Browse Articles

Analysis of spatial atlas of ADC targets in immunotherapy-treated NSCLC to link compartment-specific target expression with tumor immune contexture, clinical outcome, and on-treatment remodeling.

3004 Background: The spatial distribution, co-expression patterns, immune contexture associations, and on-treatment evolution of ADC targets in NSCLC is unknown. Methods: The samples of 100 NSCLC patients treated with PD-1/PD-L1–based immunotherapy (STING NCT04932525) were analyzed using multiplex immunofluorescence with three 7-plex panels assessing ADC targets (Claudin18.2, TROP2, B7-H3, B7-H4), receptor co-expression (HER2, EGFR, MET, STEAP2), and immune contexture (CD8, PD-1, TIM3, LAG3, TIGIT), with PanCK and CD45 for compartment assignment. Digital pathology enabled single-cell segmentation into tumor (PanCK+), stromal, and immune (CD45+) compartments. Immune contexture was defined as Desert, Excluded, or Infiltrated by CD8 distribution. ADC target expression was quantified as the proportion of PanCK+ tumor cells expressing each target or combination. Associations with objective response (ORR), progression-free survival (PFS), and overall survival (OS) were assessed. Paired baseline/on-treatment biopsies (n = 21 pairs) evaluated treatment-induced remodeling. Results: Spatial profiling quantified 30 tumor-cell ADC target phenotypes. Across NSCLC, epithelial target coverage was broad, with > 80% of tumor cells expressing EGFR or MET and > 60% co-expressing both. Co-expression patterns were histology-dependent: EGFR/MET (±HER2) predominated in adenocarcinoma, whereas TROP2/B7-H3 co-expression was enriched in squamous carcinoma. Immune contexture shaped the ADC landscape: Infiltrated tumors showed higher tumor-cell fractions expressing EGFR, MET, TROP2, HER2, STEAP2, and B7-H3 compared with Desert tumors (all p≤0.01), while PanCK+/B7-H4 and PanCK+/CLDN18 were not contexture-associated. Clinically, B7-H4 showed a striking compartment-specific association with outcome. High abundance of B7-H4–expressing immune/stromal cells was the only phenotype replicated across ORR, PFS, and OS (stromal B7H4+: ORR 65.0% vs 38.6%, p = 0.010; PFS 12.0 vs 4.0, p = 0.013; OS 36.4 vs 13.1, p = 0.016). In contrast, tumor-cell B7-H4 predicted resistance and poor survival (tumoral B7H4+: PFS 3.5 vs 10.2, p = 0.007; OS 10.9 vs 35.6, p = 0.047). On treatment, paired biopsies demonstrated target remodeling, with increased B7-H3 expression and a concordant reduction of tumor CLDN18 by composition and membrane intensity. Conclusions: ADC target abundance and co-expression in NSCLC tumor cells are immune-contexture dependent and dynamically remodeled under ICI. Distinct, histology-specific co-expression patterns inform rational mono- and dual-ADC strategies. A novel, clinically actionable finding is the opposite prognostic impact of B7-H4 by spatial compartment, supporting spatially resolved biomarkers and histology- and timepoint-aware ADC±ICI selection for precision treatment in NSCLC.

Cancer burden among adults with type 2 diabetes mellitus in the United States, 1999-2023.

e16480 Background: Type 2 Diabetes mellitus (T2DM) is associated with an increased risk of several cancers due to shared risk factors and diabetes-related metabolic disturbances such as insulin resistance, chronic inflammation, and hyperinsulinemia. This relationship may also be influenced by antidiabetic treatments and disease duration. Methods: Using CDC WONDER data for adults aged ≥25, we analyzed age-adjusted and crude mortality rates (AAMRs and CMRs) per 100,000 for Cancer (ICD-10 C00-D48 ) in T2DM (ICD-10 E11.0-E11.9 ) by year, sex, race/ethnicity, and geography. Joinpoint regression estimated average annual percentage change (AAPC) and annual percentage change (APC) with 95% confidence interval (CIs). Results: The total of 263,009 deaths related to cancer in type 2 Diabetes patients,in which most of deaths occur in Decedent's home.Overall, the AAMR increased from 2.73 (95% CI: 2.65–2.81) in 1999 to 7.08 (95% CI: 6.98–7.18) in 2023 (AAPC: 3.86 ; 95% CI: 2.90 to 4.83, p < 0.000001), with the most significant increase observed between 1999 and 2021 (APC:7.90 ; 95% CI: 6.30 to 9.53 , p < 0.000001). The increase in mortality was slightly more pronounced in women than in men (AAPC: 3.89 vs 3.78). The highest incidence rates were noted among non-Hispanic (NH) American Indian or Alaska Native, followed by NH Blacks or African Americans and Hispanics or Latino.Geographic disparities were apparent, with the West experiencing the greatest impact, while the Northeast was the least affected. Non- metropolitans consistently showed higher AAMR compared to metropolitan areas, though metropolitian locations experienced a steeper increase between the two (AAPC: 4.08 vs 3.80).The state with highest number of deaths was California (44,256). Conclusions: Patients with type 2 diabetes experience a substantial cancer burden, with notable variations across demographic and clinical subgroups. These findings highlight the need for integrated prevention strategies, early cancer screening, and optimized diabetes management to reduce cancer-related mortality in this high-risk population. Deaths and Age-adjusted Mortality Rates (AAMRs) per 100,000 for trends related to Cancer with Diabetes Mellitus type 2 from 1999 to 2023. Variable Deaths AAMR (95%CI) 1999 AAMR (95% CI)2023 Overall 263,009 2.73 (2.65 to 2.81) 7.08(6.98 to 7.18) Male 173,005 3.58(3.44 to 3.73) 9.22 (9.05 to 9.39) Female 114,207 2.2(2.11 to 2.29) 5.42(5.3 to 5.54) NH Blacks 27,906 3.56 (3.26 to 3.87) 7.83(7.49 to 8.17) NH Americans 2,352 3.55 (2.3 to 5.24) 10.57(9.02 to 12.11) West 72,938 2.07 (1.93 to 2.21) 11.43 (11.27 to 11.6) Northeast 35,527 2.79 (2.61 to 2.96) 5.52 (5.25 to 5.75) Metro 157,113 2.34 (2.27 to 2.42) (2020) 7.08 (6.96 to 7.2) Non- metro 48,079 4.34 ( 4.11 to 4.58) 12.14 (11.76 to 12.52)

