 2 LGG patients. Patients were randomized to receive combination therapy with IMA950 + poly-ICLC and varlilumab (Arm 1) or IMA950 + poly-ICLC (Arm 2) before surgery, followed by adjuvant vaccines.ResultsA total of 14 eligible patients were enrolled in the study. Four patients received pre-surgery vaccines but were excluded from postsurgery vaccines due to the high-grade diagnosis of the resected tumor. No regimen-limiting toxicity was observed. All patients demonstrated a significant increase of anti-IMA950 CD8+ T-cell response postvaccine in the peripheral blood, but no IMA950-reactive CD8+ T cells were detected in the resected tumor. Mass cytometry analyses revealed that adding varlilumab promoted T helper type 1 effector memory CD4+ and effector memory CD8+ T-cell differentiation in the PBMC but not in the tumor microenvironment.ConclusionThe combinational immunotherapy, including varlilumab, was well-tolerated and induced vaccine-reactive T-cell expansion in the peripheral blood but without a detectable response in the tumor. Further developments of strategies to overcome the blood-tumor barrier are warranted to improve the efficacy of immunotherapy for LGG patients.

BACKGROUND: The combination of monalizumab (anti-NKG2A/CD94) and durvalumab (anti-programmed death ligand-1) may promote antitumor immunity by targeting innate and adaptive immunity. This phase 1/2 study of monalizumab and durvalumab evaluated safety, antitumor activity, and pharmacodynamics in patients with advanced solid tumors. MAIN BODY: Immunotherapy-naïve patients aged ≥18 years with advanced disease, Eastern Cooperative Oncology Group performance status of 0-1, and 1-3 prior lines of systemic therapy in the recurrent/metastatic setting were enrolled. In part 1 (dose escalation), patients received durvalumab 1500 mg every 4 weeks (Q4W) with increasing doses of monalizumab Q2W/Q4W (n=15). Dose expansion in part 1 included patients with cervical cancer (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W) or metastatic microsatellite stable (MSS)-colorectal cancer (CRC) (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q4W). In part 2 (dose expansion), patients with MSS-CRC (n=40), non-small cell lung cancer (NSCLC; n=20), MSS-endometrial cancer (n=40), or ovarian cancer (n=40) received durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W. The primary endpoint was safety. Secondary endpoints included antitumor activity per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). Exploratory analyses included assessment of T-cell and natural killer (NK) cell activation and proliferation in peripheral blood and the tumor microenvironment (TME). The study enrolled 185 patients (part 1, 45; part 2, 140). No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. In part 2, the most common treatment-related adverse events were fatigue (12.1%), asthenia (9.3%), diarrhea (9.3%), pruritus (7.9%), and pyrexia (7.1%). In the expansion cohorts, response rates were 0% (cervical), 7.7% (MSS-CRC), 10% (NSCLC), 5.4% (ovarian), and 0% (MSS-endometrial). Sustained NK cell activation, CD8+ T-cell proliferation, increased serum levels of CXCL10 (C-X-C motif chemokine ligand 10) and CXCL11, and increased tumor infiltration of CD8+ and granzyme B+ cells were observed. CONCLUSIONS: Although efficacy was modest, monalizumab plus durvalumab was well tolerated and encouraging immune activation was observed in the peripheral blood and TME. TRIAL REGISTRATION NUMBER: NCT02671435.

