Browse Articles

Single-cell characterization of renal cell carcinoma brain metastasis.

e14013 Background: Brain metastasis (BM) in renal cell carcinoma (RCC) remains a major clinical challenge and is frequently resistant to immune checkpoint inhibitor (ICI) therapy. The metabolic, and immunological adaptations that enable tumor survival within the brain microenvironment remain poorly defined. A comprehensive, brain-specific characterization of tumor–microenvironment is urgently needed to understand immune dysfunction and therapeutic resistance in RCC BM. Methods: We generated a large single-nucleus RNA sequencing dataset comprising 184,037 nuclei from 14 RCC brain metastasis (BM) patients, including matched primary kidney tumors (n = 8) and extracranial metastases (n = 5). Cell populations were identified across tumor, immune, and stromal compartments. Comparative analyses were performed to identify BM-specific transcriptional, metabolic, and immune programs. Spatial transcriptomic profiling was conducted on 12 BM samples (13,128 cells) to validate cellular localization and interactions. Ligand–receptor (LR) inference was applied to reconstruct intercellular communications across tumor and microenvironmental cell types. Results: RCC BM is associated with extensive immune remodeling of the brain microenvironment, accompanied by stromal involvement. Tumor cells show neural-like features with evidence of neuronal infiltration, while stromal populations display immunomodulatory phenotypes that shape the immune microenvironment and extend beyond canonical structural roles. This immune landscape is characterized by expansion of immunosuppressive myeloid populations, depletion of antigen-presenting dendritic cells, absence of tertiary lymphoid structures, and CD8⁺ T cells exhibiting terminal exhaustion with impaired proliferative capacity. Across tumor, immune, and stromal compartments, we observed coordinated metabolic shifts including enhanced OXPHOS, and MYC-associated transcriptional programs that are consistent with tumor progression. Spatial profiling and LR analyses confirmed interactions that providing mechanistic insight and informing therapeutic targeting strategies. Conclusions: This study defines RCC BM as biologically distinct tumor entity shaped by neural adaptation, metabolic reprogramming, and profound immune dysfunction. The coordinated emergence of immunosuppressive myeloid signaling, terminal T cell exhaustion, and loss of antigen presentation. This establishes a brain-specific microenvironment that limits the efficacy of immune checkpoint blockade. Together, this work highlights context-dependent therapeutic resistance mechanisms and identifies actionable pathways that may guide the development of effective, brain-tailored immunotherapeutic strategies. Importantly, these findings provided a foundation that directly supported two clinical trials testing lenvatinib plus pembrolizumab, and zanzalitinib in RCC BM patients.

High-throughput phenotypic profiling of patient-derived colon cancer organoids to reveal a chemoresistant, AKT-driven tumor subpopulation and treatment strategy.

e15073 Background: Colorectal cancer (CRC) remains a significant clinical challenge due to its intrinsic heterogeneity, the paucity of personalized treatment options, and the commonality of chemoresistance. Methods: To better understand drug response dynamics at the single-cell level, we have developed a high-throughput, image-based phenotypic profiling pipeline using CRC patient-derived organoid (PDO) monolayer cultures. Diverse CRC PDOs representing multiple Consensus Molecular Subtypes were treated with a combination of 5-Fluorouracil and Oxaliplatin (FOX), imaged utilizing a biomarker panel identified using transcriptomic data, and analyzed using our newly developed phenotypic profiling pipeline. To further elucidate individual tumor response in vivo, we have also developed protocols to implant our PDOs into mice to create Patient Derived Xenograft (PDX) models. Results: Using our new analysis pipeline, we have identified a subpopulation of CRC cells that, after acute exposure to FOX treatment, exhibit elevated AKT signaling and increased expression of cancer stem cell markers. We observe this subpopulation across multiple PDOs, including across distinct CRC molecular subtypes, suggesting that chemotherapy itself may contribute to the enrichment of drug-resistant phenotypes driven by PI3K/AKT survival signaling. Targeting this survival phenotype, we also demonstrate that transient pre-treatment with the clinically utilized PI3K/mTOR dual inhibitor Dactolisib effectively sensitizes CRC PDOs to FOX, synergizing with this standard-of-care chemotherapy regimen and reducing the fraction of chemoresistant cells. Synergy score profiling revealed that this combination was broadly effective across diverse PDOs, with the strongest response noted in the organoid exhibiting the highest baseline AKT signaling. Preliminary data in our PDX models suggest this combination is synergistic in vivo as well. Conclusions: Our findings highlight the power of personalized organoid-based phenotypic profiling for dissecting molecular mechanisms of therapeutic resistance and support the rationale for transient PI3K/mTOR inhibition as a strategy to improve CRC treatments and outcomes.

