PURPOSE:To evaluate intrathecal QH104, an allogeneic B7 homolog 3 (B7-H3)-targeted chimeric antigen receptor (CAR) γδ T-cell therapy, in patients with leptomeningeal metastasis (LM). PATIENTS AND METHODS:In this phase 1 study (NCT06592092), three patients with LM from B7-H3-positive solid tumors were enrolled, including two with lung adenocarcinoma and one with triple-negative breast cancer. QH104 was administered at a fixed dose of 3 × 107 cells per infusion via lumbar puncture or an Ommaya reservoir. The primary objective was to evaluate clinical response. Secondary objectives included safety, overall survival, quality of life, and pharmacokinetic/pharmacodynamic profiling. RESULTS:QH104 was generally well tolerated, with no grade ≥4 treatment-related adverse events (TRAEs). One patient developed grade 3 immune effector cell-associated neurotoxicity syndrome. All TRAEs resolved with supportive care. All patients had stable disease on days 14 and 30 according to the Response Assessment in Neuro-Oncology-Leptomeningeal Metastases criteria, with symptom improvement in two patients. Cerebrospinal fluid (CSF) cytology converted to and remained negative through day 30 in one patient with positive baseline cytology. B7-H3-CAR γδ T cells persisted in CSF for at least one week and were accompanied by increased interferon gamma (IFN-γ) levels. Single-cell sequencing suggested IFN-γ-associated immune remodeling in CSF, including expansion of an inflammatory macrophage state and subsequent lymphocyte recruitment. CONCLUSIONS:This study provides preliminary proof of concept for intrathecal allogeneic B7-H3-CAR γδ T-cell therapy in LM, with early evidence of safety, clinical activity, local persistence, and IFN-γ-associated immune remodeling in CSF.

e23515 Background: Accurate risk stratification is essential for guiding postoperative adjuvant therapy in resected gastrointestinal stromal tumors (GIST). Traditional Joensuu criteria rely mainly on mitotic count, together with tumor size and primary site. While immunohistochemistry is routinely used for diagnosis, integrating biomarkers into prognostic assessment may improve identification of patients at high risk of recurrence after curative resection. We developed a prognostic model incorporating a proliferation marker (Ki-67) and a vascular marker (CD34) to improve postoperative risk stratification. Methods: We retrospectively collected 634 patients with localized GIST who underwent curative resection at the National Cancer Center of China. The primary endpoint was disease-free survival (DFS). A multivariable Cox regression model including Ki-67 index, CD34 expression, tumor size, and sex was developed; mitotic count and tumor site were evaluated for inclusion. Discrimination was compared with the modified Joensuu criteria using Harrell’s concordance index (C-index) and log-rank tests. Results: In this cohort, the Joensuu criteria showed limited DFS separation between intermediate- and high-risk groups (log-rank P=0.17). In multivariable analysis, Ki-67 index and CD34 positivity were independent prognostic factors. Mitotic count and tumor site were evaluated but were not retained in the final multivariable model. The integrated model achieved a C-index of 0.766 (95% CI, 0.632–0.877), higher than the Joensuu criteria (C-index 0.694; 95% CI, 0.573–0.795). In multivariable Cox regression for DFS (Table), higher Ki-67 index and larger tumor size were associated with increased risk, whereas CD34 positivity and female sex were protective. The model provided improved discrimination among higher-risk patients, with significant separation between intermediate- and high-risk groups (P=0.002), whereas DFS was similar between low- and intermediate-risk groups (P=0.86). Conclusions: A prognostic model integrating Ki-67 and CD34 may refine DFS risk stratification after GIST resection, particularly at the intermediate- versus high-risk boundary where standard criteria show limited discrimination. This approach may support more tailored selection of patients for postoperative adjuvant therapy. Multivariable analysis of factors associated with DFS. Variable HR 95% CI P value Ki-67 index (per 1% increase) 1.04 1.01-1.07 0.007 Tumor size (per 1 cm increase) 1.08 1.01-1.16 0.019 CD34 positive (vs negative) 0.36 0.16-0.81 0.014 Female (vs male) 0.37 0.17-0.81 0.013

Carcinoembryonic antigen (CEA) stands as a classic and widely applied tumor biomarker mainly for epithelial malignancies. Its restricted tumor expression pattern and role in cellular adhesion render it a promising therapeutic target. However, the translation of CEA into effective therapies has long been hindered by multiple challenges. As the first comprehensive review of CEA-targeted therapies, we leveraged peer-reviewed literature and officially disclosed global pharmaceutical data to delineate the landscape and evaluate the prospects across all subfields of CEA-targeted drug modalities, including antibody-drug conjugates, chimeric antigen receptor T cells, bispecific antibodies, vaccines, and radionuclide conjugates. We also dissected the underlying mechanisms of the challenges contributing to these setbacks. By proposing multifaceted and innovative strategies, this review facilitates CEA’s transition from a diagnostic and predictive biomarker to a viable therapeutic target, ultimately supporting improved clinical outcomes for patients with CEA-expressing cancers.