Open-label extension (OLE) studies help inform long-term safety and efficacy of disease-modifying therapies in multiple sclerosis (MS). We report exploratory analyses from a phase 2 trial on the longest follow-up to date of ocrelizumab-treated patients with relapsing-remitting MS (RRMS). The primary treatment period (PTP) comprised four 24-week treatment cycles; participants were randomized to double-blind ocrelizumab (2000 mg or 600 mg), placebo, or interferon β-1a (open label) for one cycle, then dose-blinded ocrelizumab 1000 mg or 600 mg for the remaining cycles. The PTP was followed by consecutive assessed and unassessed treatment-free periods (TFPs) and then the OLE (ocrelizumab 600 mg every 24 weeks). Safety and efficacy were prospectively assessed. Of 220 participants randomized, 183 (84%) completed the PTP. After the TFP, 103 entered OLE (median OLE ocrelizumab exposure 6.5 years). Most common adverse events across all periods were infusion-related reactions. MRI activity, annualized relapse rate, and confirmed disability progression (CDP) rates remained low throughout. During the assessed TFP, there was a trend toward less and later B-cell repletion, and later CDP, for patients randomized to ocrelizumab; MRI activity was observed in 16.3% of patients, the earliest 24 weeks after the last ocrelizumab dose. This is the longest follow-up of ocrelizumab-treated patients with RRMS, with no new safety signals emerging during an observation period from 2008 to 2020. Results reinforce the sustained efficacy of long-term ocrelizumab. Reduced disease activity was maintained following interruption of 6-month dosing cycles, with no evidence of rebound.

PURPOSE: Biosimilar tumor necrosis factor inhibitors (b-TNFi) reduce healthcare costs and maintain equal efficacy when compared to their originator counterparts (o-TNFi). Current practice is to start patients on a slower standard infusion rate during the initial transition from an o-TNFi to a b-TNFi. There is a knowledge gap around switching from rapid originator infusion to rapid biosimilar infusion in the pediatric inflammatory bowel disease (IBD) population. SUMMARY: We present a case series of 8 pediatric patients with IBD who were switched from a rapid-infusion o-TNFi to a rapid-infusion b-TNFi from 2016 through 2022. Our primary interest was safety, which we evaluated based on the occurrence of infusion reactions or need for new premedications within the first 6 months of starting a b-TNFi. We also examined effectiveness through the incidence of IBD-related hospitalizations, TNFi failure, and need for co-medication or dose escalation over the same period. In our cohort, 4 patients had Crohns disease and 4 had ulcerative colitis. All patients were switched to a biosimilar for nonmedical reasons. During the follow-up period, no patients had infusion reactions necessitating new premedications, serious adverse events, or medication nonresponse. CONCLUSION: Patients who directly transitioned from a rapid-infusion o-TNFi to a rapid-infusion b-TNFi did not experience serious adverse events. Given the fiscal and patient experience advantages of rapid-rate infusions, larger studies are needed to consider a change in practice.

Considering the lack of consensus related to the impact of selective IL-6 receptor inhibition on bone remodeling and the scarcity of reports, especially on large bone defects, this study proposed to evaluate the biological impact of the selective inhibitor of interleukin-6 receptor (tocilizumab) in an experimental model of critical calvarial defect in rats. In this preclinical and in vivo study, 24 male Wistar rats were randomly divided into two groups (n=12/group): defect treated with collagen sponge (CG) and defect treated with collagen sponge associated with 2 mg/kg tocilizumab (TCZ). The defect in the parietal bone was created using an 8-mm diameter trephine drill. After 90 days, the animals were euthanized, and tissue samples (skull caps) were evaluated through micro-CT, histological, immunohistochemistry, cytokines, and RT-qPCR analyses. Tocilizumab reduced mononuclear inflammatory infiltration (P0.05). The bone cells (osteoblasts, osteoclasts, and osteocytes) in the defect area were similar in both groups (P>0.05). Tocilizumab reduced inflammatory cytokines, decreased osteogenic protein, and increased proteases in a critical bone defect in rats. Ninety days after the local application of tocilizumab in the cranial defect, we did not find a significant formation of bone tissue compared with a collagen sponge.