A randomized, controlled, multicenter, phase 3 study of RP1 (vusolimogene oderparepvec) combined with nivolumab vs physician’s choice of therapy in patients with advanced melanoma that has progressed on anti–PD-1 and anti–CTLA-4 therapy (IGNYTE-3).

TPS9597 Background: Melanoma is the fifth most common cancer, with over 100,000 new cases and 8000 related deaths projected in the US for 2025. First-line systemic treatment with immune checkpoint inhibitors (ICIs) improves the objective response rate (ORR) and extends progression-free survival (PFS) and overall survival (OS) for patients with advanced disease. Among available treatments, combination anti–PD-1 (nivolumab) + anti–CTLA-4 (ipilimumab) therapy is associated with the highest ORR and best PFS and OS. However, only around half of patients respond to treatment, and limited options exist for patients whose melanoma then progresses following anti–PD-(L)1 ± anti–CTLA-4. RP1 (vusolimogene oderparepvec) is a herpes simplex virus type 1–based oncolytic immunotherapy that expresses human granulocyte-macrophage colony-stimulating factor and a fusogenic glycoprotein (GALV-GP-R − ). IGNYTE-3 will evaluate the OS and clinical benefit of RP1 + nivolumab for patients with advanced cutaneous melanoma whose disease has progressed after anti–PD-1 and anti–CTLA-4 therapy (or who are ineligible for anti–CTLA-4 therapy) vs physician’s choice. RP1 + nivolumab has demonstrated durable, clinically meaningful anti-tumor activity (ORR, 33.% per independent central review), with minimal toxicity (NCT03767348). Repetitive intralesional and intravisceral injections were well tolerated in advanced ICI-refractory melanoma. All patients had confirmed progression on prior anti–PD-1 therapy. Methods: IGNYTE-3 (NCT06264180) is a global, randomized, controlled, phase 3 trial. Key eligibility criteria include age ≥12 years, stage IIIB–IVM1a–M1d cutaneous melanoma, disease progression on ≥12 weeks of an anti–PD-1 and anti–CTLA-4 treatment (administered in combination or in sequence, with anti–PD-1 last), ≥1 measurable and injectable tumor, and adequate hematologic, hepatic, and renal function. Patients who are not candidates for anti–CTLA-4 therapy may enroll following progression on anti–PD-1 therapy alone. Patients with BRAF V600-mutant melanoma should have received anti–BRAF ± anti–MEK–targeted therapy prior to enrollment, where appropriate. Patients (N ≈ 400) will receive RP1 + nivolumab or physician’s choice (nivolumab + relatlimab, anti–PD-1 monotherapy rechallenge [nivolumab or pembrolizumab], or single-agent chemotherapy [dacarbazine, temozolomide, or paclitaxel/albumin-bound paclitaxel]). The primary endpoint of the study is OS; the key secondary endpoints are PFS and ORR per RECIST 1.1. Clinical trial information: NCT06264180 .

Empowering future public health professionals: The impact of community-based education on students’ maternal and child health competencies

Preparing future public health professionals to address real-world maternal and child health (MCH) challenges requires educational approaches that extend beyond classroom instruction. In this context, integrating community-based education (CBE) into the curriculum serves as a pivotal strategy. This study assesses the implementation and effectiveness of a CBE module in MCH, designed for strengthening the knowledge and competencies of undergraduate public health students. A mixed-method pre- and post-intervention design was used to assess changes in students’ knowledge, skills, and practical competencies following one year of supervised community engagement in a semi-urban setting in Lahore, Pakistan. Quantitative assessments included survey questionnaires, quizzes, MCQs, and OSCE, while qualitative data were collected through focus group discussions, and self-reflection logs. Descriptive statistics, a paired-samples t-test, and a marginal homogeneity test were used to assess students’ learning and research outcomes. For qualitative data, thematic analysis was conducted using a deductive-inductive approach. Pre- and post- analysis revealed significant improvements (p < 0.001) in students’ knowledge across all MCH domains, along with enhanced skills of leadership, project/time management, communication, problem-solving, teamwork, handling unexpected situations, and designing community-tailored interventions (p < 0.001) following CBE implementation. Ongoing assessments indicated consistent learning with a mean quiz score of 80.2% (SD = 7.2), and a mean MCQ exam score of 81.5% (SD = 7.6). Qualitative data further revealed increased empathy, cultural sensitivity, and professional confidence. The study concludes that the CBE program provides students with valuable insights into the specific needs and challenges of communities related to MCH, thereby enhancing their knowledge and competency development. This experience supports the continuation of CBE programs for future students.

