INTRODUCTION:Novel agents that improve outcomes in NSCLC are needed. Co-inhibition of T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitor motif domains and programmed cell death protein 1 (PD-1) may enhance anti-PD-1 activity. AdvanTIG-302 is a phase 3 trial of ociperlimab plus tislelizumab (A), pembrolizumab (B), and tislelizumab (C) in first-line stage III/IV NSCLC with programmed cell death-ligand 1 expression of 50% or more (NCT04746924). METHODS:Eligible patients were randomized (5:5:2) to A, B, or C. The primary objective was overall survival (OS) in A versus B; key secondary analyses were progression-free survival (PFS) and overall response rate (ORR). RESULTS:As of May 30, 2025, the prespecified interim analysis (N = 662) was terminated due to futility; efficacy analyses are descriptive only. Median OS (95% confidence interval [CI]) was 31.9 (25.7-not estimable [NE]), 29.4 (25.8-35.0), and 27.7 (20.0-NE) months for arms A, B, and C, respectively; the stratified hazard ratio for A versus B was 0.97 (95% CI: 0.76-1.23). For A, B, and C, median PFS (95% CI) was 14.3 (11.5-16.0), 10.5 (8.4-12.6), and 16.6 (8.9-26.3) months and ORR (95% CI) was 61.0% (55.1-66.7), 48.8% (42.9-54.7), and 55.7% (44.7-66.3), respectively. In arms A, B, and C, treatment-related adverse events occurred in 84.3%, 79.4%, and 79.3% of patients, respectively. CONCLUSION:Ociperlimab plus tislelizumab had no improvement in OS compared with pembrolizumab; median OS was comparable across arms. Data for B versus C should be interpreted cautiously given the descriptive nature of this comparison. The safety profiles of all treatment arms were well tolerated, with no new safety signals.

2571 Background: OCI (anti-TIGIT) plus TIS (anti-PD-1) may enhance antitumor immune responses in advanced solid tumors. We present a retrospective biomarker analysis of pts in AdvanTIG-105 (NCT04047862), a phase 1/1b open-label study of OCI plus TIS for treatment-naïve metastatic non-squamous (NSQ) and squamous (SQ) PD-L1-positive (TC ≥1%) NSCLC. Methods: Pts in cohort 3 (n=46) were treated with 900 mg OCI plus 200 mg TIS. Pts in cohort 10 (n=68) were treated with 450 mg (Arm A), 900 mg (Arm B), or 1800 mg (Arm C) OCI plus 200 mg TIS. Baseline tumor tissue was used to measure PD-L1 and TIGIT expression (SP263 and SP410 IHC assays). Gene expression profiling (GEP) was performed using TrueSeq RNA Access (Illumina); gene signature scores were evaluated with ssGSEA. Progression-free survival (PFS) hazard ratio (HR) was calculated by Cox proportional hazards regression. Results: At Aug 2024 data cutoff, median follow-up was 19.7 months (range: 0.7-41.6 mo) for cohort 3 and 9.8 mo (range: 0.3-21.4 mo) for cohort 10. Baseline characteristics, overall response rate (ORR), and PFS were comparable across cohorts and between biomarker-evaluable and intent-to-treat (ITT) pts. PD-L1 ≥25% vs <25% and TIGIT ≥5% vs <5% subgroups were associated with a trend toward higher ORR and longer PFS, with greater increment in pts with NSQ- vs SQ-NSCLC (Table). PD-L1/TIGIT double high subgroup showed further enriched clinical efficacy in NSCLC (Table). Anti-TIGIT mechanism of action-related GEP signatures (NK cells, Treg, macrophages) were associated with a trend toward longer PFS primarily in pts with NSQ-NSCLC. Conclusions: Pts with NSCLC with PD-L1 ≥25%, TIGIT ≥5%, or PD-L1/TIGIT double high can achieve a trend toward longer PFS and higher ORR than PD-L1 low or TIGIT low subgroups when treated with OCI plus TIS. Longer PFS in PD-L1 ≥25% or TIGIT ≥5% subgroups in NSQ- vs SQ-NSCLC may be associated with biological differences in histology. Confirmation of these results will require prospective evaluation of OCI plus TIS in randomized studies. Clinical trial information: NCT04047862 . Subgroup mPFS (mo) ORR (%) NSCLC Evaluable pts (n=113) 5.5 34.5 PD-L1 ≥25% vs <25%(n=57 vs 56) 6.9 vs 4.2HR 0.58 (95% CI: 0.37-0.9) 47 vs 22 TIGIT ≥5% vs <5%(n=62 vs 48) 6.8 vs 4.1HR 0.64 (95% CI: 0.41-1) 45 vs 19 PD-L1/TIGIT double positive vs other(n=38 vs 72) 8.3 vs 4.2HR 0.53 (95% CI: 0.33-0.86) 55 vs 22 NSQ-NSCLC PD-L1 ≥25% vs <25%(n=35 vs 32) 8.3 vs 4.2HR 0.55 (95% CI: 0.32-0.98) 49 vs 19 TIGIT ≥5% vs <5%(n=36 vs 29) 6.5 vs 4.1HR 0.53 (95% CI: 0.3-0.94) 50 vs 14 SQ-NSCLC PD-L1 ≥25% vs <25%(n=22 vs 24) 5.5 vs 5.3HR 0.63 (95% CI: 0.35-1.29) 45 vs 25 TIGIT ≥5% vs <5%(n=26 vs 19) 5.5 vs 5.5HR 0.93 (95% CI: 0.46-1.87) 38 vs 26