BACKGROUND: Converging evidence suggests that markers of Alzheimers disease (AD) pathology in cognitively unimpaired older individuals are associated with high risk of cognitive decline and progression to functional impairment. The Anti-Amyloid Treatment in Asymptomatic Alzheimers disease (A4) and Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) Studies enrolled a large cohort of cognitively normal older individuals across a range of baseline amyloid PET levels. Recent advances in AD blood-based biomarkers further enable the comparison of baseline markers in the prediction of longitudinal clinical outcomes. OBJECTIVES: We sought to evaluate whether biomarker indicators of higher levels of AD pathology at baseline predicted greater cognitive and functional decline, and to compare the relative predictive power of amyloid PET imaging, tau PET imaging, and a plasma P-tau217 assay. DESIGN: All participants underwent baseline amyloid PET scan, plasma P-tau217; longitudinal cognitive testing with the Primary Alzheimer Cognitive Composite (PACC) every 6 months; and annual functional assessments with the clinical dementia rating (CDR), cognitive functional index (CFI), and activities of daily living (ADL) scales. Baseline tau PET scans were obtained in a subset of participants. Participants with elevated amyloid (Aβ+) on screening PET who met inclusion/exclusion criteria were randomized to receive placebo or solanezumab in a double-blind phase of the A4 Study over 240+ weeks. Participants who did not have elevated amyloid (Aβ-) but were otherwise eligible for the A4 Study were referred to the companion observational LEARN Study with the same outcome assessments over 240+ weeks. SETTING: The A4 and LEARN Studies were conducted at 67 clinical trial sites in the United States, Canada, Japan and Australia. PARTICIPANTS: Older participants (ages 65-85) who were cognitively unimpaired at baseline (CDR-GS=0, MMSE 25-30 with educational adjustment, and Logical Memory scores within the normal range LMIIa 6-18) were eligible to continue in screening. Aβ+ participants were randomized to either placebo (n=583) or solanezumab (n=564) in the A4 Study. A subset of Aβ+ underwent tau PET imaging in A4 (n=350). Aβ- were enrolled into the LEARN Study (n=553). MEASUREMENTS: Baseline 18-F Florbetapir amyloid PET, 18-F Flortaucipir tau PET in a subset and plasma P-tau217 with an electrochemiluminescence (ECL) immunoassay were evaluated as predictors of cognitive (PACC), and functional (CDR, CFI and ADL) change. Models were evaluated to explore the impact of baseline tertiles of amyloid PET and tertiles of plasma P-tau217 on cognitive and functional outcomes in the A4 Study compared to LEARN. Multivariable models were used to evaluate the unique and common variance explained in longitudinal outcomes based on baseline predictors, including effects for age, gender, education, race/ethnic group, APOEε4 carrier status, baseline PACC performance and treatment assignment in A4 participants (solanezumab vs placebo). RESULTS: Higher baseline amyloid PET CL and P-tau217 levels were associated with faster rates of PACC decline, and increased likelihood of progression to functional impairment (CDR 0.5 or higher on two consecutive measurements), both across LEARN Aβ- and A4 Aβ+ (solanezumab and placebo arms). In analyses considering all baseline predictor variables, P-tau217 was the strongest predictor of PACC decline. Among participants in the highest tertiles of amyloid PET or P-tau217, >50% progressed to CDR 0.5 or greater. In the tau PET substudy, neocortical tau was the strongest predictor of PACC decline, but plasma P-tau217 contributed additional independent predictive variance in commonality variance models. CONCLUSIONS: In a large cohort of cognitively unimpaired individuals enrolled in a Phase 3 clinical trial and companion observational study, these findings confirm that higher baseline levels of amyloid and tau markers are associated with increased rates of cognitive decline and progression to functional impairment. Interestingly, plasma P-tau217 was the best predictor of decline in the overall sample, superior to baseline amyloid PET. Neocortical tau was the strongest predictor of cognitive decline in the subgroup with tau PET, suggesting that tau deposition is most closely linked to clinical decline. These findings indicate that biomarkers of AD pathology are useful to predict decline in an older asymptomatic population and may prove valuable in the selection of individuals for disease-modifying treatments.

