2596 Background: Serplulimab is a recombinant humanized IgG4 monoclonal antibody targeting PD-1. A two-cohort phase 1 study was conducted to evaluate the safety of serplulimab monotherapy in patients with advanced solid tumors (NCT03468751). Findings from the dose-finding cohort has been previously reported at the 2022 ASCO Annual Meeting (No. e14560). Here we present results from the dose expansion cohort, in which fixed-dose regimens were evaluated. Methods: This multicenter phase 1 study enrolled patients with locally advanced or metastatic solid tumors who have failed or are intolerant to standard therapy or for whom no standard therapy is available. In the dose expansion cohort, patients received intravenous serplulimab at 200 mg Q2W, 300 mg Q3W, 400 mg Q4W, or 600 mg Q6W. The primary endpoints were adverse event profile and maximum tolerated dose (MTD). Secondary endpoints included pharmacokinetic (PK), immunogenicity, pharmacodynamics (PD), and efficacy. Results: As of data cut-off on Jan 5, 2024, 37 patients received at least one dose of serplulimab at 200 mg Q2W (n = 9), 300 mg Q3W (n = 9), 400 mg Q4W (n = 10), or 600 mg Q6W (n = 9). All patients were Asian, 70.3% male; median age was 60.0 yrs (range 33–88). Patients had head and neck cancer (n = 10, 27.0%), esophageal cancer (n = 6, 16.2%), colorectal cancer (n = 4, 10.8%) or other types of tumor. Most patients had metastatic disease (64.9%). All patients had prior systemic cancer treatment, including 4 (10.8%) with prior immunotherapy; 51.4% had ≥ 3 prior lines of therapy. All 37 patients were included in safety, PK, and PD analyses; 35 response-evaluable patients were included in efficacy analysis. No dose-limiting toxicity was reported, and MTD has not been determined. Treatment-related adverse events (TRAEs) were observed in 19 patients (51.4%), including 7 (18.9%) reporting grade ≥ 3 TRAE. TRAE incidence was similar across regimen groups. Following multiple infusions, the geometric mean t ½, ss was from 341.1–751.3 h, and geometric mean CL ss was 0.006–0.009 L/h. Treatment-emergent anti-drug antibody (ADA) was detected in 7 (18.9%) patients. No difference in safety or PK was noted between ADA-positive and -negative patients. Profiles of PD-1 receptor occupancy in circulating CD3 + T cells and interleukin-2 stimulation ratio were similar across dose groups, suggesting dose-independent functional blockade. Six patients (300 mg Q3W, 4; 400 mg Q4W, 2) achieved partial response, resulting in an ORR of 17.1%. Among the responders, 12-month duration of response rate was 66.7% (95% CI confidence interval, 19.5–90.4). Median progression-free survival was 2.3 months (95% CI, 1.9–5.1). Conclusions: Fixed-dose regimens of serplulimab showed favorable safety, PK, and PD characteristics and preliminary anti-tumor activity, supporting its further investigation. Clinical trial information: NCT03468751 .
CD4+ regulatory T cells (Tregs) play a critical role in the progression of hepatocellular carcinoma (HCC). However, indiscriminate depletion of Tregs risks triggering autoimmunity. While previous research highlights the phenotypic and functional heterogeneity of Treg subpopulations, a unified classification system remains elusive. This study aims to characterize Treg subtypes in HCC patients using single-cell CITE-seq and validate their clinical relevance and prognostic potential. CITE-seq profiling of 51,067 CD4+ T cells from eight HCC patients identified distinct Treg populations in tumor, non-tumor, and peripheral blood samples. Validation studies conducted on 96 HCC patients and 53 healthy donors using flow cytometry, functional assays, and clinical data revealed a peripheral Foxp3high Treg subset that preferentially migrates to tumor sites. Upon infiltration, these Tregs undergo terminal differentiation, exhibiting heightened activation, immunosuppressive functions, and increased expression of LAYN and TRM-associated genes. Proinflammatory cytokines within the tumor microenvironment further amplify Foxp3 expression and the suppressive capacities of these cells. Mechanistic analysis implicated the CCL5/CCR5 signaling axis as essential for the recruitment of Foxp3high Tregs from peripheral blood to the tumor microenvironment. Peripheral Foxp3high Tregs strongly correlated with their tumor-infiltrating counterparts, suggesting their potential as a non-invasive biomarker. A threshold of peripheral Foxp3high Tregs/CD4+ T cells > 3.5% was found to predict overall survival and early recurrence, achieving AUROCs exceeding 0.75. In conclusion, peripheral Foxp3high Tregs transition into tumor-associated counterparts via the CCR5-CCL5 axis and proinflammatory cytokines, contributing to immunosuppression in HCC. Their abundance in peripheral blood correlates with tumor infiltration and clinical outcomes, underscoring their utility as a prognostic biomarker for HCC. Wei-Ting Ku, Chien-Hao Huang, Jayashri Mahalingam, Cheng-Heng Wu, Tsung-Han Wu, Jian-He Fan, Chung-Wei Su, Po-Ting Lin, Chien-Wei Peng, Wei Teng, Wen-Juei Jeng, Wen-Juei Jeng, Wei-Ting Chen, Chen-Chun Lin, Shi-Ming Lin, I-Shyan Sheen, Yung-Chang Lin, Chun-Yen Lin. Peripheral Foxp3 regulatory T cells develop into tumor-associated counterparts by proinflammatory cytokines and act as prognostic biomarker in patients with hepatoma [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 5243.