Minimal residual disease (MRD) reflected by specific genetic alterations in ctDNA was considered to be closely related to disease status in solid tumors. MRD detection was reported to be promising to monitor therapeutic effects and identify recurrence risks. Next-generation sequencing (NGS) based MRD assays usually require tissue samples to identify tumor-specific mutations for subsequent monitoring (tissue-informed MRD). However, baseline tissue samples were not always available in clinical settings, limiting their applications. In this study, we explored using baseline blood samples to identify mutations for post-treatment ctDNA MRD detection (blood-informed MRD) as well as tissue-informed MRD in 62 limited-stage small cell lung cancer (LS-SCLC) patients receiving CRT combined with IO treatments (NCT04952597). 62 patients with LS-SCLC underwent MRD testing using both tissue-informed and blood-informed PredicineBEACON assays during CRT treatment, either alone or in combination with IO. The assays utilized enhanced whole-exome sequencing (PredicineWES+) on initial tissue and blood samples to identify somatic mutations. Personalized MRD panels were developed for each patient, incorporating up to 50 mutations identified through bioinformatics analysis from either baseline tissue or blood, along with a standard panel of 500 key tumor mutations. The study conducted ultra-deep sequencing at 100, 000X coverage using these tailored panels to detect MRD at two critical time points: cycle 1 day 1 (C1D1) and cycle 3 day 1 (C3D1). In this study, 62 patients were subjected to both tissue-informed and blood-informed MRD testing. PredicineWES+ at baseline identified 13, 542 somatic mutations in tissue samples and 12, 133 in plasma samples, with medians of 181 and 155 mutations per patient, respectively. There was a notable overlap where 10, 503 mutations were recognized by both methods, resulting in a median concordance rate of 86.4% per patient, highlighting the WES assay's reliability in mutation detection across biopsy types. Upon MRD assessment at C3D1, a high concordance in MRD status was observed between the two methods: 35 patients tested MRD-positive and 26 MRD-negative in both assays. One patient displayed discordant results, being MRD-positive in the tissue-informed but negative in the blood-informed assay. Additionally, the study found a significant correlation in tumor fractions between the MRD tests at both C1D1 and C3D1 (R2=0.96, p<2.2e-16), as established by linear regression, underscoring their robustness in evaluating tumor dynamics. This study demonstrated high concordance of tumor-informed and blood-informed MRD assay in LS-SCLC patients treated with IO and CRT. These outcomes highlight the potential clinical applicability of using baseline ctDNA NGS assays for personalized MRD detection. Haoran Tang, Wei Tan, Pu Sun, Yang Shi, Cancan Jia, Feng Xie, Yue Zhang, Qin Luo. Comparative analysis of blood- and tissue-informed MRD studies in SCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4558.