BACKGROUND: The Anti-Amyloid in Asymptomatic Alzheimers Disease (A4) Study failed to show a treatment benefit with solanezumab, but the longitudinal consequences of elevated amyloid were observed in study participants with objective decline on the Preclinical Alzheimer Cognitive Composite (PACC) and subjective decline on the combined Cognitive Function Index (participant + study partner CFI), during the trial period. OBJECTIVES: We sought to expand on previous findings by comparing longitudinal patterns of participant and study partner CFI separately and their associations with the PACC stratified by baseline amyloid tertile over the course of the A4 Study. DESIGN: Cognitively unimpaired older adult participants and their study partners were independently administered the CFI at screen prior to amyloid PET disclosure and then at 3 subsequent visits (week 48, week 168, week 240) of the study. PACC collected at visits concurrent with CFI administration were also examined longitudinally. SETTING: The A4 Study was conducted at 67 sites in Australia, Canada, Japan, and the United States. PARTICIPANTS: 1,147 participants with elevated amyloid based on florbetapir PET were enrolled in the A4 Study and included in these analyses. 583 were on placebo and 564 were treated with solanezumab. MEASUREMENTS: The PACC was used to assess objective cognitive performance and the CFI was used to assess change in everyday cognitive functioning by the participant and their study partner independently. Amyloid level was characterized by Centiloid tertiles (77.2 CL). Participants were aware of their elevated amyloid status, but not their CL tertile, or specific level of amyloid. Longitudinal correlations between participant and study partner CFI and PACC were examined at all visits where assessments were available. The impact of baseline amyloid tertile on CFI and PACC associations was also examined. RESULTS: Both participant and study partner CFI increased over the duration of the study indicating worsening cognitive functioning. Results did not differ by treatment group. The association between higher CFI and worse PACC for both for participant and study partner became progressively stronger over the course of the study. PACC had a significantly higher correlation with study partner CFI than with participant CFI by week 168. The stronger correlations between study partner CFI and PACC were driven by those in the highest amyloid tertile. CONCLUSION: Both participant and study partner report captured subtle changes in everyday cognitive functioning for participants with biomarker confirmed and disclosed preclinical AD. Moreover, study partner report was most highly aligned with cognitive decline, particularly among those with the highest amyloid load.

The current third-line (and beyond) treatment options for RAS-mutant metastatic colorectal cancer have yielded limited efficacy. At the time of study start, the combination of sotorasib, a KRAS (Kirsten rat sarcoma viral oncogene homolog)-G12C inhibitor, and panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, was hypothesized to overcome treatment-induced resistance. This phase 1b substudy of the CodeBreaK 101 master protocol evaluated sotorasib plus panitumumab in patients with chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. Here, we report the results in a dose-exploration cohort and a dose-expansion cohort. Patients received sotorasib (960 mg, once daily) plus panitumumab (6 mg kg-1, once every 2 weeks). The primary endpoints were safety and tolerability. Secondary endpoints included efficacy and pharmacokinetics. Exploratory biomarkers at baseline were assessed. Forty-eight patients (dose-exploration cohort, n = 8; dose-expansion cohort, n = 40) were treated. Treatment-related adverse events of any grade and grade ≥3 occurred in 45 (94%) and 13 (27%) patients, respectively. In the dose-expansion cohort, the confirmed objective response rate was 30.0% (95% confidence interval (CI) 16.6%, 46.5%). Median progression-free survival was 5.7 months (95% CI 4.2, 7.7 months). Median overall survival was 15.2 months (95% CI 12.5 months, not estimable). Prevalent genomic coalterations included APC (84%), TP53 (74%), SMAD4 (33%), PIK3CA (28%) and EGFR (26%). Sotorasib-panitumumab demonstrated acceptable safety with promising efficacy in chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. ClinicalTrials.gov identifier: NCT04185883 .