Monoclonal gammopathy–associated autoinflammation: A systematic review and meta-analysis of Schnitzler syndrome.

e19579 Background: Schnitzler syndrome is a rare, underdiagnosed disorder that usually presents with late-onset systemic inflammation and monoclonal gammopathy. Key clinical findings include chronic urticarial rash, fever, bone pain, and lymphadenopathy. Given that most data regarding this rare disease are derived from small observational studies, this study aims to systematically characterize the demographic, clinical, laboratory, and treatment outcomes of patients with Schnitzler syndrome. Methods: A thorough literature search of the PubMed, Scopus, and Web of Science databases was performed in September 2025. Data on medical history, presentations, complications, diagnostics, treatment patterns, and outcomes were obtained. Results: This pooled analysis includes 187 articles reporting 243 individual cases of Schnitzler syndrome over the years 1989–2025. The mean patient age was 57.4 years ±12.2 with a male-to-female ratio of 1.32:1, indicating a slight male predominance. The most frequently reported manifestations were chronic urticarial rash (226/243, 93.0%), fever (194/243, 79.8%), and arthralgia (145/243, 59.7%), with lymphoid involvement mainly manifesting as lymphadenopathy (63/243, 25.9%); progression to lymphoproliferative disorders was rare (15/243, 6.2%). Most patients presented with an IgM gammopathy (193/243, 79.4%), confirming IgM as the predominant class. In a smaller subset, IgG (26/243, 10.7%) and IgA (3/243, 1.2%) gammopathy was present. Regarding light chain type, kappa predominated (162/243, 66.7%), with fewer cases of lambda (22/243, 9.1%). When stratified by immunoglobulin class, age differed significantly between patients with IgM and IgG gammopathy (58.5 vs 50.8 years, p = 0.015). IL-1 inhibitors were frequently used, with 124/243 patients receiving this therapy (51.0%). Corticosteroids of various formulations were administered in 154/243 patients (63.4%). Treatment response was favorable in most patients, with 126/243 achieving a complete clinical response (51.9%) and 47/243 a partial response (19.3%). Sixteen patients showed no response (6.6%). On multivariate analysis, IL-1 inhibitor use was independently associated with higher odds of complete response (OR 7.89; 95% CI 1.70–36.65). In the minority of patients who relapsed after an initial response to IL-1 inhibitors due to treatment discontinuation or tapering, the addition of corticosteroids restored the response. Conclusions: Schnitzler syndrome is a rare autoinflammatory condition predominantly affecting older males, characterized by chronic urticaria, fever, and IgM kappa gammopathy. While IL-1 inhibitors and corticosteroids offer high rates of clinical response, the frequent relapse upon tapering underscores the need for long-term maintenance. Studies are needed to explore if anti-plasma cell therapy would decrease relapse and induce long-term remission.

Preliminary results from an ongoing phase 1 study of LB2102, a dnTGFBR2-armored DLL3-targeted autologous CAR-T cell therapy, in patients with relapsed or refractory SCLC or LCNEC.

8012 Background: Delta-like ligand 3 (DLL3) is a promising target for small cell lung cancer (SCLC) and other neuroendocrine tumors. We present results from an ongoing dose-escalation study of LB2102, an autologous CAR-T cell therapy engineered to target DLL3 and armored with a TGF-β receptor blockade to overcome the immunosuppressive tumor microenvironment. Methods: This open-label, multicenter, phase 1 study evaluates LB2102 in patients with SCLC or large cell neuroendocrine carcinoma (LCNEC), relapsed or refractory to ≥1 prior line of therapy (LOT). Dose escalation follows an i3+3 design, with dose levels (DL) of 0.3, 1.0, 2.0, 4.0, 8.0, 12.0, and 16.0x10 6 CAR+ T cells/kg. Subjects received a single infusion of LB2102 after standard lymphodepletion (LD). The primary objectives are to assess safety and tolerability, and to determine the recommended phase 2 dose. Results: As of 05-JAN-2026, 20 subjects received LB2102 (DL1–DL5, n = 3 each; DL6 was skipped based on data; DL7, n = 5). Seventeen subjects had SCLC and 3 LCNEC; 13 (65%) had a history of brain metastases. Median age was 56.5 yrs (range 20–73 yrs) with median 1 prior LOT (range 1–7); 95% received bridging therapy between apheresis and LB2102. The most-common grade ≥ 3 LB2102-related adverse events (TRAEs) were hematologic and co-attributed to LD. Four subjects (20%) had cytokine-release syndrome (CRS; 3 Grade 1 and 1 Grade 2); all resolved. Two subjects developed ICANS (1 Grade 1 and 1 Grade 3); both resolved. There were no dose-limiting toxicities (DLTs) or TEAE-related deaths. Other grade ≥ 3 non-hematologic LB2102-related TEAEs were dyspnea, prolonged QT, and hypoxia (all n = 1 at DL7). Of 17 response-evaluable subjects, best overall responses per RECIST1.1 criteria were 3 partial responses (PR, one each at DL3, DL4, and DL7) and 10 stable diseases (SD, at DLs 2–7), for an objective response rate (ORR) of 3/17 (18%) and a disease control rate (DCR) of 13/17 (76%). Median DOR among patients with a PR was 208 days. CAR-T expansion in peripheral blood (measured by qPCR) was observed at DL3 (N = 3), DL4 (N = 3), DL5 (N = 3), and DL7 (N = 5; 1 patient excluded due to incomplete PK profile): median C max was 694, 581, 527, and 2851 copies/µg gDNA; median T max was 15, 15, 6, and 6 days, respectively. Patients with partial responses had relatively higher PK exposure (median C max ) compared to the PK exposure of patients with stable diseases and progressive diseases. Median tumor expression of DLL3 at baseline was 97% (n = 16, range 45%–100%) and at Day 29 post-infusion was 90% (n = 8, range 55%–100%). Conclusions: LB2102 demonstrated consistent CAR-T expansion and encouraging anti-tumor activity at doses ≥ 2x10 6 CAR+T cells/kg (ORR 27% and DCR 91%). LB2102 was well tolerated with no DLTs and manageable CRS and ICANs. Clinical trial information: NCT05680922 .