Abstract Background: PD-L1 expression was associated with anti-immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) + anti-PD-(L)1 treatment, in which a high PD-L1 subgroup showed improved efficacy. We investigated if anti-TIGIT mechanism of action (MOA)-related markers were associated with the efficacy of ociperlimab + tislelizumab in Cohort 3 (1L PD-L1+ NSCLC) of the phase 1/1b AdvanTIG-105 trial (NCT04047862) and evaluated a potential patient-enrichment strategy based on tumor tissue gene expression profile (GEP). Methods: Tumor tissue GEP was tested using TruSeq RNA Access technology. Ventana SP263 PD-L1 immunohistochemistry (IHC) assay was used to evaluate PD-L1 expression. Median progression-free survival (mPFS) by investigator was calculated descriptively by Kaplan-Meier methodology. 95% confidence intervals for mPFS were generated using the Brookmeyer method. The primary inferential PFS comparison used unstratified log-rank test with 2-sided descriptive P-values. Results: At data cutoff (Feb 2, 2023), 24 of 45 patients had GEP results. Anti-TIGIT MOA-related genes and signatures correlated with ociperlimab + tislelizumab treatment response. Patients with high (H) vs low (L) expression of TIGIT, CD226, CCR8, or a tumor-associated macrophage (TAM) signature had significantly longer mPFS (Table). Dual biomarkers combining both anti-PD-L1 (PD-L1 IHC) and one of the anti-TIGIT MOA-related factors (TIGIT, CCR8, TAM signature GEP) identified subgroups of PD-L1 H + TIGIT MOA-related factor H patients with improved PFS vs other subgroups (Table). A highly overlapped PD-L1 H + TIGIT H + CCR8 H + TAM signature H patient population was observed in dual biomarker analyses. Conclusions: Anti-TIGIT MOA-related genes and signatures correlated with efficacy in ociperlimab + tislelizumab-treated 1L PD-L1+ NSCLC. Combining anti-TIGIT MOA-related factors with PD-L1 expression identified a subgroup of patients with improved efficacy. TABLE 1. NAND Table. Efficacy Analyses in Patient Subgroups TIGITa CD226b CCR8b TAMb Subgroup H L H L H L H L n 8 16 12 12 12 12 12 12 mPFS, months (95% CI) NR (2.6, NR) 5.26 (2.07, 11.86) NR (4.21, NR) 4.68 (1.41, 15.05) 15.21 (2.6, NR) 4.7 (1.71, 7.16) 15.21 (4.21, NR) 4.17 (1.71, 5.45) PFS, P-value 0.0326 0.0327 0.0131 0.0153 PD-L1c + TIGITb PD-L1c + CCR8b PD-L1c + TAMb Subgroup TIGITHPD-L1H TIGITHPD-L1L TIGITLPD-L1H TIGITL PD-L1L CCR8HPD-L1H CCR8HPD-L1L CCR8LPD-L1H CCR8L PD-L1L TAMHPD-L1H TAMHPD-L1L TAMLPD-L1H TAML PD-L1L n 8 4 8 4 11 1 5 7 9 3 7 5 mPFS, months (95% CI) NR (1.41,NR) 4.76 (2.6,NR) 8.62 (2.07,NR) 2.94 (1.25,NR) NR (1.41,NR) 2.6 (NR,NR) 5.19 (2.07,NR) 4.21 (1.25,7.16) 23.89 (1.41,NR) 5.32 (4.21,NR) 5.29 (2.07,NR) 2.6 (1.25,NR) Cutoff: aTop 1/3; bMedian; cTC≥25% Citation Format: Se Hyun Kim, Jiayuan Zhang, Wei Tan, Han Yan, Tian Tian, Hao Zheng, Ziqi Zhou, Ruihua Wang, Yun Zhang, Zhirong Shen, Hye Ryun Kim, Diansheng Zhong, Shun Lu. Exploration of potential biomarkers correlated with efficacy of ociperlimab (anti-TIGIT) plus tislelizumab (anti-PD-1) in 1L PD-L1+ non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT053.

目的 比较内镜手术[内镜下黏膜剥离术(endoscopic submucosal dissection,ESD)或内镜下全层切除术(endoscopic full thickness resection,EFTR)]和腹腔镜手术治疗胃困难部位间质瘤的安全性和有效性.方法 回顾性分析我院2017年1月至2021年12月行内镜下治疗和腹腔镜治疗的位于胃困难部位且术后病理证实为胃肠道间质瘤患者的临床资料,比较两组患者的基线资料、手术安全性、短期预后及随访结果.结果 共纳入64例患者,30例行内镜下治疗,34例行腹腔镜治疗.腹腔镜组肿瘤直径(3.51±0.80)cm大于内镜组(2.88±0.80)cm,差异有统计学意义(P<0.01),两组患者性别、年龄、首发症状、个人史、肿瘤部位、肿瘤危险度、核分裂象、术后辅助治疗情况比较,差异均无统计学意义(P>0.05).内镜组患者术后进食时间早于腹腔镜组[(3.1±0.5)d vs(5.4±2.0)d,P<0.01],术后住院时间短于腹腔镜组[(6.8±1.3)d vs(9.6±4.1)d,P=0.001],两组患者手术整块切除率(86.7％vs 91.2％)、R0切除率(100％vs 100％)、术后并发症发生率(6.9％vs 9.7％)以及发生并发症患者手术部位的比较,差异均无统计学意义(P>0.05).两组患者随访期间均无复发和转移病例.结论 在经验丰富的医疗中心对胃困难部位间质瘤行腹腔镜手术和内镜手术均安全可行,且内镜手术较腹腔镜手术具有手术创伤小、恢复快、术后进食时间早、住院时间短的优势.

