Incyte (United States)

N/A

Atopic dermatitis is a common disease that afflicts millions but is still diagnosed and treated in many cases by scoring and treatment by trial-and-error. We carried out a clinical study employing non-invasive multiphoton microscopy alongside spatial transcriptomic analysis with the goal of correlating in vivo imaging spatial parameters with gene expression analysis. The study found numerous strong correlations and tantalizingly demonstrated non-invasive multiphoton imaging capable of predicting spatial transcriptomic alterations.

186 Background: INCA33890 is an anti–PD-1/TGFβR2 bispecific antibody designed to antagonize TGFβR2/PD-1 signaling in immune cells co-expressing both targets. In the INCA33890-101 study (NCT05836324), patients (pts) with refractory non-MSI-H mCRC were treated with INCA33890 monotherapy at 3 expansion doses. Responses were observed in pts with and without active liver metastases. Here, we analyze associations between baseline biomarkers and clinical outcomes. Methods: Fresh or archival (≤3 years from study registration) baseline biopsies were required in the dose expansion part and assessed using immunohistochemistry (IHC) for CD8 and PD-L1 (SP263) and whole transcriptome and next-generation sequencing for DNA aberrations (both Tempus xT). Baseline ctDNA was analyzed using Predicine Atlas during dose escalation and expansion. Efficacy was assessed by investigators per RECIST v1.1. Results: As of July 25, 2025, efficacy data with INCA33890 monotherapy were available from 105 pts; 16 pts (15.2%) had a partial response (PR), including pts with liver and peritoneal metastases (Table). Of the 78 pts with evaluable baseline biopsies for IHC analysis, pts with PR or stable disease (SD) showed greater PD-L1 tumor area positivity scores than those with progressive disease (PD) (nominal p<0.05). mRNA expression of inflammatory genes (IFN-γ, CXCL9, CXCL10 and T-cell inflamed signature) were higher in pts with PR/SD vs PD. Pts with blood tumor mutation burden (bTMB) >20 mut/MB had a trend towards higher ORR (33.3%) vs pts with bTMB <20 mut/MB (12.5%). Consensus molecular subtypes (CMS) were assessed in 44 pts. Although CMS 4 is commonly associated with the presence of TGF-β, it was not associated with a higher ORR (7.7% [1/13]). Responses were also observed in CMS 2 (21.7% [5/23]) and CMS 1 (50% [1/2]), but not in CMS 3 (n=6). There was no relationship with tumor mRNA expression of TGFβ or TGFβ-associated signatures with clinical outcomes. In addition, SMAD4 mutations, determined by ctDNA, were present in both responders and non-responders. Mutations in KRAS (64%), TP53 (72%), and APC (47%) were the most common aberrations and had no impact on clinical outcomes. Conclusions: INCA33890 demonstrated preliminary efficacy in pts with non-MSI-H mCRC across a variety of subgroups. Higher baseline PD-L1 expression and mRNA expression of inflammatory genes enriched for clinical benefit while overexpression of TGF-β did not seem to enhance efficacy. Updated data will be presented. Clinical trial information: NCT05836324 . Efficacy across subgroups. N ORR, % DCR, % Overall 105 15.2 28.6 With/without Liver Metastases 75/30 12.0/23.3 20.0/50.0 Peritoneal Metastases 40 10.0 20.0 No Liver or Peritoneal Metastases 20 30.0 60.0 PD-L1 TAP <1% 22 9.1 22.7 PD-L1 TAP >1% 56 17.9 25.0 PD-L1 TAP >5% 13 38.5 61.5 bTMB high >20 mut/MB 15 33.3 40.0 bTMB <20 mut/MB 64 12.5 28.1

560 Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality. In the pivotal IMbrave150 trial, atezolizumab plus bevacizumab achieved a complete response (CR) rate of only 5.5%, with an objective response rate (ORR) of 27.3%. Preclinical and clinical evidence suggest that stereotactic body radiotherapy (SBRT) can enhance the efficacy of immunotherapy. We therefore conducted a phase I trial to evaluate the safety, feasibility, and immunologic effects of high-dose SBRT combined with atezolizumab and bevacizumab in patients with advanced HCC. Methods: This single-center, open-label, dose-escalation study (NCT05488522) enrolled patients with multifocal unresectable and/or metastatic, systemic-therapy naïve HCC. All received atezolizumab 1200 mg and bevacizumab 15 mg/kg every 21 days. SBRT (17 Gy/fraction) was delivered to one or more lesions on 1 to 3 occasions (depending on assigned dose level), 4 weeks apart using a Rolling 6 design. The first SBRT fraction was administered one week after the start of systemic therapy. The primary endpoint was dose-limiting toxicity (DLT) defined as Grade ≥3 events attributable to SBRT. Secondary endpoints included objective response rate by RECIST 1.1, overall and disease-free survival, and immune correlates from peripheral blood mononuclear cells (PBMCs). Results: Thirteen patients were treated (5 with one fraction, 6 with two fractions, and 2 with three fractions). Median age was 66 years; 77% were Child-Pugh A; 69% ECOG 0. Across all three cohorts, no radiation-related ≥Grade 3 DLTs were observed; the maximum tolerated dose was not reached. The ORR was 53.9% (7/13), and the best responses included 5 complete responses (38.5%) and 2 partial responses (15.4%); none of the patients with a complete response experienced recurrence. The median disease-free survival was 14.1 months, and the overall survival was 25.8 months. Immune profiling of PBMCs demonstrated that responders exhibited an increased frequency of CD8+ T cells expressing high levels of PD-1, along with proliferative (Ki-67) and activation (HLA-DR) markers, consistent with an “intermediate exhausted” but functionally active phenotype. Responders also displayed enhanced CD4+ Th1 activation, including upregulation of interferon-I signaling and ISG15, indicating a coordinated Th1-polarized immune response. Conclusions: High-dose SBRT combined with atezolizumab/bevacizumab in advanced HCC was feasible, safe, and yielded durable CRs in ~40% of patients. Median DFS and OS exceeded historical benchmarks. These results suggest that SBRT, when combined with atezolizumab and bevacizumab, may stimulate systemic immune activation and reinvigorate both CD8⁺ and CD4⁺ T-cell compartments in patients who experience prolonged clinical benefit. Clinical trial information: NCT05488522 .