Magnesium neuroprotection in retinal ganglion cells: A computational study of frequency-dependent therapeutic windows and intervention timing

Retinal ganglion cells (RGCs) are vulnerable to excitotoxic damage mediated by excessive NMDA receptor activation and calcium overload. Extracellular magnesium (Mg 2+ ) blocks NMDA receptors in a voltage-dependent manner, offering potential neuroprotection. However, the optimal Mg 2+ concentrations and timing for effective intervention remain poorly defined. We developed a conductance-based computational model of an RGC incorporating Hodgkin-Huxley dynamics, AMPA and NMDA receptor-mediated synaptic transmission, and intracellular calcium dynamics. We systematically varied Mg 2+ concentration (0.2–2.5 mM) and stimulation frequency (10–100 Hz) to identify therapeutic windows balancing neuroprotection with function preservation. At physiological frequencies (10–60 Hz), elevated Mg 2+ reduced calcium (Ca 2+ ) accumulation by 50–85% without affecting spike output. At excitotoxic frequencies (80 Hz), a narrow therapeutic window of 1.6–2.0 mM was identified, lying within a broader 1.4–2.0 mM spike-loss plateau (20% loss), where calcium additionally fell below the toxicity threshold while spike output was preserved. Intervention timing analysis revealed that Mg 2+ protection efficacy is maximal with pre-treatment or immediate intervention (100%), and declines steeply with delay—reflecting the rapid early rise in Ca 2+ rather than a fixed biological deadline (≥50% protection requires intervention within 0.2 s in our abrupt-onset protocol; ∼11% by 0.5 s). Re-analysis in terms of normalized Ca 2+ progress revealed that the critical constraint for ≥50% protection is intervention before ∼35% of peak Ca 2+ accumulation—a state-based threshold reflecting relative phase sensitivity that generalizes across timescales. Sensitivity analyses confirmed robustness of the therapeutic window across physiologically plausible parameter ranges, and numerical validation demonstrated accuracy of the computational approach. These findings demonstrate that Mg 2+ -mediated neuroprotection is highly dependent on both concentration and timing, with implications for therapeutic strategies targeting glutamate excitotoxicity in glaucoma and retinal ischemia.

Recent developments in black phosphorus quantum dots (BPQDs) for energy storage and optoelectronic devices

Hydrogelation via Supramolecular Copolymerization of Structural Water within Adaptive Metal–Organic Fibers (Adv. Mater. 31/2026)

Phase‐Behavior‐Driven Hydrogen‐Bond Engineering Enables Temperature‐Resilient Fibrous Zinc‐Ion Batteries

ABSTRACT Fibrous energy‐storage systems serve as a core component in the next‐generation flexible and wearable electronics, yet their practical application is hindered by the limited temperature resilience of aqueous electrolytes and the mechanically fragile electrolyte‐electrode interfaces. Herein, we design an in situ deep‐eutectic hydrogel electrolyte based on a hydroxyl‐rich glycerol‐ethylene glycol‐H 2 O system, in which the hydrogen‐bond network is engineered to modulate the chemical potential of water and the free‐energy landscape governing phase transitions. Strong H 2 O‐H 2 O H‐bonds are converted into a more uniformly distributed weak H‐bond network in the electrolyte, thereby reducing the thermodynamic driving force for ice formation at low temperatures while suppressing H 2 O volatilization at elevated temperatures. Meanwhile, in situ photopolymerization enables the direct formation of a conformal hydrogel layer on the electrode surface, improving interfacial adhesion and mitigating parasitic reactions such as hydrogen evolution and Zn corrosion. Benefiting from the coupled thermodynamic and interfacial regulation, Zn||PANI coin cell exhibits stable operation over an ultrawide temperature range of −50°C–100°C and delivers a cycling life exceeding 10 000 cycles with 86.71% capacity retention at 25°C. A fibrous Zn||PANI cell further maintains reliable cycling for over 500 cycles at −25°C, demonstrating the applicability of this strategy for temperature‐resilient wearable energy‐storage systems.

Fine-grained evaluation of neighborhood quality in China using street view images and big data technologies

Abstract With the advent of the post-materialist and post-industrialization era, quality of place has gradually become a hotspot of urban research. But the research has mainly focused on the city or national scale, and there is a lack of exploration on the small scale within the city. In this paper, we take neighborhoods as the research scale, design a neighborhood quality assessment system that can measure both the soft and hard environments of cities by using big data technologies such as deep learning and street view images to obtain microdata at the neighborhood level, and the entropy method was used to assess the quality of 5829 major neighborhoods (sub-districts) in 232 prefecture-level cities across China. The assessment results demonstrate that: (1) In China, the construction of “soft” environment is more important for enhancing the neighborhood quality. (2) Most of the high-quality neighborhoods in China are located in its economically developed regions, indicating that the enhancement of neighborhood quality is, to some extent, dependent on a region’s economic level. (3) High-quality neighborhoods have been constructed in a relatively balanced manner in all dimensions, while low-quality neighborhoods show obvious deficiencies in the dimension of creativity. (4) Lastly, this paper includes a heterogeneity analysis on the neighborhood quality of cities in different regions, at different administrative levels, and with different industrial focuses, which reveals that even though China’s construction efforts on “hard” environments of cities are pretty much the same, significant differences exist in those on “soft environment”. This paper not only enriches the body of literature in the field of place quality but also provides significant theoretical support for urban planners and policymakers in planning and design, urban renewal, and the optimization of urbanization policies.