31 Background: T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor in combination with an anti-programmed cell death protein 1 (PD-1) antibody has shown antitumor activity in solid tumors. AdvanTIG-105 (NCT04047862) is a phase 1/1b open-label study designed to assess the safety and preliminary antitumor activity of OCI, an anti-TIGIT monoclonal antibody (mAb), + TIS, an anti-PD-1 mAb, in pts with unresectable, locally advanced or metastatic solid tumors. In the dose-escalation part, OCI + TIS was well tolerated with preliminary antitumor activity observed, and the recommended phase 2 dose (RP2D) of OCI 900 mg intravenously (IV) every three weeks (Q3W) + TIS 200 mg IV Q3W was established. We report results from the dose-expansion part (GC/GEJC Cohort 9) of the AdvanTIG-105 study. Methods: Eligible pts had histologically/cytologically confirmed stage IV GC/GEJC. Pts were excluded if they had squamous cell, undifferentiated or other histological types of GC, had GC/GEJC with positive HER2 expression, or if they had received any prior therapy for metastatic disease. Pts received either the RP2D of OCI + TIS with oxaliplatin + capecitabine Q3W for 6 cycles (C), followed by maintenance therapy with the RP2D of OCI + TIS, + capecitabine Q3W, or the RP2D of OCI + TIS with cisplatin + 5-fluorouracil Q3W for 6 C. Treatment continued until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DoR), disease control rate (DCR) per RECIST v1.1, and safety. Results: As of September 29, 2022, 60 pts with a median age of 61.5 years (range 35-82) were enrolled; 59 were efficacy evaluable. Median study follow-up was 31.1 weeks (range 1.4-78.4). ORR was 50.8% (95% CI: 37.5, 64.1); DCR was 84.7% (95% CI: 73.0, 92.8) with a median DoR of 8.1 months (95% CI: 4.5, not evaluable [NE]). Median PFS was 8.2 months (95% CI: 5.8, NE). In a subgroup analysis, ORR in pts with PD-L1 tumor area positivity (TAP) score ≥5% (n=27) was 59.3% (95% CI: 38.8, 77.6), and 50.0% (95% CI: 30.7, 69.4) in pts with PD-L1 TAP <5% (n=28). All 60 pts reported ≥1 treatment-emergent adverse event (TEAE), the most common being anemia (43.3%) and platelet count decreased (41.7%). In total, 43 pts (71.7%) had ≥grade 3 TEAEs and 28 (46.7%) had serious adverse events. TEAEs leading to discontinuation of TIS and OCI occurred in 5 (8.3%) pts. TEAEs led to death in 2 (3.3%) pts; one event (neutropenic sepsis) was related to chemo, while the other (pulmonary embolism) was not treatment related. Conclusions: OCI 900 mg + TIS 200 mg + chemo was generally well tolerated and showed encouraging antitumor activity in pts with stage IV GC/GEJC. Clinical trial information: NCT04047862 .

Background Ociperlimab, a novel, humanized monoclonal antibody (mAb), binds to T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) with high affinity and specificity. Tislelizumab is an anti-programmed cell death protein 1 mAb. We report results from a phase I, first-in-human, dose escalation study evaluating the safety, pharmacokinetics (PK), and preliminary antitumor activity of ociperlimab plus tislelizumab in patients with advanced solid tumors.Methods Eligible patients previously treated with standard systemic therapy, or for whom treatment was not available or tolerated, received ociperlimab intravenously on Cycle (C) 1 Day (D) 1 and tislelizumab 200 mg intravenously on C1 D8. If tolerated, patients received ociperlimab plus tislelizumab 200 mg sequentially on D29 and every 3 weeks (Q3W) thereafter until discontinuation. Dose escalation for ociperlimab was planned with four dose levels (50 mg, 150 mg, 450 mg, and 900 mg) according to a 3+3 design. An additional dose level of ociperlimab 1800 mg was also assessed. Primary endpoints were safety, determination of the maximum tolerated (or administered) dose, and the recommended phase II dose (RP2D). Secondary endpoints included overall response rate (ORR), duration of response (DoR), disease control rate (DCR) (Response Evaluation Criteria in Solid Tumors version 1.1), PK, and biomarker analysis.Results At data cut-off (September 29, 2022), 32 patients had received ≥1 dose of ociperlimab plus tislelizumab 200 mg Q3W. The maximum administered dose was ociperlimab 1800 mg plus tislelizumab 200 mg Q3W. The median age of enrolled patients was 59.5 years (range: 31–79). Most patients (96.9%) experienced ≥1 treatment-emergent adverse event (TEAE); 62.5% of patients experienced ≥grade 3 TEAEs and 50.0% of patients experienced serious TEAEs. No dose limiting toxicity events were reported. The maximum tolerated dose was not reached. The RP2D was ociperlimab 900 mg plus tislelizumab 200 mg Q3W. Overall, ORR was 10.0%, median DoR was 3.6 months, and DCR was 50.0%.Conclusions Ociperlimab plus tislelizumab was well tolerated in patients with advanced solid tumors, and preliminary antitumor activity was observed with 450 mg, 900 mg, and 1800 mg ociperlimab. Phase II/III trials of ociperlimab 900 mg plus tislelizumab 200 mg Q3W are underway in a range of solid tumors.Trial registration number NCT04047862.

肠道微生物及其代谢产物可作为维持肠道微生态的重要影响因素,胃肠道壁内的感觉神经末梢可能对细菌信号作出反应,为肠道运动和微生物稳态的关键生物过程提供基础.本文主要讲述肠道微生物相关的结肠动力学机制,从肠道微生物相关的信号转导、与Toll样受体的相互作用、细菌代谢产物与结肠动力的相关关系四个方面进行阐述,同时也探索了细菌微泡充当肠道微生物和宿主之间通信的连接桥梁的观点.为结肠动力学机制提供了新的研究思路,从而促进肠道动力相关疾病的病因研究和个体化治疗的发展.