BackgroundPatients with multiple myeloma are immunosuppressed due to both the disease itself and immunosuppressive therapies. Thus, when presenting with respiratory failure and pulmonary opacities, pneumonia must be considered. However, while rare, immunomodulating medications used in the treatment of multiple myeloma can also cause potentially life-threatening respiratory failure, a distinction which has important treatment implications.Case presentationAn 80-year-old male with recently diagnosed multiple myeloma undergoing treatment with lenalidomide and daratumumab presented with acute, rapidly progressive hypoxic respiratory failure ultimately requiring intubation and mechanical ventilatory support. Imaging revealed bilateral pulmonary opacities, however infectious workup was negative, and he was ultimately diagnosed with lenalidomide-induced interstitial pneumonitis, a rare but serious adverse effect of this medication. He was treated with drug discontinuation and methylprednisolone, and quickly recovered.ConclusionLenalidomide is an immunomodulating medication used in the treatment of multiple myeloma, and is associated with rare but serious cases of drug-induced interstitial pneumonitis. Thus, if a patient receiving lenalidomide develops shortness of breath and/or hypoxia, drug-induced pneumonitis must be on the differential. Permanent drug discontinuation with or without corticosteroids is the mainstay of treatment, and patients are often able to fully recover, underscoring the need for early recognition of this condition.

Understanding factors that affect the clustering and association of antibodies molecules in solution is critical to their development as therapeutics. For 19 different monoclonal antibody (mAb) solutions, we measured the viscosities, the second virial coefficients, the Kirkwood-Buff integrals, and the cluster distributions of the antibody molecules as functions of protein concentration. Solutions were modeled using the statistical-physics Wertheim liquid-solution theory, representing antibodies as Y-shaped molecular structures of seven beads each. We found that high-viscosity solutions result from more antibody molecules per cluster. Multi-body properties such as viscosity are well predicted experimentally by the 2-body Kirkwood-Buff quantity, G22, but not by the second virial coefficient, B22, and well-predicted theoretically from the Wertheim protein-protein sticking energy. Weakly interacting antibodies are rate-limited by nucleation; strongly interacting ones by propagation. This approach gives a way to relate micro to macro properties of solutions of associating proteins.

The continuing mutability of the SARS-CoV-2 virus can result in failures of diagnostic assays. To address this, we describe a generalizable bioinformatics-to-biology pipeline developed for the calibration and quality assurance of inactivated SARS-CoV-2 variant panels provided to Radical Acceleration of Diagnostics programs (RADx)-radical program awardees. A heuristic genetic analysis based on variant-defining mutations demonstrated the lowest genetic variance in the Nucleocapsid protein (Np)-C-terminal domain (CTD) across all SARS-CoV-2 variants. We then employed the Shannon entropy method on (Np) sequences collected from the major variants, verifying the CTD with lower entropy (less prone to mutations) than other Np regions. Polyclonal and monoclonal antibodies were raised against this target CTD antigen and used to develop an Enzyme-linked immunoassay (ELISA) test for SARS-CoV-2. Blinded Viral Quality Assurance (VQA) panels comprised of UV-inactivated SARS-CoV-2 variants (XBB.1.5, BF.7, BA.1, B.1.617.2, and WA1) and distractor respiratory viruses (CoV 229E, CoV OC43, RSV A2, RSV B, IAV H1N1, and IBV) were assembled by the RADx-rad Diagnostics core and tested using the ELISA described here. The assay tested positive for all variants with high sensitivity (limit of detection: 1.72-8.78 ng/mL) and negative for the distractor virus panel. Epitope mapping for the monoclonal antibodies identified a 20 amino acid antigenic peptide on the Np-CTD that an in-silico program also predicted for the highest antigenicity. This work provides a template for a bioinformatics pipeline to select genetic regions with a low propensity for mutation (low Shannon entropy) to develop robust 'pan-variant' antigen-based assays for viruses prone to high mutational rates.