Abstract Intra-tumour heterogeneity (ITH) and cellular plasticity contribute to therapy resistance. Single-cell transcriptomics is the gold standard for assessing ITH, but this approach remains costly and slow. Here, we show that distinct melanoma transcriptomic states exhibit unique cellular morphologies, and introduce ORIGAMI, a scalable flow cytometry assay leveraging cell surface area (S) and volume (V) measurements to resolve melanoma cell state diversity and to track therapy-induced transitions. MAPK- and CDK4/6-targeted therapies induce predictable shifts in cell geometry: drug-tolerant persister cancer cells increase cell surface area along a de-differentiation trajectory and/or increase volume while acquiring senescent-like features. Using ORIGAMI-guided screening, we identified brefeldin A (BFA) and other ER-Golgi modulators as agents that reduce surface area, promote differentiation, and sensitize melanoma cells to targeted therapies. Therapy-induced high-volume cells exhibit lysosomal scaling and increased sensitivity to nigericin, a natural polyether related to the lysosomal iron sequestering compounds and ferroptosis inducers salinomycin and narasin. Nigericin and BFA combined with MEK- and CDK4/6-inhibitors are highly potent in vitro across cell states and genotypes, and significantly extend survival in NRAS-mutant melanoma patient-derived xenografts without overt toxicity. Moreover, this combination induces hallmarks of immunogenic cell death and enhances anti–PD-1 efficacy in immunotherapy-refractory preclinical models. Beyond melanoma, the combination shows broad anti-tumour activity across a large panel of cancer lines derived from varied tissues. These findings establish a generalizable, geometry-based framework to monitor ITH, anticipate plasticity, and inform genotype-agnostic combination strategies that negate non-genetic adaptive resistance while potentiating immunotherapy.

The primary objective of this project is to improve machining process performance using in-process machining data from the machine tool controller and external sensors. Advances in the Industrial Internet of Things (IIoT) enable monitoring of machines using controller data. Examples of the data provided by a controller include execution status of the controller, part count, block of code being executed, door status, tool position, the spindle and axis load, etc. MTConnect and OPC-UA are the two common protocols for capturing machine information. In this collaboration, methods for retrieving the machine controller data from selected machine tool controls and making these data accessible in different subsystems (such as digital twins and machine maintenance portals, etc.) will be developed and tested. In addition, analytics to improve machining process performance (by increasing productivity and reducing downtime) will be developed.

Radiolabeled human mass balance studies are crucial for identifying circulating metabolites and understanding drug absorption, excretion, and clearance pathways. Metabolite profiling involves quantifying all drug-related entities, including parent drug and metabolites in plasma and excreta, using extended liquid chromatography methods coupled with detection through scintillation counting, accelerator mass spectrometry, or non-radiolabeled approaches. Given the labor-intensive nature of sample extraction and analysis, we propose a new paradigm that maximizes gathering information through sample pooling strategies. Our proposal introduces sample pooling strategies by integrating both individual and pooled sample schemes, simplifying decisions, and consolidating existing knowledge into a cohesive document. This aligns with the low statistical power typically associated with mass balance studies that dose six to eight subjects. In metabolite profiling, it is common practice to pool samples either from the limited number of subjects participating in a human mass balance study or from different time points of sample collection. This approach improves efficiency while preserving data integrity. Pooling reduces resource constraints and enables the concentration of samples with relatively low radioactivity levels, resulting in higher quality metabolite profiles. Nevertheless, there are situations when analyzing samples from individual subjects or time points may be preferred. This proposal presents guidance and decision trees designed to facilitate informed decisions about sample pooling to maximize data quality of metabolite profiling in human mass balance studies while efficiently managing resources. These recommendations stem from discussions within the mass balance working group of the IQ Consortium.

This work presents a highly integrated CMOS radiometer IC for remote temperature sensing applications. The proposed IC supports the 1.36GHz bands and is implemented using a 65nm CMOS process. The implemented RFIC employs a Dicke radiometer architecture, including a complete RF front-end, modulator, PLL, and even a digitally controlled duty-cycle calibration circuit. The proposed duty-cycle calibrator dynamically compensates for gain mismatch and temporal fluctuations between the dual receiver paths, thereby significantly improving the accuracy and reliability of the measured temperature. The fabricated radiometer IC occupies a compact area of 3.57×1.78mm<sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> and consumes only 72mW of power.