Background OCI is a humanized monoclonal antibody (mAb) against T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) with high affinity and specificity, enabling Fc-mediated effector functions that induce antibody-dependent cellular cytotoxicity.1 The Phase 1/1b open-label AdvanTIG-105 trial was designed to assess the safety and efficacy of OCI plus TIS (an anti-programmed cell death protein 1 mAb) in patients with advanced solid tumors (NCT04047862).2 In the dose-escalation part, the combination was well tolerated, and preliminary antitumor responses were observed. Here, we report PD biomarker data from peripheral blood. Methods Eligible patients had locally advanced/metastatic, unresectable solid tumors previously treated with standard systemic therapy or for which treatment was not available/tolerated, ECOG PS ≤1 and had received no prior anti-TIGIT therapy. Patients received five escalating doses of OCI (50–1800mg) intravenously (IV) on Cycle (C) 1 Day (D) 1 and TIS 200mg IV was initiated on C1D8. If tolerated, patients received OCI (50–1800mg) plus TIS 200mg on D29 (C2D1) and every three weeks thereafter until discontinuation. Peripheral blood samples were collected to monitor changes in total and TIGIT-expressing immune cell subsets pre- and post-treatment. Meso Scale Discovery V-plex panels were used to assess cytokine/chemokine release in plasma samples. Wilcoxon signed-rank test compared pre- and post-treatment cytokine/chemokine levels; p values are descriptive. Results At data cutoff (09/01/2021), 32 patients had received ≥1 dose of OCI plus TIS. Total peripheral regulatory T cells (Tregs) decreased following OCI monotherapy (at C1D2 and C1D8) with doses of 900mg and 1800mg (not dose proportional), but not 450mg; the decrease was maintained with subsequent combination with TIS (at C1D15 and C2D1). CD4+ and CD8+ T-cell populations were not impacted at any OCI dose. TIGIT downregulation was observed on Tregs, CD4+, and CD8+ T cells at C1D8 with multiple OCI doses (not dose proportional); the reduction was sustained after combination with TIS. Plasma IL12/23p40 (p<0.001), CCL4 (p<0.05), and CXCL10 (p<0.05) were notably induced post-OCI (C1D8), and further elevated following combination with TIS (p<0.001, p<0.001, and p<0.0001, respectively) at C2D1. Plasma IFNγ and TNFα increased post-OCI at C1D8 and were dramatically induced post-combination at C2D1 (p<0.0001 and p<0.001, respectively). Conclusions OCI, with or without TIS, led to Treg reduction at higher doses, TIGIT downregulation, and proinflammatory cytokine/chemokine release, reflecting the potential mechanism of action of OCI as an Fc-competent anti-TIGIT mAb. Acknowledgements This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Sophie Cook, PhD, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd. Trial Registration NCT04047862 References Chen X, Xue L, Ding X, et al. A Fc-competent anti-human TIGIT blocking antibody BGB-A1217 elicits strong immune responses and potent anti-tumor efficacy in pre-clinical models. J Cancer Res. 2021 Abstract 1854;81(13 Supplement):1854–54 Frentzas S, Meniawy T, Kao S, et al. AdvanTIG-105: Phase 1 dose-escalation study of anti-TIGIT monoclonal antibody ociperlimab (BGB-A1217) in combination with tislelizumab in patients with advanced solid tumors. J Clin Oncol. 2021;15:2583. Ethics Approval The protocol, informed consent forms, any information given to the patients, and relevant supporting information were submitted, reviewed, and approved by the Institutional Review Board and Independent Ethics Committee before this study was initiated. This study was conducted in full conformance with the International Council for Harmonization E6 guideline for Good Clinical Practice, the International Council for Harmonization E2A guideline for Clinical Safety Data Management, and the principles of the Declaration of Helsinki or the laws and regulations of the country in which the research was conducted.

Background: T-cell immunoreceptor with immunoglobulin and tyrosine based inhibitory motif domain (TIGIT) is a co-inhibitory immune checkpoint receptor expressed on several types of immune cells, which can suppress T-cell activation, promote T-cell exhaustion, and suppress natural killer cell mediated cytotoxicity. Recent clinical data with anti-TIGIT monoclonal antibodies (mAbs) indicate that TIGIT blockade is a highly promising therapy when combined with PD-1/PD-L1 blockade. However, unlike PD-1 receptor occupancy (RO), there is a lack of information regarding RO in peripheral blood and tumors at different dose regimens with anti-TIGIT therapies. This study aims to predict intratumoral RO for a series of anti-TIGIT antibodies with known pharmacokinetic (PK) and binding characteristics (ociperlimab [BGB-A1217], vibostolimab, domvanalimab, etigilimab, tiragolumab) utilizing a physiologically-based PK (PBPK)/RO model. Methods: The PBPK/RO model describes biodistribution of mAbs within bodily fluids, detailed transport across the endothelial barrier, two-step binding with the membrane-bound TIGIT receptor (taking into account target expression level, number of cells expressing target receptor and internalization process), linear and non-linear clearance of mAbs (via uptake by endothelium and internalization of mAb:TIGIT complexes, respectively). Physiological parameters were taken from the literature, while other parameters were identified based on available in vitro and in vivo data. Clinical PK data of anti-TIGIT mAbs were used for model calibration. Results: The model-predicted results for RO in peripheral blood demonstrated almost complete occupancy, which is supported by clinical data available for ociperlimab and domvanalimab (predicted 99.9% vs observed 100%). A similar tendency was observed for all studied cell types (CD8, CD4, regulatory T cells) despite the significant differences in TIGIT expression on different cell types. According to model predictions, the intratumoral RO was close to the values reported for blood over a range of doses close to the recommended Phase 2 dose (e.g. ociperlimab 900 mg Q3W median trough RO with 95% CI: blood 99.96% [99.89, 99.98] vs tumor 99.75% [98.88, 99.94]). The direct comparison of extended dosing regimens (e.g. ociperlimab 150/200/300 mg per week regimens) demonstrated a sustainable level of TIGIT blockade and comparable values of trough RO. Conclusions: The PBPK/RO model accurately predicted the RO in peripheral blood and tumors for different anti-TIGIT mAbs by taking into account their PK and binding properties. Moreover, the model allowed a direct comparison of RO across different regimens and different anti-TIGIT mAbs. The predicted TIGIT receptor occupancy within the tumor may be useful for future dose selection or optimization in clinical trials. Citation Format: Dmitry Shchelokov, Oleg Demin Jr, Oleg Demin, Ahsan Rizwan, Yun Zhang, Wei Tan, Srikumar Sahasranaman, Nageshwar Budha. Prediction of intratumoral TIGIT receptor occupancy after the treatment with anti-TIGIT antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5421.