The tumor suppressor NDRG2 recruits protein phosphatase 2A to suppress STAT5 phosphorylation in adult T-cell leukemia/lymphoma

Phase 1 study of the tetravalent death receptor 5 agonist ozekibart (INBRX-109) combined with chemotherapy in locally advanced or metastatic, unresectable colorectal adenocarcinoma (CRC).

3533 Background: Patients with metastatic CRC are typically treated with fluorouracil-based chemotherapy in combination with leucovorin and irinotecan (FOLFIRI) or oxaliplatin (FOLFOX). However, patients who progress after 2 lines of therapy have limited treatment options, with poor outcomes (response rates of ≤6%). Ozekibart (INBRX-109) is a next-generation, tetravalent death receptor 5 agonist that has demonstrated robust efficacy as a single agent in chondrosarcoma. Additionally, ozekibart in combination with FOLFIRI showed early signs of antitumor activity in a small cohort of patients with CRC in the ongoing INBRX-109 phase 1 study (NCT03715933) (Berz D, et al. J Clin Oncol. 2025. Abstract 129). Based on these findings, the CRC cohort in this study was expanded to include additional patients who had received 2 or 3 prior lines of systemic therapy. We present initial findings from this cohort. Methods: Ozekibart + FOLFIRI was examined in patients with locally advanced or metastatic, unresectable CRC in the expansion cohort C4d of the open-label, INBRX-109 phase 1 study. Eligible patients were aged 18 to < 85 years, had received 2 or 3 prior lines of systemic therapy, and had no chronic or acute liver disease. Previous irinotecan-containing regimens were allowed but not as an immediate prior line of therapy. Patients received ozekibart 3 mg/kg every 4 weeks + FOLFIRI every 2 weeks. Safety and clinical response were primary endpoints. Results: As of the data cutoff (October 15, 2025), 44 patients had received ozekibart + FOLFIRI in this cohort. Median age was 54.5 years (range, 29-77 years), and > 70% were in the fourth-line treatment setting; 81.8% had previously received an irinotecan-based regimen. Overall, 28 patients (63.6%) remain on treatment; 11 patients had disease progression, 1 patient discontinued due to adverse events (AEs), and 4 patients discontinued for other reasons. Among evaluable patients for response at data cutoff (n = 26), ozekibart + FOLFIRI led to an ORR of 23% (all partial responses) and a disease control rate of 92%. Consistent with the safety profile of FOLFIRI, the most common AEs (in > 25% of patients) were anemia (any grade, 36.4%; grade ≥3, 9.1%), diarrhea (34.1%; 9.1%), nausea (31.8%; 0%), fatigue (27.3%; 2.3%), and alopecia (27.3%; 0%). Increased alanine aminotransferase was the only grade ≥3 hepatotoxicity event and occurred in 1 patient. Conclusions: Ozekibart + FOLFIRI demonstrated encouraging preliminary efficacy in a heavily pretreated patient population with metastatic, unresectable CRC. The safety profile of ozekibart + FOLFIRI was manageable, with most AEs being low grade. Our findings support further evaluation of ozekibart + FOLFIRI in advanced CRC. Updated data will be provided at the time of presentation. Clinical trial information: NCT03715933 .

Breath analysis of volatile organic compounds with mid-infrared laser spectroscopy in a cohort of lung cancer patients and control subjects.

8029 Background: Exhaled volatile organic compounds (VOCs) represent potential non-invasive biomarkers for lung cancer detection. This study assessed a mid-infrared cavity ring-down spectroscopy (CRDS) platform for measuring key breath VOCs in a large clinical cohort including lung cancer patients across stages/histologies, carcinoma in situ, and non-cancer controls. Methods: This prospective single-center validation study enrolled 1,041 participants: approximately 500 with pathologically confirmed lung cancer (various stages and histologies), 25 with carcinoma in situ, healthy controls, patients with benign pulmonary diseases, and those with low- and high-risk pulmonary nodules. Breath samples were collected under standardized fasting and mouth-rinsing conditions and analyzed using a self-developed mid-infrared CRDS system targeting isoprene, acetone, and formaldehyde (detection limit < 10 ppb). The primary endpoint was diagnostic accuracy for distinguishing lung cancer (including carcinoma in situ) from healthy controls, measured by area under the receiver operating characteristic curve (AUC). Sample size was powered to detect an AUC difference of ≥0.15 from 0.50 (null hypothesis) with > 85% power at α = 0.05. Group comparisons used independent t-tests or Mann-Whitney U tests with Bonferroni correction for multiple testing. Predictive modeling employed logistic regression and machine learning (random forest and XGBoost) with 5-fold cross-validation; feature importance and SHAP values were assessed. Performance metrics included AUC, sensitivity, specificity, and 95% confidence intervals (CI). Results: Isoprene exhibited the most consistent group differences across comparisons (P < 0.001 in lung cancer vs healthy and carcinoma in situ vs healthy). Random forest and XGBoost models yielded AUC of 0.94 (95% CI, 0.92-0.96) for lung cancer vs healthy controls and 0.97 (95% CI, 0.95-0.99) for carcinoma in situ vs healthy controls. At optimal thresholds, sensitivity and specificity reached 90-96% and 92-95%, respectively, in primary analyses. Subgroup performance remained robust in non-smokers and stage I patients. Decision curve analysis demonstrated net clinical benefit across 1-20% risk thresholds compared with low-dose CT screening strategies. Acetone and formaldehyde provided supplementary contributions in pathological subtype and benign disease distinctions. Conclusions: Mid-infrared CRDS-based breath VOC analysis shows feasible diagnostic performance for lung cancer detection, including strong results in carcinoma in situ and early-stage disease, in this large cohort. Multi-center prospective validation is needed to confirm clinical utility and integration into screening strategies.