Objective The aim of this study is to investigate the potential profile of decision-making conflicts in early-stage non-small cell lung cancer (NSCLC) patients, and to explore the mediating role of financial toxicity between psychological resilience and decision-making conflicts. Methods A cross-sectional survey was conducted to analyze 310 patients with early-stage NSCLC who visited a tertiary Grade A oncology hospital in Beijing, China from August 2023 to April 2024. General information questionnaires, the Cancer Specific Resilience Scale (RS-SC), the Decision Conflict Scale (DCS), and the COST-PROM were collected. Results Decision conflict among early-stage NSCLC patients was classified into three subgroups: 44.5% of patients exhibited low decision conflict (mean score 10.97 ± 1.73), 30.3% exhibited moderate decision conflict (mean score 18.21 ± 2.89), and 25.2% exhibited high decision conflict (mean score 23.90 ± 3.31). Independent factors associated with decision conflict included lower education level, lower monthly income, unemployment, and participation in the New Rural Cooperative Medical Insurance (all P < 0.05). Mediation analysis showed that financial toxicity significantly mediated the relationship between psychological resilience and decision conflict. The direct effect of psychological resilience on decision conflict was significant (β = -0.162, P = 0.004), as was the indirect effect through financial toxicity (β = -0.041, P = 0.017). Financial toxicity accounted for 18.1% of the total mediation effect. Conclusions Early-stage NSCLC experience varying degrees of decision conflict. Financial toxicity plays a partial mediating role between psychological resilience and decision conflict. Interventions aimed at reducing financial toxicity may improve psychological resilience and reduce decision conflict in these patients.

Abstract Background: FAST-TIL (HS-IT101) is an innovative autologous tumor-infiltrating lymphocyte (TIL) therapy product developed using a fully enclosed, automated platform. It features minimal dependence on IL-2, requires very small amounts of starting tumor tissue (<0.05 g), and completes manufacturing in only 14 days. The Phase I clinical trial of FAST-TIL (HS-IT101) in patients with advanced solid tumors, including melanoma (NCT06342336), is ongoing, and we report preliminary clinical data with a median follow-up of 6 months. Methods: This is a Phase I, open-label, single-arm, multicenter clinical trial evaluating autologous FAST-TIL (HS-IT101) in patients with advanced melanoma who have progressed on or are intolerant to prior systemic therapy. The primary endpoint is safety, assessed by the incidence and severity of adverse events according to CTCAE v5.0. Secondary endpoints include preliminary efficacy measures and pharmacokinetic. Results: As of August 2025, 12 patients with advanced melanoma (2 cutaneous, 8 acral, and 2 mucosal) had received FAST-TIL (HS-IT101) treatment, with a median age of 60.5 years. Eleven patients had previously progressed on or were resistant to immune checkpoint inhibitor (ICI) therapy. Lymphodepletion regimens included LD-NMA conditioning (n=2: cyclophosphamide 300 mg/m² qd and fludarabine 30 mg/m² qd on Days -5 to -3) and MD-NMA conditioning (n=10: cyclophosphamide 750 mg/m² qd on Days -4 to -2, and fludarabine 30 mg/m² qd on Days -4 to -1). Following TIL infusion, patients received subcutaneous interleukin-2 (IL-2) at 2 MIU/m² once daily for 3 days. Most adverse events (AEs) were attributable to the lymphodepleting chemotherapy and IL-2 administration. No grade 4 or 5 AEs were observed, and all AEs resolved promptly with supportive care and minimal complications. Cytokine release syndrome (CRS) of grade ≤2 occurred in 5 patients (41.7%). No cases of tumor lysis syndrome (TLS) or immune effector cell-associated neurotoxicity syndrome (ICANS) were reported. In the efficacy-evaluable MD-NMA cohort (n=10), the objective response rate (ORR) was 50%, including 2 patients with confirmed complete response (CR) and 3 with confirmed partial response (PR). As of December 2025, with a median follow-up of 6 months, the median progression-free survival (mPFS) had not been reached.T-cell receptor (TCR) clonal analysis in 4 patients demonstrated robust persistence of infused T-cell clones in peripheral blood, comprising 41% to 77% of the TCR repertoire on Day 168 post-infusion. Conclusion: FAST-TIL (HS-IT101) demonstrates a favorable safety profile, promising antitumor activity, and durable clinical responses in patients with advanced melanoma. These findings support further evaluation in larger, controlled studies to confirm its therapeutic potential and establish its role in advanced melanoma treatment. Citation Format: Di Wu, Yuan Fang, Zhen Guo, Jie Liu, Jing Lin, Yaotiao Deng, Shijie Lan, Shuhang Wang, Ganchen Gao, Pengxiang Wang, Xinhua Zhang, Yi Zhao, Yu Chen, Yu Jiang, Ning Li. Fast-manufactured, low IL-2-dependent FAST-TIL for the treatment of advanced melanoma in asian patients: Median 6-month follow-up data from a phase I clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT195.