Engineering Ultrahigh‐Contrast Photoactivated Room‐Temperature Phosphorescence With a Robust and Universal Ureido‐Functionalized Siloxane Network

ABSTRACT Photoactivated room‐temperature phosphorescence (pRTP) host‐guest systems have received widespread attention due to their non‐invasive photoresponsiveness, high reversibility, and color tunability. However, traditional polymer hosts often lack efficient photoactivation and sufficient stability due to passive oxygen penetration. Herein, we report a ureido‐functionalized siloxane network derived from the hydrolysis of γ‐ureidopropyltriethoxysilane (UPTES), which serves as a universal photoactivation platform for constructing pRTP systems via doping with various phosphorescent guest molecules. The UPTES‐based systems can achieve superior photoactivation efficiency through the UV‐induced oxygen consumption, boosting phosphorescence intensity by up to approximately 2100‐fold and extending lifetime by approximately 65‐fold. This ultrahigh contrast originates from the strongly active oxygen‐trapping capability of the ureido groups within the siloxane network, which is crucial for establishing the initial ‘off’ state of guest phosphorescence via efficient oxygen‐mediated quenching of triplet excitons. Notably, owing to the dense and robust siloxane network, these systems show excellent stability, maintaining efficient pRTP performance for at least 90 days even in aqueous solutions, organic reagents, or concentrated acid. This work not only presents an ultrastable host matrix for designing ultrahigh‐contrast pRTP materials, but also enables the on‐demand customization of pRTP systems for advanced multi‐level information encryption.

Transforming polyethylene terephthalate (PET) into carbon-based nanomaterials: Advancing sustainable solutions for green energy and environmental remediation

Impact of drying on yield and composition of extracellular vesicles from Centella asiatica

Kif15 orchestrates neuronal–microglial communication via CX3CL1 to impede nerve regeneration

Real-world cost effectiveness of androgen receptor pathway inhibitors for metastatic hormone sensitive prostate cancer: An economic evaluation utilizing data from the International Registry for Men with Advanced Prostate Cancer (IRONMAN).

11164 Background: Several therapies are approved for metastatic hormone sensitive prostate cancer (mHSPC), with differing efficacy and costs. While many cost-effectiveness analyses (CEAs) rely on randomized trial data, such analyses lack generalizability to real-world practice. We evaluated the real-world cost effectiveness (CE) of adding androgen receptor pathway inhibitors (ARPIs) to androgen deprivation therapy (ADT) for first-line (1L) mHSPC using the IRONMAN registry (NCT03151629). Methods: We conducted a US public payer perspective CEA using individual patient-level IRONMAN data. Eligible patients (pts) received 1L ADT alone, ADT + enzalutamide (ENZ), or ADT + apalutamide (APA) with ≥1 follow-up visit. A 3-state Markov model with 1-month cycles and a 10-year horizon was used. Progression-free survival (PFS) was proxied by time-to-next-treatment (TTNT); overall survival (OS) was time from 1L initiation to death or last follow-up. Costs and outcomes were discounted at 3% per year. Outcomes were measured in life-years gained (LYG) and incremental cost-effectiveness ratios (ICER) were reported. Uncertainty was assessed via one-way sensitivity analysis and probabilistic sensitivity analysis. A scenario analysis evaluated hypothetical ENZ price reductions aligned with planned Inflation Reduction Act negotiations. Results: 1187 pts with mHSPC met inclusion (ADT: n=405, ENZ: n=412, APA: n=370; Table 1). In the base case, both ARPI strategies improved OS versus ADT alone, though only APA provided a statistically significant reduction in risk (ENZ: HR 0.78, 95% CI 0.58-1.03, p=0.08; APA: HR 0.50, 95% CI 0.36-0.70, p<0.001). Using TTNT as a proxy for PFS, ADT alone had a reduced risk compared to either ARPI (ENZ: HR 1.97, 95% CI 1.39-2.77, p<0.001; APA: HR 1.51, 95% CI 1.05-2.18, p=0.028); underreporting of subsequent therapies in the ADT alone group may have contributed to this finding. Median follow-up was 26.7 months; median TTNT and OS were not reached. Neither ARPI strategy was CE at conventional US thresholds (ENZ: ICER = $444,947/LYG; APA: ICER = $669,530/LYG), and ENZ would require a 79% price discount to meet CE thresholds. Sensitivity analyses supported the base case results. Conclusions: Adding ENZ or APA to ADT for 1L mHSPC improved OS but was not found to be to be cost-effective at current US prices over a 10-year horizon. Substantial ENZ price reductions would be required to reach commonly used CE thresholds. Baseline characteristics. ADT(N = 405) ENZ(N = 412) APA(N = 370) Median age at study entry (IQR) 71 (64, 78) 71 (65, 76) 71 (65, 76) PSA at study entry (ng/mL) Median (IQR) 9 (1, 53) 4 (1, 21) 3 (0, 13) Range 0, 5430 0, 3560 0, 5530 Missing (%) 137 (34) 62 (15) 56 (15) Duration of follow-up (months) Median (IQR) 24 (10, 41) 28 (17, 41) 28 (17, 40) Range 3, 80 3, 67 2, 64

Low-density lipoprotein receptor–related protein 1 overexpression as an identifier of brain metastasis and survival for patients with lung cancer.