A meta-analysis of perioperative immunotherapy modalities in patients with dMMR/MSI-H gastric and gastroesophageal junction adenocarcinoma.

e16127 Background: Immunotherapy for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) gastric/gastroesophageal junction (G/GEJ) adenocarcinoma lacks large-scale clinical evidence, especially in neoadjuvant therapy. Here, we used meta-analysis to investigate the efficacy and safety of different immunotherapy-based regimens in neoadjuvant treatment of G/GEJ cancer, and explored the relationship between effective regimens and tumor characteristics by online datasets. Methods: Following PRISMA guidelines, we searched databases and conference abstracts, including 23 clinical trials of neoadjuvant immune checkpoint inhibitors (ICIs)-based therapy for resectable dMMR/MSI-H G/GEJ cancer. We performed meta-analysis using STATA18 software. Tumor mutations were analyzed via TCGA somatic mutation data with maftools (R package), including TMB calculation and subclonal/CNV/MHC gene analysis. Tumor immune microenvironment was assessed using GEO scRNA-seq data via Cell Ranger/Seurat/Harmony processing, cell type annotation and MHC-I/II molecule analysis in tumor cells. Results: Meta-analysis showed ICIs-based therapies had significantly higher pathological complete response (pCR = 0.68) and major pathological response (MPR = 0.99) than chemotherapy alone(pCR = 0.08, MPR = 0.01). ICIs combined with chemotherapy achieved the best efficacy followed by dual ICIs, with tolerable adverse events. The R0 resection rate was approximately 100% for all regimens, while ICIs combined with chemotherapy demonstrated the highest downstaging rate. Asian populations benefited more from single-agent ICIs while Europeans had better responses to dual ICIs. Results by analyzing TCGA database revealed dMMR/MSI-H GC had higher tumor mutational burden, subclonal mutations, copy number variations and expression of MHC-I/II moleculars than dMMR/MSI-H colorectal cancer and microsatellite stability GC. Further, single-cell sequence analysis showed that the infiltration of CD8 + T and CD4 + T cells was higher in dMMR/MSI-H GC, indicating that dMMR/MSI-H GC possessed high tumor heterogeneity and immunogenicity. Conclusions: ICIs combined with chemotherapy is the optimal neoadjuvant regimen for dMMR/MSI-H G/GEJ cancer with manageable toxicity, followed by dual ICIs. Single-agent ICIs are more beneficial for Asians. Tumor heterogeneity may contribute to the superior efficacy of combination therapy, providing evidence for clinical regimen selection.

Evaluation of AI-guided questioning versus standard information delivery in a simulated newly diagnosed breast cancer population.

1623 Background: Patients newly diagnosed with breast cancer frequently experience information overload and anxiety, which can impair understanding and participation in shared decision-making. Artificial intelligence (AI)–guided educational approaches may support individualized information delivery; however, their impact on patient understanding and emotional response remains incompletely characterized. Methods: We conducted a prospective, randomized vignette-based survey study among adults (≥18 years) asked to imagine receiving a new diagnosis of early-stage breast cancer. Participants were randomized 1:1 to receive either standard written information or AI-guided questioning that adapted presentation of identical content based on stated preferences and level of detail. Outcomes included a composite breast cancer knowledge score (range 0-20) (primary endpoint), perceived information overload, anxiety, decision confidence, and clarity (all Likert-scale measures, range 1-5). Group comparisons were performed using Welch's two-sample t-test. Exploratory subgroup analyses included educational level and health-related background. Results: 102 participants completed the survey (51 per group). Mean knowledge scores were higher in the AI-guided group compared with standard information (17.6 vs 13.2, p=0.00022). Participants receiving AI-guided questioning reported lower information overload (2.31 vs 3.35, p=0.00012), lower anxiety (3.67 vs 4.16, p=0.031), greater decision confidence (4.06 vs 2.84, p=1.2×10⁻⁶), and higher perceived clarity (4.20 vs 3.18, p=2.9×10⁻⁵). Exploratory analyses showed greater benefits among participants without graduate education or health-related background (both p<0.001), with smaller, non-significant differences in those with higher education or healthcare experience. Conclusions: In a simulated newly diagnosed breast cancer population, AI-guided questioning was associated with improved understanding, reduced information overload and anxiety, and greater decision confidence compared with standard information delivery. Exploratory analyses suggested that benefits were more pronounced among participants without graduate-level education or medical background, supporting a potential role for human-centered AI in equitable patient education. Given exploratory nature and unequal subgroup distributions, confirmation in prospectively stratified studies is needed. Outcomes by information delivery approach. Outcome (range) Standard information (n=51) AI-guided questioning (n=51) p value Knowledge score (0-20) 13.2 17.6 0.00022 Information overload (1-5)† 3.35 2.31 0.00012 Anxiety (1-5)† 4.16 3.67 0.031 Decision confidence (1-5)‡ 2.84 4.06 1.2×10⁻⁶ Clarity (1-5)‡ 3.18 4.20 2.9×10⁻⁵ †Lower scores indicate better outcome. ‡Higher scores indicate better outcome.