Injectable hydrogel platforms have emerged as a powerful localized approach to direct and potentiate immune responses within draining lymph nodes (dLNs), the critical orchestrators of systemic anti-tumor immunity. To address the challenge of efficiently targeting delivery to dLNs, we developed an integrated nanovaccine platform, designated HM@FP Gel, by co-encapsulating hybrid membrane nanovesicles, co-delivery of autonomous tumor antigen and adjuvant signals, with a bifunctional anti-PD-1/IL-2 fusion protein within a thermosensitive, photo-crosslinkable collagen matrix. Upon subcutaneous injection, this platform forms an in-situ depot that provides sustained co-delivery, achieving similar to 80% cumulative release of both payloads over 4 days in vitro and significantly prolonging local retention while enhancing targeted accumulation in dLNs compared to free formulations. This sustained and targeted delivery robustly activated dendritic cells in vitro and, in a murine model of post-resection MC38 colon carcinoma, effectively reprogrammed the microenvironment of dLNs. Key hallmarks of this immunomodulation included the expansion of effector T cell populations, suppression of regulatory T cells, and a profound reduction of PD-1 expression within dLNs. Consequently, HM@FP Gel elicited durable systemic antitumor immunity, achieving 100% survival at day 60 post-resection and markedly suppressing local recurrence. These results establish a versatile hydrogel-based strategy for next-generation cancer vaccines that leverages localized delivery to achieve precise and potent dLN activation.

Oral nanodrug delivery systems have gained prominence in pharmaceutical research due to their high safety, excellent patient compliance, and significant clinical translation potential. However, the multiple physiological barriers of the gastrointestinal tract severely limit the absorption of peptide/protein-based biologics, resulting in low bioavailability. Nanotechnology-based delivery systems can enhance gastrointestinal permeability and drug stability, enabling site-specific accumulation while minimizing off-target effects. Recent advances have demonstrated remarkable progress in treating gastrointestinal diseases (e.g., inflammatory bowel disease) and have provided novel non-invasive therapeutic strategies for systemic disorders such as diabetes and cancer. This review systematically elucidates the mechanisms of gastrointestinal barriers and their impacts on drug delivery, cutting-edge advancements in nanocarriers for treating digestive and systemic diseases, and key challenges in clinical translation, aiming to provide a theoretical foundation and future perspectives for advancing oral nanomedicines.

Antibody-based therapies have gained significant traction in oncology, as evidenced by their prominent presence at international conferences such as American Association for Cancer Research (AACR) and American Society of Clinical Oncology (ASCO). Modalities including antibody–drug conjugates (ADCs), bispecific antibodies (BsAbs), and T-cell engagers (TCEs) are increasingly recognized as pillars of precision medicine. Driven by advances in molecular engineering, antibody formats and mechanisms of action have evolved beyond conventional antigen blockade to encompass multimodal cytotoxicity and immune modulation. ADCs now leverage optimized linkers and payloads for targeted delivery and potent tumor cell killing. BsAbs simultaneously engage tumor and immune cell targets to enhance immune activation, while TCEs enable T cells to recognize intracellular antigens presented via MHC, overcoming the limitations of extracellular targeting. Emerging design strategies are increasingly tailored to target-specific features such as expression levels, internalization capacity, and cellular subtype. Innovations include non-internalizing ADCs for low-abundance targets and biased antibody architectures that preferentially activate CD8+ T cells. These developments are expanding the therapeutic landscape toward greater efficacy, safety, and personalization. This review outlines the global landscape of antibody drug development, highlighting a paradigm shift toward target-driven design principles that integrate structural innovation with functional precision.