2029 Background: Brain metastasis (BM) is a major cause of mortality in lung cancer. Low-density lipoprotein receptor–related protein 1 (LRP1) has been implicated in tumor invasion and microenvironment regulation; however, its clinical relevance in lung cancer brain metastasis remains unclear. Methods: This retrospective, single-center study included 103 lung cancer patients (including NSCLC and SCLC) diagnosed between January 2013 and February 2025. LRP1 protein expression was evaluated by immunohistochemistry in primary lung tumors and lesions of lung cancer with brain metastasis (unpaired samples). Mean optical density was quantified, and the optimal cutoff for high versus low expression was determined using receiver operating characteristic analysis. Overall survival (OS) and distant metastasis–free survival (DMFS) were assessed using Kaplan–Meier analysis and Cox proportional hazards models, adjusting for pathological type, age, sex, T stage, and N stage. Gene set variation analysis (GSVA), immune cell infiltration analysis (CIBERSORT), and immunotherapy response prediction using TIDE were performed to explore biological characteristics associated with LRP1 expression. Results: LRP1 expression was significantly higher in lung cancer tissues from patients with BM compared with those without BM (P < 0.0001). Among patients with BM, high LRP1 expression was associated with poorer OS (P = 0.0352) and shorter DMFS (P = 0.0183). In multivariable analysis, high LRP1 expression remained independently associated with inferior OS (HR 3.064, 95% CI 1.039–9.034; P = 0.042). GSVA suggested that LRP1-high tumors may be characterized by enrichment of TGF-β, NOTCH, and HEDGEHOG signaling pathways. Immune deconvolution analysis revealed higher infiltration of resting memory CD4⁺ T cells and M0 macrophages in the LRP1-high group. LRP1-low expression was associated with a more favorable predicted response to immunotherapy, as indicated by lower TIDE scores. Conclusions: LRP1 overexpression is associated with brain metastasis, unfavorable survival, and distinct immune features in lung cancer, suggesting its potential value as a prognostic biomarker.

Natural history of weight changes in pancreatic cancer: A longitudinal analysis.

e24063 Background: Unintentional weight loss is common in people with pancreatic cancer and predicts poor outcomes. This study characterized temporal patterns of weight change following a pancreatic cancer diagnosis in a large, diverse patient population in a community oncology setting. Methods: Adults diagnosed with stage I–IV pancreatic cancer from 2020–2024 were identified from an internal registry. Longitudinal weights from six months prior to and 18 months after diagnosis were extracted from electronic medical records (EPIC). Among 635 eligible patients, 402 had baseline weights within one week of diagnosis. Percent weight change from diagnosis was modeled with separate pre- and post-diagnosis slopes, adjusted for age, sex, and stage, with patient-level random effects. Kaplan-Meier methods estimated length of follow-up and landmark overall survival. P<0.05 was considered statistically significant. Results: Median age was 69 (range 34-93) years; 48% were female, 71% White and non- Hispanic/Latino (98%). 52% had stage IV disease. Weight declined by 0.57% (95% CI, −0.64 to −0.49) per week before diagnosis and 0.28% (95% CI, −0.32 to −0.22) per week after diagnosis. Mean cumulative change was +14.7% (95% CI, +12.9% to +16.5%) at six months pre-diagnosis, +7.3% (95% CI, +6.5% to +8.2%) at 3 months pre-diagnosis, -3.6% (95% CI, -4.2% to -2.9%) at 3 months post-diagnosis, -7.1% (95% CI, -8.4% to -5.9%) at 6 months post-diagnosis, and -14.3% (95% CI, -16.7% to -11.9%) at 12 months post-diagnosis. Median follow-up was 19.6 months; 225 deaths (56%) occurred. One- and two-year survival rates were 0.53 and 0.34, respectively. Conclusions: Weight loss began up to six months before diagnosis and persisted afterward, averaging a 14% reduction within a year. These findings highlight the need for nutritional intervention at diagnosis and demonstrates the value of consistent and longitudinal weight management to identify at risk for future severe weight loss.

Association of dynamic changes in tumor markers with overall survival in patients with mucinous appendiceal adenocarcinoma.

e16477 Background: Mucinous appendiceal adenocarcinoma (MAA) is the most common subtype of AA, but it is difficult to accurately measure disease burden using standard cross-sectional imaging. The aim of this study was to determine the association between tumor marker (TM) dynamics and overall survival (OS) in MAA patients. Methods: This was a single-institution, retrospective analysis of MAA patients. TMs analyzed were CEA, CA 19-9, and CA-125. TM response was defined as stable TM if <25% change from baseline and decreased/increased if ≥25% change from baseline. Distributions of OS were estimated by the Kaplan-Meier method. Cox proportional hazards model was used to estimate Hazard Ratio (HR) and p-value. Results: A total of 875 patients with MAA and TM measurements on at least two separate dates were identified and included in this analysis. Evaluating the prognostic effect of a rise in TM after 5-7 months off treatment, we found 220 (31%), 47 (13%), and 46 (13%) patients had TM increase from baseline for CEA, CA 19-9, and CA-125, respectively. Increase in CEA was associated with worse mOS (172.8 mo increase vs. 281.5 mo stable, HR: 1.96; p=0.0002). Patients within the top decile of CEA increase had even shorter mOS at 124.5 mo (HR 1.79 vs. stable CEA; p<0.0001). This association was true for patients with both low-grade (G1, 195.9 mo vs. 264.2 mo, HR: 1.64; p=0.0299) and high-grade (G2/G3, mOS: 143.1 mo vs. 208.3 mo, HR: 2.70; p<0.0001) disease. Rise in CA19-9 was similarly associated with worse mOS (173.5 vs. 264.0 mo, HR: 2.32; p=0.0018). Rising CA-125 had a trend (mOS: 213.1 vs. 281.5 mo, HR: 1.47; p=0.15) towards worse OS that did not reach statistical significance. Evaluating the prognostic significance of decreasing TM while on systemic therapy, we found that among 82 patients with baseline elevated CEA, 44 (54%) had a 25% decrease within 3 months from start of therapy, which was associated with improved mOS (114.4 mo decreased vs. 79.6 mo stable, HR: 0.54; p=0.049). There were insufficient numbers of patients for similar analysis for CA 19-9 or CA-125. Conclusions: Increases in CEA and/or CA 19-9 during surveillance periods are associated with worse survival for MAA patients. For patients with a positive baseline CEA, decrease on systemic therapy is associated with improved survival. Given these findings, serial measurement of TM is warranted for patients with MAA to identify high risk patients for either initiation or change in systemic therapy. Analysis of TM change during systemic therapy and observation. Off Treatment N HR mOS TM ↑ mOS TM Stable P-value CEA 704 1.96 172.8 mo 281.5 mo 0.0002 Grade 1 433 1.64 195.9 mo 264.2 mo 0.0299 Grade 2/3 249 2.70 143.1 mo 208.3 mo <0.0001 CA 19-9 318 2.32 173.5 mo 264.0 mo 0.0018 CA-125 356 1.47 213.1 mo 281.5 mo 0.15 Systemic Therapy (CEA) mOS TM ↓ All Patients 104 0.69 115.4 mo 94.4 mo 0.2 Positive Baseline CEA 82 0.54 114.4 mo 79.6 mo 0.049