Objective:To explore the application value of online and offline interactive teaching combined with three-dimensional quality theory mutual evaluation in the standardized residency training of general practitioners.Methods:Twenty-four general practitioners who were trained in The Second Hospital of Tianjin Medical University from January 2019 to December 2019 were selected as the control group, receiving traditional teaching; another 22 residents who were trained from March 2020 to February 2021 were selected as the observation group, taking online and offline interactive teaching combined with mutual evaluation of three-dimensional quality theory. After the training, the theoretical knowledge, skill operation and case analysis assessment scores, clinical ability and teaching satisfaction were compared between the two groups. SPSS 25.0 software was used for t test and rank sum test. Results:There was no significant difference in the scores of theoretical knowledge assessment, operation skills assessment, and case analysis assessment between the two groups before the training. After the training, the scores of the two groups were all increased, and the observation group had higher scores than the control group ( P<0.05). There was no significant difference in the scores of each dimension in the Direct Observation of Procedural Skills (DOPS) scale between the two groups before training, while after training, the scores of each dimension in the DOPS scale of the two groups were increased ( P<0.05), and the scores in the observation group were higher than those in the control group. The difference of mutual evaluation results after the training between the two groups was statistically significant, and the results of the observation group were higher than those of the control group ( P<0.05). Conclusion:The application of online and offline interactive teaching combined with mutual evaluation of three-dimensional quality theory in the standardized residency training of general practitioners can help improve the theory, skill practice, case analysis assessment performance and clinical ability of residents, and also obtain higher teaching satisfaction.

3077 Background: CBP-1008 is a first-in-class bi-specific ligand drug conjugate targeting folate receptor α (FRα) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) with a high potency tublin inhibitor payload, monomethyl auristatin E (MMAE). A first-in-human, multicenter, phase I study of CBP-1008 (NCT 04740398) is ongoing, and we herein report the preliminary result of part A which is to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of CBP-1008 in solid tumors. Methods: Dose escalation commenced in single-patient cohorts for the first 2 planned dose levels and then followed by a standard 3 + 3 scheme. CBP-1008 was administered as intravenous infusion at escalating doses (0.015, 0.03, 0.12, 0.15, and 0.18 mg/kg). The primary endpoints were to determine the safety and maximum tolerated dose (MTD). Adverse events (AEs) and dose-limiting toxicities (DLTs) were evaluated. Results: Eighteen patients with advanced solid tumors who had failed multiple systemic treatment regimens were enrolled. The diseases include colorectal cancer (n = 7), breast cancer (n = 5), non-small cell lung cancer (n = 2), ovarian cancer (n = 2), adrenocortical carcinoma (n = 1), and follicular dendritic cell sarcoma (n = 1). The DLTs observed included grade 4 hypophosphatemia (0.15 mg/kg), grade 4 neutropenia (0.12, 0.15, and 0.18 mg/kg), grade 4 febrile neutropenia (FN) (0.18 mg/kg), grade 3 hyperglycemia (0.15 mg/kg), and grade 3 alanine aminotransferase (ALT) elevation (0.18 mg/kg). The most common all grade AEs suspected to be drug-related were fever (83.3%, totally limited to grade 1-2), aspartate aminotransferase (AST) elevation (72.2%, 5.6% evaluated as grade 3-4), leukopenia (66.7%, 27.8% as grade 3-4), neutropenia (66.7%, 38.9% as grade 3-4) and hypohemoglobinemia (55.6%, 5.6% as grade 3-4), with no drug-related deaths. MTD is estimated between 0.15 mg/kg and 0.18 mg/kg Q2W. Best overall response was partial response (PR) in 1 patient at 0.18 mg/kg and 4 patients (22.2%) achieved stable disease (SD). Responses occurred in patients with FRα and/or TRPV6 -positive expression advanced solid tumors. Conclusions: CBP-1008 has demonstrated acceptable safety profile. Tumor response correlating with dosing and FRα/TRPV6 receptor expression levels has been well observed. Clinical trial information: 04740398.