Donor-dependent amplification capacity and phenotype of ex vivo–expanded iNKT cells.

e14526 Background: Invariant natural killer T (iNKT) cells combine rapid innate-like effector function with T-cell specificity, making them a compelling platform for CAR engineering. CAR-iNKT cells show potent antitumor activity, improved tumor infiltration, and a favorable safety profile with low GvHD risk, supporting their potential as off-the-shelf therapies, particularly for solid tumors. However, their clinical translation remains challenging due to low natural abundance, manufacturing complexity, and difficulties in achieving robust in vivo expansion and persistence. Methods: PBMCs from 14 healthy donors were used for iNKT cell expansion. iNKT cells were isolated using anti-iNKT microbeads (Miltenyi Biotec), stimulated with X-ray–irradiated, α-galactosylceramide–pulsed PBMCs, and cultured in RPMI-1640 with 10% FBS and IL-2. Differentiation status was assessed by CD45RA/CCR7 flow cytometry. Cells were lentivirally transduced with CD19 or GD2 CARs and further expanded. Antitumor activity was evaluated against lymphoma (Ramos, Jurkat, Raji) and neuroblastoma (SH-SY5Y) cell lines. Statistical analysis used Student's t test. Results: The proliferative capacity of iNKT cells from 14 donors was evaluated after ~3 weeks of in vitro culture, revealing marked interindividual variability ranging from 210-fold to 42,200-fold expansion under identical conditions. Six donors exhibited high amplification ( > 1,000-fold), while eight showed low amplification ( < 1,000-fold). Flow cytometric analysis demonstrated a significantly higher proportion of CD4⁺ cells in PBMCs from high-amplification donors compared with low-amplification donors (high/low = 1.43, P = 0.02). Although trends were observed for individual naïve- and central memory-like iNKT subsets, significant differences emerged when subsets were combined: naïve/central memory cells were enriched in the high group (high/low = 1.78, P = 0.02), whereas effector memory/effector cells were higher in the low group (high/low = 0.71, P = 0.02). No difference in CD4⁺/CD8⁺ ratio was observed. Expansion capacity was unrelated to age, sex, or BMI. Additionally, iNKT cells from selected donors were successfully transduced with lentiviral CAR constructs targeting CD19, GD2, MSLN, or other antigens and demonstrated potent antitumor activity against a range of hematologic and solid tumor cell lines, outperforming CAR-T cells in vitro. However, donor-dependent effects on CAR transduction efficiency and cytotoxicity require further validation in larger cohorts. Conclusions: iNKT cells exhibit marked donor-dependent variability in ex vivo expansion associated with immunophenotypic differences in donor PBMCs, highlighting donor selection as a critical factor for CAR-iNKT manufacturing. Further studies in larger cohorts are warranted to define predictive biomarkers of expansion efficiency and therapeutic potency.

Bulumtatug fuvedotin (BFv; 9MW2821) plus toripalimab in perioperative patients with muscle-invasive bladder cancer (MIBC): Results of cohort A from a phase 2 study.

4609 Background: Radical cystectomy with pelvic lymph node dissection (RC+PLND) has always been the standard treatment for MIBC. Perioperative treatment, especially cisplatin-based neoadjuvant therapy, could reduce the risk of tumor recurrence effectively and prolong the survival of patients. BFv, a novel Nectin-4 antibody-drug conjugate, combined with toripalimab, has demonstrated promising efficacy and safety profile in advanced urothelial cancer patients. This provides possibilities for the perioperative treatment of MIBC. Here we report the preliminary results of BFv plus toripalimab in patients with perioperative MIBC (cohort A). Methods: Patients with MIBC (cT2-4aN0-1M0) can be enrolled in cohort A. Eligible patients will receive BFv plus toripalimab for 4 cycles in neoadjuvant stage, and then proceed with RC+PLND. After surgery, patients will receive BFv plus toripalimab for 6 cycles and toripalimab only for the next 11 cycles in the adjuvant stage. The primary endpoint was pathological complete response (pCR). Main secondary endpoints were pathological downstaging (PDS) rate and disease-free survival (DFS), overall survival (OS) and safety. Results: As of 4 Jan 2026, 32 patients were enrolled in the cohort A. 7 patients had completed neoadjuvant therapy and 6 of them were performed with RC+PLND. One patient achieved CR in the neoadjuvant stage and refused to undergo the surgery. pCR rate was 66.7% (4/6, 95%CI 22.3-95.7), PDS rate was 83.3% (5/6, 95%CI 35.9-99.6). DFS and OS were not mature. Safety profile was consist with previous study. No new safety signals of BFv or toripalimab were observed in this study. Conclusions: This study showed remarkable preliminary efficacy of BFv plus toripalimab in perioperative patients with MIBC. It may offer a new choice for MIBC patients and deserve to be further investigation. Clinical trial information: NCT07314723 .

Phase I, multicenter, first-in-human (FIH) global study of SIM0505, an anti-CDH6 (CDH6) antibody-drug conjugate (ADC) in patients with advanced solid tumors.