Impact of Ori-TTV particles on in vivo CAR-T cell engineering for the treatment of hematologic malignancies.

6558 Background: CAR-T cell therapy has revolutionized hematological malignancy treatment, yet traditional autologous therapies face substantial logistical and financial challenges. An efficient in vivo CAR-T cell generation platform represents a transformative approach to make immunotherapies more accessible. Here, we report the design and validation of Ori-TTV, a T cell-specific lentiviral vector system capable of directly generating functional CAR-T cells within the body. Methods: Ori-TTV was engineered with five synergistic components: (1) an Ori Multiple Targeting Domain (Ori-MTD) for selective delivery to T lymphocytes; (2) a de-targeted fusogen; (3) a T cell-specific synthetic promoter; (4) phagocytosis-resistant modifications; and (5) serum-resistant surface engineering. Ori-TTV encodes a dual-target CAR recognizing CD19 and BCMA, enabling treatment of B-cell malignancies (e.g., non-Hodgkin lymphoma) and plasma cell–derived cancers (e.g., multiple myeloma) with potential extension to autoimmune diseases. Results: Ori-TTV particles are produced at high functional titers comparable to conventional broad-tropism lentiviruses and demonstrate significant resistance to macrophage phagocytosis (>50% reduction). The T cell-specific synthetic promoter drives CAR/GFP expression comparable to the EF-1α promoter in primary T cells while maintaining minimal off-target expression in non-T cells, including HEK293T producer cells and various tumor lines. Ori-TTV efficiently transduces resting T cells, achieving >80% CAR expression in PBMCs in vitro . The resulting CAR-T cells exhibit a predominantly memory phenotype with increased TSCM cells compared to Kymriah-like ex vivo CAR-T cells. Serial killing assays demonstrated potent, multi-round cytotoxicity against CD19+ and BCMA+ target cell lines with varying antigen densities. In vivo efficacy was evaluated in humanized mouse models of NHL and MM. The PBMC humanized mice were challenged with tumors and administered Ori-TTV. Bioluminescence imaging demonstrated robust tumor regression, with complete remissions in the majority of treated animals. Pharmacodynamics revealed efficient in vivo transduction, with CAR-T expansion kinetics showing peak levels at day 13 (20–30% of circulating T cells). Expanded CAR-T cells maintained a memory-enriched phenotype with significantly increased TSCM cells. Long-term monitoring confirmed durable responses without toxicity or vector-related adverse events. Furthermore, in CD34+ humanized mice, single-injection Ori-TTV caused durable depletion of peripheral B cells. Conclusions: These findings establish Ori-TTV as a next-generation lentiviral vector system enabling safe, efficient, and selective in vivo CAR-T cell generation. It has the potential to redefine CAR-T therapy by eliminating manufacturing barriers, reducing costs, and expanding patient access.

Pre-operative intratumoral toll-like receptor 9 (TLR9) agonist vidutolimod (Vidu) and stereotactic body radiation therapy (SBRT) in early triple-negative breast cancer (eTNBC): Randomized phase 2 CyberImmunoBreast trial.