2583 Background: Anti-programmed death 1 (PD-1) therapy has improved clinical outcomes for patients (pts) with advanced solid tumors but unmet needs remain. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) is a co-inhibitory, immune checkpoint receptor. Ociperlimab (OCI; BGB-A1217) is a novel, humanized, monoclonal antibody that binds to TIGIT with high affinity and specificity. OCI has demonstrated competent binding with C1q and all Fcγ receptors and induces antibody-dependent cellular cytotoxicity. Preclinical studies demonstrated dual targeting with OCI and tislelizumab (TIS), an anti-PD-1 antibody, produces synergistic immune cell activation and enhanced antitumor activity. Methods: AdvanTIG-105 is a phase 1, open label, multicenter, dose-escalation study (NCT04047862) that assessed the safety and preliminary antitumor activity of OCI plus TIS in pts with advanced, metastatic, unresectable solid tumors, for which standard therapy was ineffective or unavailable. Eligible pts had an Eastern Cooperative Oncology Group performance score ≤1 and no prior therapy targeting TIGIT. Pts received OCI intravenously (IV) on Day 1 of Cycle 1 and TIS 200 mg IV on Day 8. Pts were monitored for dose-limiting toxicities (DLTs) until Day 28. If tolerated, OCI and TIS were administered sequentially on Day 29 and every 3 weeks (Q3W) thereafter. Pts received escalating doses of OCI (50-900 mg) plus TIS 200 mg. The study objective was determination of recommended phase 2 dose (RP2D) of OCI plus TIS. Study endpoints included assessment of adverse events (AEs), pharmacokinetics and antitumor activity. Data cut-off was October 12 2020. Results: 24 pts with various advanced solid tumors received OCI plus TIS. At baseline, pts had undergone a median of 2 prior treatment regimens; 9/24 (37.5%) pts had received prior immunotherapy. Median follow-up time was 17 weeks. No DLTs were observed. 20 pts had ≥1 treatment emergent AE (TEAE) and most TEAEs were grade ≤2; fatigue (6 pts) and diarrhea (4 pts) were most commonly reported. No pts had grade ≥4 TEAEs or TEAEs leading to death. There were 2 grade 3 immune related AEs (colitis and low cortisol). One pt on OCI 450 mg achieved partial response and 9 pts had stable disease. The longest duration of stable disease was 36 weeks (1 pt on OCI 150 mg). After administration, serum concentration of OCI decreased in a biphasic manner. Exposure to OCI increased proportionally with dose, and TIGIT receptor occupancy was sustained at ≥50 mg doses. Conclusions: OCI in combination with TIS was well tolerated across all doses in pts with advanced solid tumors. The RP2D was OCI 900 mg plus TIS 200 mg Q3W. Clinical trial information: NCT04047862.

目的 分析食管支气管源性囊肿(esophageal bronchogenic cysts,EBC)临床特点.方法 收集2015年12月至2019年12月武汉大学人民医院收治的5例EBC患者的临床资料,观察患者的一般资料、临床症状、内镜表现、影像学表现、病理特点、治疗方式、随访情况.结果 5例EBC患者中男3例,女2例,年龄(51.2±6.0)岁(43～58岁),2例患者有胸痛及吞咽梗阻症状,其余3例均为行胃镜检查时偶然发现;4例患者EUS表现为食管固有肌层低回声病灶;2例患者胸部CT提示低密度影;2例患者行外科手术治疗,3例行内镜下黏膜剥离术(ESD)治疗.结论 EBC患者临床症状不典型,多以咳嗽、胸痛及胸部不适、吞咽梗阻为主,胸部CT检查及EUS检查特异性不高,确诊仍需病理学检查,较大病灶建议外科手术治疗,较小病灶可行内镜下治疗.

Sunitinib (S) is a multi-targeted tyrosine kinase inhibitor. It is synergistic with chemotherapy in preclinical models. We hypothesized that sunitinib in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) would be a tolerable and effective regimen in advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. Since the outcomes of advanced gastric and GEJ adenocarcinoma patients are poor, we decided to study a combination of FOLFIRI + S, to establish tolerability and efficacy. This was a phase I study for patients with advanced chemo-naïve gastric or GEJ adenocarcinoma. Dose escalation used a standard 3 + 3 design. The primary objective was to determine the tolerability and safety of FOLFIRI + S. Secondary objectives were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). A total of 23 patients participated in the study (male 78%, female 22%). The median age was 61 (range: 38–77) years. Median follow-up time was 67.5 (95% CI 58.9–76) months. The most frequently reported adverse events were anemia (78%; G3/4: 4%), neutropenia (78%; G3/4: 43%), nausea (74%; G3/4:13%), diarrhea (65%; G3/4: 4%), vomiting (61%, G3/4: 9%) lymphopenia (52%; G3/4: 13%), and fatigue (52%; G3/4:17%). Two dose-limiting toxicities were noted each at dose level (DL) 1 and 1A, one at DL 1B, and three at DL 2. Maximum tolerated dose was determined at DL 1B. At the time of data reporting, 21 patients had died. The median OS and PFS were 12.4 (95% CI 8.9, 16.5) months and 6.2 (95% CI 3.4, 13.5) months, respectively. Of all patients, 35% (eight out of 23) had a partial response. FOLFIRI + S has signs of clinical activity in patients with advanced gastric and GEJ adenocarcinoma, and the side-effect profile was similar to previously reported studies. Current treatment paradigms in gastric cancer probably negate further study of this regimen. ClinicalTrials.gov identifier: NCT00524186.