5580 Background: Cadherin 6 is a transmembrane glycoprotein overexpressed in multiple cancers, including ovarian cancer (OC) and uterine serous cancer (USC). SIM0505 is an ADC comprised of an anti-CDH6 humanized IgG1 monoclonal antibody, a stable linker cleaved within tumor cells, and a novel topoisomerase I inhibitor, CPT116. Here, we report initial results from a global FIH study of SIM0505 (NCT06792552). Methods: This is a Phase 1 study to evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of SIM0505 in patients (pts) with advanced solid tumors. SIM0505 was administered IV every 21 days from 1.6 mg/kg to 9.6 mg/kg. Dose levels from 3.2-8.0 mg/kg were backfilled. Results: As of 26 Dec 2025, 38 pts were enrolled without preselection for CDH6 expression (29 OC, 4 USC, 2 endometrioid endometrial cancer, 3 renal cell cancer) from 1.6 mg/kg to 9.6 mg/kg in the dose-escalation part. The median age was 57.0 years (range 42-78). The median number of prior therapy regimens was 5 (range 1-11). Of the 29 OC pts, 27 (93.1%) were high grade serous and 23 (79.3%) were platinum resistant. 22 (75.9%), 20 (69.0%) and 2 (6.9%) had received bevacizumab, PARPi and mirvetuximab soravtansine (MIRV), respectively. The median treatment duration was 10.6 weeks (range 3.0-33.6). Any-grade and Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 37 (97.4%) and 21 (55.3%) pts, respectively. Any-grade and Grade ≥3 treatment-related adverse events (TRAEs) occurred in 35 (92.1%) and 17 (44.7%) pts, respectively. The most common (≥10%) Grade ≥3 TRAEs were thrombocytopenia (23.7%), neutropenia (21.1%), and white blood cell count decreased (18.4%). One pt at 9.6 mg/kg had dose-limiting toxicity of Grade 4 febrile neutropenia and thrombocytopenia and discontinued treatment. Another patient discontinued treatment due to Grade 2 interstitial lung disease. Serious TRAEs were observed in 6 (15.8%) pts. No TEAEs led to death. MTD was not reached. Among 30 evaluable pts, 11 partial responses (PR, 9 OC and 2 USC) and 13 stable disease were observed. 8 PRs occurred among 14 evaluable OC pts at potential therapeutic dose range of 4.8-8 mg/kg. 9 of 21 Gynecological Cancer Intergroup (GCIG) evaluable pts had CA-125 response. The exposure of SIM0505 was proportional to dose in general, with a half-life of about 8 days. The PK profile was similar to that of total antibody, indicating good stability of the ADC in the circulation. Conclusions: SIM0505, a first in class CDH6 CPT116 payload ADC showed manageable safety and tolerability, including at higher dose levels with encouraging efficacy in OC and USC, with a favorable PK profile. These data support initiating the dose optimization portion of the study in gynecological cancers. Clinical trial information: NCT06792552 .

Predictive value assessment of the Meet-URO and IMDC scores in metastatic renal cell carcinoma (mRCC) receiving first-line ICI–ICI vs ICI–TKI combinations (Meet-URO 33 study).

e16509 Background: The prognostic value of the IMDC and Meet-URO scores is well-established in clinical trials and real-world analyses in untreated and pretreated mRCC patients. However, their predictive performance in the novel 1 st line setting of immune-combinations is still unclear. Methods: We conducted an Italian multicenter retrospective-prospective real-world study of mRCC patients receiving 1 st line ICI–ICI or ICI–TKI. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method. The predictive value of the Meet-URO score (5 categories) and the IMDC score (3 categories) was assessed using Cox proportional hazards models including formal treatment-by-risk interaction testing in univariable and multivariable analyses. Results: A total of 1907 patients were enrolled from 58 centres and 1511 patients (79%) were included in the analysis. Median age was 65.8 years, 85% had clear-cell histology, 76% received ICI–TKI and 24% ICI-ICI. After a median follow-up of 27.8 months, in the overall population, in the ICI-TKI group and in the ICI-ICI group: mOS was 37.8, 39.0 and 37.8 months, respectively; PFS was 17.9, 19.4 and 13.1 months, respectively. Hazard ratios for ICI–TKI vs ICI–ICI were consistent across all Meet-URO and IMDC groups for both OS and PFS (Table 1). No significant treatment-by-risk interaction was observed for Meet-URO score (OS p=0.73; PFS p=0.86) or IMDC risk group (OS p=0.73; PFS p=0.37). Conclusions: In this large real-world cohort, Meet-URO and IMDC prognostic scores did not show predictive value for selecting between 1 st line ICI–ICI and ICI–TKI combinations. These findings suggest that established risk models should not guide treatment choice between immune-based combinations in mRCC, but other factors should be considered (e.g. metastatic sites, tumor burden). Clinical trial information: CESC IOV 2023-78. Risk group N mOS ICI-TKI vs ICI-ICI (months) OS HR (95% CI) P value mPFS ICI-TKI vs ICI-ICI (months) PFS HR (95% CI) P value Meet-URO score 1 213 NR (≥45.7) vs NR (≥20.6) 1.32 (0.41–4.29) 0.73 34.5 vs 14.2 0.62 (0.31–1.25) 0.86 Meet-URO score 2 442 57.9 vs NR (≥XXX) 0.80 (0.52–1.25) 28.0 vs 26.8 0.85 (0.61–1.19) Meet-URO score 3 351 32.2 vs 37.8 1.05 (0.71–1.56) 18.2 vs 13.1 0.68 (0.49–0.94) Meet-URO score 4 376 25.7 vs 17.6 0.89 (0.63–1.24) 15.0 vs 7.1 0.71 (0.53–0.95) Meet-URO score 5 129 11.5 vs 7.2 0.71 (0.40–1.25) 6.8 vs 3.1 0.71 (0.41–1.21) IMDC favorable 282 57.9 vs NR (≥ 38.4) 1.20 (0.43–3.32) 0.73 39.5 vs 15.0 0.69 (0.36–1.32) 0.37 IMDC intermediate 901 37.2 vs 42.2 0.88 (0.67–1.14) 19.7 vs 15.7 0.74 (0.60–0.91) IMDC poor 328 13.7 vs 16.6 0.94 (0.66–1.32) 9.1 vs 7.1 0.77 (0.57–1.04)

HER2-independent antitumor and pharmacodynamic responses to trastuzumab deruxtecan in patients with advanced solid tumors.