e12635 Background: Vidu is a virus-like particle encapsulating a TLR9 agonist, CpG-A, promoting Th1-based innate and adaptive immune responses. Vidu showed antitumor activity in patients with PD-1/PD-L1 inhibitor-resistant melanoma. Irradiation is considered as a potential anti-tumor immune-stimulator. We assess the ability of these two modalities to increase stromal tumor-infiltrating lymphocytes (sTILs), a biomarker associated with improved outcomes in eTNBC (NCT04807192). Methods: Untreated eTNBC patients are randomized 1:1 to SBRT (1x 8 Gy) on the tumor bed (Arm 1) vs SBRT followed by 4 doses of Vidu injected subcutaneously on D1 and intratumorally on D5, D9, and D16 (Arm 2) before surgery. Tissue and blood samples were collected at baseline (BL) and surgery. The primary endpoint is the change of sTILs from BL to surgery, with a predefined efficacy threshold of a 10% absolute mean increase. Secondary endpoints include safety and tolerability, clinical outcome parameters, and exploratory translational research, including immune cell profiling in peripheral blood, digital spatial profiling of protein and RNA expression in tissue, and assessment of T-cell receptor (TCR) diversity. We present the interim results of the first 8 patients. Results: Four patients were recruited in each arm. At BL, patients had NST histology, cN0, and median tumor size 2.2 cm (1.0-3.0). All patients with Vidu showed an increase of sTILs ranging from 10 to 75%, and also follicular and interfollicular hyperplasia in their axillary sentinel lymph node; none in the SBRT-alone arm exhibited these features. Analyzed tissue samples revealed an on-target effect of Vidu with the increase of MyD88 and decrease of IKBKG. At proteins level, the addition of Vidu to SBRT displayed an activation of INFg/IL6 pathway and higher impact on tumor proliferation, cell death and immune cells. CD4 and CD8 T-cells, memory cells, macrophages, myeloids and neutrophils were upregulated; cells expressing CD20, CD34 or CD56 were decreased. Addition of Vidu to SBRT favored the maintenance of immune checkpoint proteins expression in TME and their downregulation in tumor. At the transcriptional level, Arm 2 displayed an increase in immune response, immune receptor activity, antigen presentation, cell migration, apoptosis, and recruitment of immune cells. Decreased TCR score suggests a promotion of clonal specific T-cells. In blood, granulocytic myeloid derived suppressor cells (gMDSC) decreased in Arm 2. Conclusions: Intratumoral Vidu injection increased significantly sTILs in all treated patients and induced favorable immunological modulation of the tumor and its microenvironment. Thus, Vidu may potentially alter response to neo-/adjuvant treatments and patients’ outcomes, warranting further investigations. Clinical trial information: NCT04807192 .

Limb compression therapy and chemotherapy-induced peripheral neuropathy in women with gynecologic cancers: A prospective self-controlled study (NEURO-GLOVE Trial)—Updated long-term analysis.

5545 Background: No established strategy prevents taxane-induced CIPN. We evaluated if dual-site mechanical compression reduces CIPN severity at 3 and 6 months post-treatment. Methods: In this prospective, self-controlled study (Dec 2023–Dec 2024), 76 women receiving carboplatin–paclitaxel were enrolled. During infusions, compression was applied to the non-dominant hand (two surgical gloves) and ipsilateral foot (Class II stocking); contralateral limbs served as controls. The primary endpoint was the incidence of Grade ≥2 sensory/motor neuropathy (CTCAE v5.0) at End-of-Treatment (EOT), 3 months, and 6 months. Results: Among 76 patients (median age 61), Grade ≥2 CIPN was lower in compression vs control limbs at Cycle 3 (27/76 [35.5%] vs 41/76 [53.9%]; P=.001) and EOT (45/76 [59.2%] vs 53/76 [69.7%]; P=.021). Benefits persisted at 3 months (22/76 [28.9%] vs 40/76 [52.6%]; P=.015) and 6 months (15/74 [20.3%] vs 25/74 [33.8%]; P=.002). Longitudinal analysis showed significant time-by-limb interactions for hand sensory (P=.003), foot sensory (P=.018), and motor domains (P=.041). EORTC QLQ-CIPN20 sensory scores showed high accuracy (AUC 0.92 at Cycle 3; 0.97 at EOT). Conclusions: Compression significantly reduces acute and persistent CIPN. Sustained benefits at 3 and 6 months suggest prevention of irreversible damage, supporting compression as an effective neuroprotective strategy. Clinical trial information: NCT07105553 . Limb-specific incidence of moderate-to-severe chemotherapy-induced peripheral neuropathy by EORTC QLQ–CIPN20 across time. Time point Limb Moderate–severe CIPN†, n/N (%) Discordant cases ‡, n McNemar p (compression vs control) RD %, Control–Compression (95% CI) P value vs baseline § Baseline CompressionControl 0/76 (0.0)0/76 (0.0) – – – – Cycle 3 Compression Control 27/76 (35.5)41/76 (53.9) Compression only: 2Control only: 16 0.001 +18.4% (4.5 to 32.4) <0.001 <0.001 EOT Compression Control 45/76 (59.2)53/76 (69.7) Compression only: 1Control only: 9 0.021 +10.5% (3.5 to 24.5) <0.001 <0.001 3-month follow-up Compression Control 22/76 (28.9)40/76 (52.6) Compression only: 2Control only: 20 0.015 +23.7% (10.0 to 37.4 <0.001 <0.001 6-month follow-up Compression Control 15/74 ** (20.3)25/74 (33.8) Compression only: 0Control only: 10 0.002 +13.5% (1.5 to 25.4) <0.001 <0.001

Treatment-free survival (TFS) in patients with advanced urothelial carcinoma (aUC) treated with enfortumab vedotin (EV)–based therapy.