To mitigate the loss of lives during the COVID-19 pandemic, emergency use authorization was given to several anti-SARS-CoV-2 monoclonal antibody (mAb) therapies for the treatment of mild-to-moderate COVID-19 in patients with a high risk of progressing to severe disease. Monoclonal antibodies used to treat SARS-CoV-2 target the spike protein of the virus and block its ability to enter and infect target cells. Monoclonal antibody therapy can thus accelerate the decline in viral load and lower hospitalization rates among high-risk patients with variants susceptible to mAb therapy. However, viral resistance has been observed, in some cases leading to a transient viral rebound that can be as large as 3-4 orders of magnitude. As mAbs represent a proven treatment choice for SARS-CoV-2 and other viral infections, evaluation of treatment-emergent mAb resistance can help uncover underlying pathobiology of SARS-CoV-2 infection and may also help in the development of the next generation of mAb therapies. Although resistance can be expected, the large rebounds observed are much more difficult to explain. We hypothesize replenishment of target cells is necessary to generate the high transient viral rebound. Thus, we formulated two models with different mechanisms for target cell replenishment (homeostatic proliferation and return from an innate immune response antiviral state) and fit them to data from persons with SARS-CoV-2 treated with a mAb. We showed that both models can explain the emergence of resistant virus associated with high transient viral rebounds. We found that variations in the target cell supply rate and adaptive immunity parameters have a strong impact on the magnitude or observability of the viral rebound associated with the emergence of resistant virus. Both variations in target cell supply rate and adaptive immunity parameters may explain why only some individuals develop observable transient resistant viral rebound. Our study highlights the conditions that can lead to resistance and subsequent viral rebound in mAb treatments during acute infection.

IntroductionGastric cancer poses a major therapeutic challenge. Improved visualization of tumor margins at the time of gastrectomy with fluorescent tumor-specific antibodies could improve outcomes. The present report demonstrates the potential of targeting gastric cancer with a humanized anti-carcinoembryonic antigen (CEA) antibody in orthotopic mouse models.MethodsMKN45 cells were injected subcutaneously into nude mice to establish xenograft models. Tumor fragments collected from subcutaneous models were then implanted into the greater curvature of the stomach to establish orthotopic models. For tumor labeling, a humanized anti-CEA antibody (M5A) and IgG as a control, were conjugated with the near-infrared dye IRDye800CW. Time (24-72 h) and dose (50-100 μg) response curves were performed in subcutaneous models. Orthotopic models received 50 μg of M5A-IR800 or 50 μg IgG-IR800 as a control and were imaged after 72 h. Fluorescence imaging was performed on the mice using the LI-COR Pearl Imaging System.ResultsIn subcutaneous models, tumor to background ratios (TBRs) reached 8.85 at 72 h. Median TBRs of orthotopic model primary tumors were 6.25 (interquartile range [IQR] 6.03-7.12) for M5A-IR800 compared to 0.42 (IQR 0.38-0.54) for control. Abdominal wall metastasis median TBRs were 13.52 (IQR 12.79-13.76) for M5A-IR800 and 3.19 (IQR 2.65-3.73) for the control. Immunohistochemistry confirmed CEA expression within tumors.ConclusionsHumanized anti-CEA antibodies conjugated to near-infrared dyes provide specific labeling of gastric cancers in mouse models. Orthotopic models demonstrated bright and specific labeling with TBRs greater than ten times that of control. This tumor-specific fluorescent antibody is a promising potential clinical tool for improving visualization of gastric cancer margins at time of surgical resection.

BackgroundZilovertamab is a humanized monoclonal antibody targeting ROR1, an onco-embryonic antigen expressed by malignant cells of a variety of solid tumors, including breast cancer. A prior phase 1 study showed that zilovertamab was well tolerated and effective in inhibiting ROR1-signaling, which leads to activation of ERK1/2, NF-κB, and NRF2 target genes. This phase 1b study evaluated the safety and tolerability of zilovertamab with paclitaxel in patients with advanced breast cancer.Patients and methodsEligible patients had locally advanced, unresectable, or metastatic HER2- breast cancer with Eastern Cooperative Group performance status of 0-2 and without prior taxane therapy in the advanced setting. Study treatment included 600 mg of zilovertamab administered intravenously (IV) on Days 1 and 15 of Cycle 1 and then Day 1 of each 28-day cycle along with paclitaxel weekly at 80 mg/m2 IV.ResultsStudy patients had received a median of 4 prior therapies (endocrine therapy + chemotherapy) for locally advanced, unresectable, or metastatic disease. No patient discontinued therapy due to toxicity ascribed to zilovertamab. Adverse events were consistent with the known safety profile of paclitaxel. Of 16 patients, 6 (38%) had a partial response, and 6/16 (38%) patients had stable disease as best tumor response.ConclusionThe combination of zilovertamab and paclitaxel was safe and well tolerated in heavily pre-treated advanced breast cancer patients. Further evaluation of ROR1 targeting in breast cancer patients with zilovertamab is warranted.Trial registrationNCT02776917. Registered on ClinicalTrials.gov on 05/17/2016.