3031 Background: Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody conjugated to topoisomerase 1 inhibitor, deruxtecan, payload that is an effective treatment strategy across several tumor types and various HER2 expressions. The relative contributions of each of the underlying mechanisms driving the broad clinical activity require further elucidation for the ongoing rational development of this promising agent. To this end, our pilot study (NCT04294628) evaluates the pharmacodynamics (PD) of T-DXd in patients (pts) with solid tumors displaying a variety of HER2 expression levels. Methods: This multicenter pilot study enrolled pts with HER2-expressing advanced solid tumors as defined by HER2 immunohistochemistry (IHC) score of 1+ or greater or ERBB2 amplifications (amp) or mutations (mut). Baseline HER2 expression was evaluated by Ventana PATHWAY immunohistochemical (IHC) analysis. T-DXd was administered at 5.4 mg/kg intravenously once every 3 weeks, in 21-day cycles (C), with mandatory tumor biopsies collected at baseline, post-dose C1, and pre-dose C3. Blood samples for biomarker analyses were collected throughout the study. PD biomarkers for topoisomerase 1 (TOP1) target engagement, consequent DNA damage repair (DDR), and tumor immune microenvironment changes were analyzed. Overall response was also evaluated. Results: Sixty-one pts received T-DXd. Eligibility HER2 (eHER2) status was determined from pt records: 21 IHC 1+, 22 IHC 2+, 7 IHC 3+, 8 ERBB2 amp, 3 ERBB2 mut. Of the 41 pts with baseline biopsies centrally assessed for HER2 (bHER2) by IHC, 13 had bHER2 scores discordant with eHER2, including 8 patients who were eHER2 1-2+ but were bHER2 null. No new safety signals were observed. One pt had a complete response (cervical, bHER2 3+), 14 pts had confirmed partial responses (PR), including 3 who were bHER2 null (2 ovarian, 1 uterine), and 5 pts had unconfirmed PR (uPR). Of the 21 paired biopsies assessable for PD response, 15 demonstrated TOP1 target modulation and 14 of those 15 also demonstrated DDR induction. Substantial tumor infiltration and activation of CD8+ T cells at baseline and/or following T-DXd administration occurred in several patients and were particularly prevalent in those with response. In the one responding patient where lesion-specific analyses were possible, we observed significant diameter reduction (3.9 cm to 1.9 cm) and PD responses in a bHER2 null lesion. Conclusions: Clinical responses and target modulation were observed in pts irrespective of bHER2 expression. Lesion-specific analyses provide evidence of antitumor activity and target engagement even in a bHER2-null lesion. Genomic analyses to identify additional molecular determinants of response or resistance to T-DXd are ongoing. This project was funded in part by the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024. Clinical trial information: NCT04294628 .

Impact of time-of-day of immune checkpoint inhibitor infusion on clinical outcomes in patients with metastatic renal cell carcinoma (mRCC).

4552 Background: Emerging evidence suggests that circadian rhythms may influence the efficacy of immune checkpoint inhibitors (ICIs) by modulating immune cell activity and T-cell trafficking. This study evaluated whether the timing of ICI administration (early vs. late) affects progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC). Methods: We conducted a single-center retrospective study of 97 patients with Stage IV mRCC treated with first-line ICIs. Patients were categorized by infusion timing: "Early" (n=68) vs. "Late" (n=29), with the cutoff defined by the median infusion time of 2:00 PM. Treatment regimens included ipilimumab/nivolumab (37%), nivolumab (36%), and pembrolizumab (27%); 23% received ICI in combination with a VEGF-targeted tyrosine kinase inhibitor. Outcomes were analyzed using Kaplan-Meier curves and multivariable Cox regression models, adjusting for age and International Metastatic RCC Database Consortium (IMDC) risk scores. Results: The median age was 65 years (IQR 59–71), 77% of patients were male, and 88% had clear cell histology. IMDC risk categories were intermediate (56%), poor (27%), and favorable (18%). At a median follow-up of 54.8 months, early infusion was associated with significantly improved OS (median 54 vs. 29 months; adjusted HR 1.79; 95% CI 1.02–3.12; p = 0.041) and PFS (median not reached; adjusted HR 3.59; 95% CI 1.27–10.20; p = 0.016) after adjustment for age and IMDC risk. Landmark 60-month OS was 40% vs. 31%, and PFS was 79% vs. 60% for the early vs. late groups, respectively. The incidence of any-grade immune-related adverse events (irAEs) was similar (54% in the early group vs. 52% in the late group), and poor IMDC risk remained a significant predictor of OS in the multivariable model (HR 3.09; 95% CI 1.22–7.8; p = 0.017). Conclusions: In this mRCC cohort, ICI administration before 2:00 PM was associated with significant improvements in both PFS and OS, including a nearly two-fold increase in median overall survival compared to late-afternoon administration. These findings are hypothesis-generating and suggest that the timing of immunotherapy may be an immediately actionable, high-impact variable in optimizing mRCC treatment. Prospective validation is warranted.