4576 Background: EV as monotherapy or with pembrolizumab (EVP) has shown robust efficacy in patients with aUC. Despite lack of data, treatment breaks (TB) with EV are frequently utilized due to toxicity or patient/physician preference. In this retrospective real-world analysis, we evaluated TFS after temporary or permanent EV discontinuation in patients with aUC. Methods: A multicenter cohort of patients with aUC treated with EV/EVP between 01/2015 through 12/2025 were included. Patients were categorized in groups with or without TB (defined as ≥6 weeks between EV doses without progression). Baseline characteristics were summarized using descriptive statistics, and comparison was performed using the chi-square test/Fisher's exact and t-test, as appropriate. TFS was estimated using the Kaplan–Meier method among TB+ patients. Overall survival (OS) and progression-free survival (PFS) were estimated for both cohorts using the Kaplan-Meier method and compared using the log-rank test. Univariable and multivariable models adjusted for baseline variables evaluated factors associated with TFS, OS and PFS. Results: From a total of 172 patients eligible for inclusion, 25 (14%) received TB and 148 (86%) did not. Median age was 72.5 years. Most patients were White (76.3%), had primary bladder cancer (89%), and received EVP (63%). Overall, 30% had ≥1 prior line of therapy. Baseline characteristics did not differ significantly between patients with and without TB. Most common reason for TB was treatment toxicity (52%) and a minority (20%) continued pembrolizumab during their break. The median TFS was 3.6 months (95% CI 3.0, 8.3), with 28% experiencing a TFS ≥24 weeks. TB did not compromise outcomes, and patients with a TB demonstrated longer median PFS (13.5 vs. 7.7 months, p=0.05) and OS (not reached vs 21.8 months, p=0.008). Prior radiation therapy (OR 0.18 (95% CI 0.06-0.53, p=0.002) and prior adjuvant chemoimmunotherapy (OR 0.18 (95% CI 0.04-0.77, p=0.02) were independently associated with decreased odds of experiencing a TB. Conclusions: Treatment break on EV therapy did not compromise outcomes and resulted in TFS lasting ≥6 months in a subset of patients. Rational treatment de-escalation strategies in selected patients need to be prospectively investigated to mitigate long-term toxicity in patients with aUC undergoing EV-based therapy.

Final results of a single-arm, open-label, multicenter phase 2 study of the radiopharmaceutical [ ¹⁷⁷ Lu]Lu-DOTA-TATE and [ ⁶⁸ Ga]Ga-DOTA-TATE in adults with advanced intracranial meningioma.

2090 Background: A subset of meningiomas has an aggressive clinical course requiring multimodal therapies. Yet, treatment options beyond surgery and radiation are limited. Somatostatin receptor 2 (SSTR2) is uniformly expressed in meningiomas and can be targeted by the radiopharmaceutical agent [ 177 Lu]Lu-DOTA-TATE ( 177 Lu-Dotatate). [ 68 Ga]Ga-DOTA-TATE ( 68 Ga-Dotatate) PET is emerging as a promising imaging modality to assess treatment response in SSTR2-expressing tumors. However, prospective clinical data supporting the use of 177 Lu-Dotatate and 68 Ga-Dotatate in treatment-refractory meningiomas is limited. Methods: In this multicenter, open-label, phase 2 clinical study (NCT03971461), adult patients with progressive intracranial meningiomas received 177 Lu-Dotatate at 7.4 GBq (200 mCi) every 8 weeks for 4 doses. The primary endpoint was 6-month progression-free survival (PFS-6). Up to 5 meningioma lesions per patient were assessed by gadolinium-enhanced T1 MRI every 12 weeks. 68 Ga-Dotatate PET was obtained before/after 177 Lu-Dotatate treatments. Lesional 68 Ga-Dotatate PET activity was assessed relative to liver/spleen or superior sagittal sinus (SSS). Results: 32 patients (female = 21, male = 11) with progressive meningiomas (WHO grade 1 = 7, grade 2 = 24, grade 3 = 1) were enrolled. Median age was 65.5 (range 41-78) years. All patients had at least one prior tumor surgery and at least one course of radiation. Overall, 177 Lu-Dotatate was well tolerated and the most common grade 3/4 adverse events were transient cytopenia in 15 patients (47%). One patient (3%) discontinued treatment due to grade 4 thrombocytopenia. PFS-6 was reached in 22 patients (69%), which includes 5 of 7 (71%) with grade 1 and 17 of 24 (71%) with grade 2 meningiomas. Best radiographic response by MRI was partial response (PR) in 5 (16%) and stable disease (SD) in 20 (63%) patients. Eight patients (16 lesions) were evaluable by paired MRI and 68 Ga-Dotatate PET pre- and post-treatment. Referenced to SSS, 68 Ga-Dotatate avidity reduced by ≥50% in 2 lesions (PR), 25-49% (minor response, MR) in 3 lesions and remained stable ( < 25% reduction and < 25% increase) in 11 lesions. Using liver/spleen as a reference (6 patients, 14 lesions), 68 Ga-Dotatate uptake was reduced in 9 lesions and stable in 5 lesions. 68 Ga-Dotatate PET assessments were generally concordant with MRI-based treatment response assessments. Conclusions: The primary endpoint (PFS-6) was met in this phase 2 study with 69% of patients achieving PFS-6, thereby surpassing established historical benchmarks. 177 Lu-Dotatate was generally well tolerated and deserves further study in patients with advanced meningiomas. Exploratory 68 Ga-DOTATATE PET studies showed decreased uptake in a subset of lesions and bears promise as an imaging biomarker to assess treatment response. Clinical trial information: NCT03971461 .

Dying tumor cells as a driver of tumor repopulation after insufficient thermal ablation of papillary thyroid carcinoma.