ObjectivesImmunotherapy with immune checkpoint inhibitors has shown only limited success in the management of metastatic soft tissue sarcoma. Overall response rates (ORR) with single agent pembrolizumab were 18% and median PFS was 18 weeks on the clinical trial SARC028. One strategy to improve the responses to immunotherapy is with stereotactic body radiation therapy (SBRT), which can enhance the antitumor CD8 T cell response through the release of tumor-specific antigens, potentially priming a more diverse class of T cell receptors.MethodsThis is a phase 0, pilot prospective study taking place at a single center with 2 arms. In Arm A, patients are treated with pembrolizumab 400 mg IV infusion on day 1 of a 42-day cycle. Stereotactic body radiation therapy (SBRT) is delivered in 1-5 fractions starting on C1D15-28 and given every other day. In Arm B, patients who have started an immune checkpoint inhibitor within 60 days are treated with SBRT in addition to the current therapy.ResultsIn this study we outline testing the feasibility of adding SBRT to pembrolizumab.ConclusionThe ultimate goal of combination therapy is improved overall response, including tumors not treated with SBRT. This trial can be found registered online: NCT05488366.

The clinical success of immune checkpoint inhibitors has underscored the key role of the immune system in controlling cancer. Current FDA-approved immune checkpoint inhibitors target the regulatory receptor pathways of cytotoxic T-cells to enhance their anticancer responses. Despite an abundance of evidence that natural killer (NK) cells can also mediate potent anticancer activities, there are no FDA-approved inhibitors targeting NK cell specific checkpoint pathways. Lirilumab, the most clinically advanced NK cell checkpoint inhibitor, targets inhibitory killer immunoglobulin-like receptors (KIRs), however it has yet to conclusively demonstrate clinical efficacy. Here we describe the crystal structure of lirilumab in complex with the inhibitory KIR2DL3, revealing the precise epitope of lirilumab and the molecular mechanisms underlying KIR checkpoint blockade. Notably, the epitope includes several key amino acids that vary across the human population, and binding studies demonstrate the importance of these amino acids for lirilumab binding. These studies reveal how KIR variations in patients could influence the clinical efficacy of lirilumab and reveal general concepts for the development of immune checkpoint inhibitors targeting NK cells.

A 10‐year‐old female neutered Labrador Retriever presented with epistaxis, discoloration and crusting of the nose and a necrotic lesion on the lip. Bloodwork revealed pancytopenia, azotemia, hypoalbuminemia and hyperglobulinemia. Aggregates of amorphous basophilic material were seen in a room‐temperature blood smear which were not present in the sample after warming to 37°C, and grossly a cryoprecipitate was noted in the patient's serum at 4°C. This was interpreted as cryoglobulin. Computed tomography showed multiple heterogeneous lesions in the spleen. Cytology of the splenic lesions revealed marked plasma cell infiltration, consistent with neoplasia. Bone marrow aspiration revealed an increased proportion of plasma cells (approximately 38% of the total cells). Serum protein electrophoresis showed a monoclonal spike in the gamma globulin region. A diagnosis of multiple myeloma associated with cryoglobulinemia was made. The patient received palliative care with prednisolone while the owner was considering chemotherapy. However, she rapidly deteriorated and was euthanized. The combination of cryoglobulin precipitation and hyperviscosity syndrome was considered responsible for the patient's original symptoms. Cryoglobulinemia is an extremely rare phenomenon that is often associated with lymphoproliferative disorders. This report describes its association with multiple myeloma in a dog presenting with atypical initial signs. [ABSTRACT FROM AUTHOR]