6067 Background: Adenoid cystic carcinoma (ACC) is a rare head and neck malignancy characterized by highly variable clinical outcomes and a lack of validated biomarkers to guide risk stratification or therapeutic decision-making. Despite a generally low tumor mutational burden, patients frequently experience late recurrence and distant metastasis, underscoring the need for biologically informed prognostic models. Existing genomic and transcriptomic classifiers have failed to adequately explain this heterogeneity. We therefore performed integrated multi-omic profiling to define biologically grounded prognostic subtypes and clinically actionable biomarkers in ACC. Methods: We established a multi-omics cohort of 55 surgically resected ACC tumors, including salivary gland–derived and pulmonary ACC, with matched adjacent normal tissues. Whole-exome sequencing, RNA sequencing, quantitative proteomics, and phosphoproteomics were performed. Cross-omics concordance and driver-anchored pathway effects were assessed. Transcriptomic and proteomic data were integrated using Similarity Network Fusion (SNF) to derive molecular subtypes. Prognostic proteins were evaluated using Cox regression. Targeted quantitative mass spectrometry was applied for orthogonal validation and for quantifying antibody–drug conjugate (ADC) targets and pathway stoichiometry. Results: ACC exhibited a low-mutational genomic landscape but profound proteomic and phosphoproteomic remodeling, with systematic activation of replication, cell-cycle, chromatin remodeling, and receptor tyrosine kinase–adhesion pathways, accompanied by suppression of immune-associated signaling. Driver effects were more consistently captured at the protein level than at the RNA level, indicating a proteome-driven tumor biology. SNF-based multi-omic integration identified three molecular subtypes with significantly different disease-free survival (DFS; log-rank P=0.0064), outperforming the conventional ACC-I/II classifier. These subtypes formed a biological continuum defined by metabolic robustness and cell-cycle competence. A compact three-protein signature independently stratified DFS. Quantitative profiling demonstrated broad and functionally relevant expression of ADC targets, including TROP2 and B7-H3, and identified ratio-based functional indices (e.g., IGF2/IGF1R and TP63/NOTCH1) associated with risk groups. Conclusions: ACC is a proteome-driven malignancy in which post-transcriptional regulation and signaling stoichiometry dominate clinical behavior. Integrated multi-omic analysis redefines ACC prognostic architecture and yields quantitative, translatable biomarkers that may inform precision risk stratification and therapeutic strategies in this rare head and neck cancer.

Abstract Background: CVL006 is a novel bispecific antibody designed for synergic antitumor activity by simultaneously blocking two mechanistically distinct pathways VEGF/VEGFR signaling and the PD-L1/PD-1 axis. In this Open-label, Multicenter Phase I Clinical Study of CVL006, Safety, pharmacokinetics (PK) and preliminary efficacy will be assessed in adult subjects with advanced solid tumors, and, thus, the recommended phase II dose (RP2D) will be established (NCT06621615). Method: All subjects in this study received CVL006 every 2 weeks (Q2W). Primary objectives were to evaluate safety, tolerability, and clinical efficacy by objective response rate (ORR). Results: As of the data cutoff date of Nov 14, 2025, 29 subjects with various advanced solid tumors received CVL006 at 0.03-20 mg/kg, 12 subjects in phase Ia, 7 subjects in phase Ib and 10 subjects in phase Ic. Phase Ia and phase Ib were completed and Phase Ic is ongoing. Phase Ia results show that CVL006 is well-tolerate, MTD has not reached, and RP2D is 20 mg/kg. All these AEs were recovered after symptomatic treatment. In the 20 mg/kg dose group, CVL006 showed linear pharmacokinetics and a low incidence of ADA positivity.18 subjects had at least one efficacy assessment. In the 10 mg/kg dose group (N=3), 2 stable disease (SD) cases with lesion shrinkage first appeared. At dose of 20 mg/kg, 9 subjects with different tumour types, were evaluated for efficacy and 6 of 9 subjects had a response : 4 SD and 2 partial response (PR). Conclusion: CVL006 monotherapy appeared to be well tolerated and had encouraging preliminary efficacy in patients with advanced solid tumors, warranting further investigation. Citation Format: Jin Li, Ning Li, Shuhang Wang, Ye Guo, Kai Yao, Yanjie Zhu, Feng Ye, Hao Zeng, Steve Shen, Jin Zhang. An open-label, multicenter Phase I clinical study of CVL006, a novel PD-L1/VEGF bispecific antibody, in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2666.

Dong et al. revealed that circulating CX3CR1+ terminally differentiated effector memory (Temra) cells are key predictors of immunotherapy response. A 20-gene Temra transcriptional signature that stratifies responders from non-responders was developed, achieving an area under the curve (AUC) of 0.834 in a prospective multi-center cohort. The study establishes a blood-based biomarker that captures the pre-existing functional state of systemic immunity, offering a translational tool to guide immunotherapy.