肠道菌群可被视为人体的一种"新器官",它能产生多种物质,从而对机体造成多方面的影响.短链脂肪酸(short chain fatty acids,SCFAs)是肠道菌群产生的一类信号分子,在许多疾病的发生、发展中起重要作用.本文主要讲述SCFAs与各种疾病的关系,通过分析SCFAs在肠道疾病、肥胖相关疾病、自闭症、气道炎症性疾病、高血压等疾病中的作用机制,为相应疾病的病因和治疗提供新的思路,从而更好地实现对相关疾病的精准治疗与个体化治疗.

e15569 Background: Sunitinib (S) is a multi-targeted tyrosine kinase inhibitor with activity against VEGFR, PDGRF, KIT, FLT-3, and RET. S is synergistic with chemotherapy in preclinical models. We hypothesized that S+FOLFIRI combination will have increased efficacy in advanced EGC. Methods: This was a phase I study for patients with advanced chemo naïve EGC. Dose escalation used a standard 3+3 design. The primary objective was to determine the tolerability and safety of S+FOLFIRI. Secondary objectives were overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Results: Twenty-three patients participated in the study (Male 78%, Female 22%). Median age was 60 (Range: 37-77) years. Median follow up time was 67.5 (95% CI: 58.9, 76) months. The most frequently reported adverse events were neutropenia (78%; G3/4: 43%), nausea (74%; G3/4:13%), diarrhea (65%; G3/4: 4%), vomiting (61%, G3/4: 9%) lymphopenia (52%; G3/4: 13%) and fatigue (52%; G3/4:17%).Two dose limiting toxicities (DLTs) were noted each at dose level (DL) 1 and 1A, one at DL 1B and 3 at DL 2 (Table 1). Maximum tolerated dose was determined at DL 1B. At the time of data reporting 21 patients had died. Two patients came off the study per investigator request. All patients were evaluated for efficacy. The median OS and PFS were 12.4 (95% CI: 8.9, 16.5) months and 6.2 (95% CI: 3.4, 13.5) months, respectively. Conclusions: S+FOLFIRI was reasonably tolerated, with a manageable safety profile and signs of clinical activity in patients with advanced EGC. This study was supported by a research grant from Pfizer, Inc. Clinical trial information: NCT00524186. [Table: see text]

The present phase II study has demonstrated that augmenting neutrophil function by the addition of pegfilgrastim can potentiate the clinical activity of rituximab in indolent B-cell non-Hodgkin lymphoma while retaining the excellent safety profile. Strategies to boost the innate immune system such as this combination warrant further study, especially in the frail, elderly population for whom therapeutic options are limited owing to poor tolerance. Background: To explore the role of augmenting neutrophil function in B-cell lymphoma, we conducted a phase II study evaluating the safety and clinical efficacy of pegfilgrastim and rituximab in low-grade CD20(+) B-cell non-Hodgkin lymphoma (B-NHL). Patients and Methods: Twenty patients with indolent B-NHL were treated with rituximab (375 mg/m(2)) every other week for 4 doses, followed by every 2 months for 4 additional doses. Pegfilgrastim was administered subcutaneously 3 days before each dose of rituximab. Clinical activity and tolerability were assessed using standard criteria. Biologic monitoring included phenotype characteristics of the host neutrophils, changes in oxidative burst, and functional assays. Results: The patient demographics included median age of 64 years, 70% were male, 70% had follicular lymphoma, and 90% had stage III-IV disease. The median number of previous therapies was 2 (range, 0-5); 90% had received previous anti-CD20 monoclonal antibody therapy. The addition of pegfilgrastim to rituximab did not increase rituximab-related toxicities. The overall response rate was 60% (12 of 20), with a complete response (CR) rate of 35% (7 of 20). The median progression-free survival (PFS) duration was 17.9 months (95% confidence interval, 9.9-27.6 months); the median overall survival was not reached. A shorter time-to-peak oxidative burst after the first dose of pegfilgrastim was associated with greater CR rates (P = .04) and longer PFS (P = .03). Conclusion: The pegfilgrastim-rituximab combination was well tolerated, with favorable outcomes compared with historical controls. A shorter time-to-peak oxidative burst was associated with higher CR rates and longer PFS. Our results support further evaluation of strategies that enhance the innate immune system to improve rituximab activity in B-NHL.