Introduction: The Nucala Effectiveness Study (NEST) assessed the effectiveness of mepolizumab in patients with severe asthma (SA) in countries previously underrepresented in real-world studies. Methods: A multi-country, bi-directional, self-controlled, observational cohort study conducted in Colombia, Chile, India, Türkiye, Saudi Arabia, United Arab Emirates, Kuwait, Oman, and Qatar. Historical and/or prospective data from patients with SA were assessed 12 months pre- and post-mepolizumab initiation. Primary endpoint: incident rate ratio (IRR) of clinically significant exacerbations (CSEs). Key secondary endpoints: healthcare resource utilisation (HCRU), oral corticosteroid (OCS) use, lung function and symptom control (Asthma Control Test [ACT] scores). Results: Overall, 525 patients with SA burden pre-initiation (geometric mean blood eosinophil count [BEC] 490.7 cells/µl; 31.4% prior biologic use; 37.3% obese) received at least one dose of mepolizumab 100 mg subcutaneously. Post-initiation, a significant reduction in CSEs was observed (76% [p < 0.001]; IRR [95% confidence interval] 0.24 [0.19–0.30]); 72.0% of patients had no CSEs. Mepolizumab treatment led to a reduction in OCS use (52.8% pre-initiation vs. 16.6% post-initiation) and a mean (standard deviation [SD]) change in OCS dose of − 18.1 (20.7) mg post-initiation; 36.1% of patients became OCS-free. Fewer patients were hospitalised post-initiation (22.5% pre-initiation vs. 6.9% post-initiation). Improvements in mean (SD) forced expiratory volume in 1 s (62.8 [20.2]% pre-initiation vs. 73.0 [22.7]% post-initiation) and ACT scores (15.0% pre-initiation vs. 64.5% of patients post-initiation with well-controlled asthma) were observed. Proportion of patients with BEC ≥ 500 cells/µl decreased from 84.4% pre-initiation to 18.1% post-initiation. Conclusion: Mepolizumab was effective in reducing the burden of SA by significantly reducing CSEs, reducing OCS use and HCRU, and improving lung function and asthma control, which could translate to improvements in health-related quality of life in patients with SA and high OCS dependency in the countries studied. A graphical abstract is available with this article. Plain Language Summary: Severe asthma occurs when asthma symptoms remain uncontrolled despite optimised treatment. In many low-middle income countries, and in some countries in the Middle East, Asia, Latin America and the Arab Gulf, the management and treatment of patients with severe asthma remain poor, with many patients having unscheduled hospital visits or admission, and use of steroids for a prolonged period. Mepolizumab is an injectable monoclonal antibody approved as an add-on treatment for severe asthma in patients ≥ 6 years of age. In clinical trials, mepolizumab has demonstrated reductions in the risk of clinically significant exacerbations (CSE; an asthma exacerbation that requires systemic corticosteroids and/or an emergency room visit and/or hospitalisation) and the need for oral corticosteroid (OCS) treatment in patients with severe asthma by reducing inflammation caused by eosinophil (a type of white blood cell) production. The Nucala Effectiveness Study (NEST) was performed to observe the effectiveness of mepolizumab in people with severe asthma in Colombia, Chile, India, Turkey, Saudi Arabia, United Arab Emirates, Kuwait, Oman and Qatar. The frequency of CSEs and other outcomes was compared 12 months pre- and post-mepolizumab initiation. Post-initiation, the risk of CSEs was significantly reduced by 76% (p < 0.001), and 72% of patients had no CSEs. Fewer patients were dependent on OCS, with 36.1% of patients not using OCS at all, and fewer patients were hospitalised. Lung function and asthma control also improved. NEST shows that mepolizumab could benefit people with severe asthma living in countries where disease-related burden and OCS use remain high. [ABSTRACT FROM AUTHOR]