e18046 Background: Although high-quality clinical evidence remains limited, the use of thermal ablation for papillary thyroid carcinoma (PTC) is increasing. Emerging data suggest that thermal ablation may accelerate tumor progression in a subset of patients, yet the underlying biological mechanisms are poorly understood. This study aimed to elucidate the clinical features and underlying mechanisms of accelerated tumor relapse after thermal ablation. Methods: Clinical pathological features of post-ablation surgical specimens were analyzed and Xenium in situ spatial transcriptomics was conducted. In vitro and in vivo models were established to simulate accelerated tumor repopulation following insufficient thermal ablation and to investigate the underlying mechanisms. Time-lapse imaging and RNA sequencing were performed to characterize how heat-induced dying cells influence the behavior of surviving cells. Quantitative PCR, Western blotting, immunohistochemistry (IHC), and flow cytometry (FACS) were used to validate candidate molecular mechanisms, and enChIP-MS was applied to identify upstream regulatory factors. Results: Compared with patients receiving initial surgical treatment, patients receiving thermal ablation present with significant higher proliferation index (Ki-67% 8% vs 1%), and the phenomenon is significantly presented in area close to the ablative zone. Mechanistically, heat-induced dying cells promoted the repopulation of surviving cells in a contact-dependent manner after insufficient thermal ablation, and this effect was not attributable to a single mode of cell death. Dying cells upregulated DLL4, which activated Notch signaling in surviving cells and drove their proliferation. Moreover, anti-DLL4 antibody treatment effectively attenuated the dying cell–mediated proliferative effect both in vitro and in vivo. Upstream analysis revealed that HNRNPU was enriched at the DLL4 promoter after heat treatment, facilitating DLL4 transcription and amplifying its expression. Conclusions: Insufficient thermal ablation significantly accelerate tumor progression. Heat-induced dying cells play a vital role in the process via activation of the DLL4–Notch pathway. As a relative less malignant tumor, the use of treatment without strong clinical evidence and underdetermined risks should be with caution.

Two-dimensional mathematical modeling of tumor invasion using the generalized integral transform technique: Role of haptotaxis in spatial tumor-ECM dynamics.

e15005 Background: Tumor invasion is a spatially heterogeneous and multiscale process driven by interactions between cancer cells, the extracellular matrix (ECM), and matrix degrading enzymes (MDEs). Mathematical modeling is essential for investigating invasion mechanisms that are difficult to assess experimentally. Directed migration, particularly haptotaxis along gradients of matrix bound ECM components, is a key determinant of invasion morphology and aggressiveness. While one dimensional models provide insight, two dimensional (2D) formulations are required to capture realistic spatial invasion patterns. However, 2D models present significant numerical challenges due to strong nonlinear coupling and steep gradients, motivating advanced computational approaches such as the Generalized Integral Transform Technique (GITT). Methods: A dimensionless 2D system of coupled partial differential equations was developed to describe tumor cell density, ECM density, and MDE concentration within a confined tissue domain. Tumor cell migration combined random motility and haptotaxis toward ECM gradients. ECM degradation was locally driven by enzymatic activity, while MDE dynamics included diffusion, tumor induced production, and decay. Homogeneous Neumann boundary conditions represented a closed system. The system was solved using GITT, transforming the PDEs into a coupled set of ordinary differential equations via eigenfunction expansions in both spatial directions. The resulting stiff ODE system was integrated using the IMSL DIVPAG routine. Convergence with respect to truncation order was assessed, and numerical verification was performed through comparison with the Method of Lines. Parametric analyses focused on haptotactic sensitivity. Results: The proposed approach produced stable and convergent solutions for all state variables, with excellent agreement relative to reference numerical solutions. Low haptotactic sensitivity (γ = 0.0025) resulted in diffuse and nearly isotropic tumor expansion dominated by random motility. Increasing haptotactic sensitivity (γ = 0.01) led to strongly localized and anisotropic invasion patterns, characterized by sharp fronts, spatial channeling, and intensified ECM degradation. Despite increased nonlinearity, GITT maintained accuracy provided sufficiently high truncation orders were employed. Conclusions: The results demonstrate that GITT is a robust and efficient framework for two dimensional tumor invasion modeling. Haptotaxis emerged as a key regulator of invasion aggressiveness and spatial heterogeneity, shaping tumor morphology and ECM remodeling. This approach provides mechanistic insight into ECM guided migration and supports future in silico studies of tumor microenvironment interactions and anti invasive strategies.

Early-phase operational readiness gaps in oncology cell and gene therapy trials and implications for scalable trial infrastructure.

11067 Background: First-in-human (FIH) and Phase 1 oncology cell and gene therapy (CGT) trials have highlighted that operational readiness, rather than scientific feasibility, is often the primary constraint on trial execution and patient access. Many clinical sites lack the infrastructure, staffing, and process maturity required to support CGT trials, limiting enrollment and scalability. Methods: Operational lessons were analyzed across multiple early-phase oncology CGT programs, including autologous and allogeneic platforms. Assessments focused on trial execution during FIH and Phase 1 activation, site readiness, vector and cellular product handling, storage and chain-of-custody requirements, coordination among manufacturing, sites, and couriers, staffing and training needs, and turnaround times from leukapheresis or biopsy to dosing. Results: Consistent site readiness gaps were identified in apheresis coordination, vector storage and handling, chain-of-custody documentation, and real-time cross-functional communication. Autologous programs showed increased operational complexity driven by patient-specific manufacturing, narrow scheduling windows, and variable vein-to-vein turnaround times. Allogeneic programs had reduced scheduling constraints but introduced challenges related to centralized manufacturing oversight and site-level accountability. Across platforms, CGT trials required specialized staffing and training beyond standard oncology research models. Insufficient early operational enablement resulted in delayed dosing and reduced patient access by ~1-3 months. Conclusions: Lessons from early-phase oncology CGT trials demonstrate that proactive operational readiness, particularly at the site level, is essential to enable scalable trial infrastructure and equitable patient access. Early readiness assessments, targeted workforce training, and integrated manufacturing-logistics coordination are critical to support efficient CGT trial execution and future expansion. Learning Objectives: Recognize common operational readiness gaps identified during FIH and Phase 1 oncology CGT trials. Understand how manufacturing, logistics, and site coordination impact early-phase trial execution. Apply early operational learnings to inform scalable CGT trial infrastructure. Key Takeaways: Operational readiness is a primary determinant of early CGT trial success. Many sites require significant enablement to conduct CGT trials effectively. Early investment in readiness improves turnaround times and patient access.