Objectives:Reflux disease including gastroesophageal reflux and laryngopharyngeal reflux (LPR) is often found in obstructive sleep apnea (OSA) patients. Endoscopic examination is a gold standard diagnosis for reflux disease. However, the invasive procedure limits its widespread use. The pathophysiological characteristics of LPR are associated with refluxate components, of which pepsin is known to damage the tissues of the larynx and pharynx. Therefore, the detection of salivary pepsin to diagnose LPR becomes a potentially clinical application with noninvasiveness. In this study, we aimed to (1) validate the feasibility of salivary pepsin test for LPR in OSA patients, (2) establish the threshold of salivary pepsin in diagnosing LPR, and (3) explore the relationship between OSA and LPR. Materials and Methods:Seventy adult polysomnography-diagnosed OSA patients were enrolled. Reflux finding score (RFS) and salivary pepsin test were utilized to evaluate LPR. RFS is a set of eight objective laryngoscopic findings (total score: 0-26), with a total score of >7 as RFS-positive representing LPR-positive. The salivary pepsin concentration was detected by enzyme-linked immunosorbent assay with a standard protocol. Results:Salivary pepsin test was performed quickly and smoothly in all subjects with no discomfort or side effects. Based on RFS positive, the prevalence of LPR was up to 86% in our study population. There is a trend that the median salivary pepsin concentration in RFS-positive patients was higher than RFS-negative patients (14.9 ng/ml vs. 7.23 ng/ml). The cutoff point (2.3 ng/ml) of salivary pepsin concentration yielded a sensitivity of 93% in the diagnosis of LPR. Neither apnea/hypopnea index nor salivary pepsin concentration was different between LPR-positive versus LPR-negative groups and nonsevere versus severe OSA groups. Conclusion:LPR is highly prevalent in OSA patients. Salivary pepsin test could be an alternative to endoscopic findings for the diagnosis of LPR with noninvasiveness. The threshold of salivary pepsin concentration of 2.3 ng/ml offers 93% sensitivity in the diagnosis of LPR. The relationship between OSA and LPR is bidirectional and more likely to be an overlapping syndrome-combined laryngopharyngeal reflux and OSA (CLOSA). Pharmacologic therapy for LPR is needed in patients with CLOSA for comprehensive treatment.
CDK 4/6 inhibitors improve survival in HR+ and HER2 breast cancer patients but carry risks of QT prolongation. Single ECG readings may be unreliable. This study assesses QT prolongation via 12-hour ECG monitoring for three CDK 4/6 inhibitors. A prospective cohort study (Apr 2023-Aug 2024) included HR+, HER2- breast cancer patients receiving CDK 4/6 inhibitors. Exclusions were QTc >500 msec and persistent Af. Ribociclib/Palbociclib followed a 21/7 regimen; Abemaciclib was continuous. ECG monitoring occurred pre-treatment and on day 14 (Ribociclib/Palbociclib) or day 14 only (Abemaciclib). ECGs were recorded from 8 PM-8 AM and stored on the PCA 500 cloud. Drug blood concentrations were measured on day 8, with dose adjustments as needed. From July 16, 2023, to July 31, 2024, 33 patients were included: Ribociclib (N=19), Abemaciclib (N=9), and Palbociclib (N=5). Case 36 underwent testing at 600 and 400 mg Ribociclib due to QT prolongation. • Ribociclib: Median baseline QTcF was 422 msec, rising to 431 msec (400 mg, N=7) and 440 msec (600 mg, N=13) post-treatment. QTcF Max >500 msec increased from 23% to 54% in the 600 mg group. • Palbociclib: Median QTcF rose from 431 msec (washout) to 439 msec (100 mg, N=4) and decreased to 421 msec (125 mg, N=4). QTcF Max >500 msec rose from 20% to 40% post-treatment. • Abemaciclib: Post-treatment QTcF medians were 425 msec (100 mg, N=1), 433 msec (150 mg, N=5), and 434 msec (alternative 150 mg, N=3). QTcF Max >500 msec increased to 56% post-treatment. Ribociclib and Abemaciclib prolonged QTcF Max >500 msec, especially at higher doses. Palbociclib had less QT prolongation and reduced QTcF at 125 mg. 12-hour ECG monitoring underscores the need for closer cardiac safety measures. Chia-Lun Chang, Wan-Chen Hsieh, Wei-Wen Chang, Ping-Kun Hsiao, Mao-Chih Hsieh, Tzeon-Jye Chiou, Tzu-Yao Liao, H-Eugene Liu, Hsin-Hsien Yu, Chih-Hsin Lee. QT prolongation induced by CDK-4/6 inhibitors in breast cancer: A prospective cohort study utilizing 12-hour continuous ECG monitoring [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 788.
Early detection of osteoporosis is becoming imperative in an aging society, as low bone mineral density (BMD) poses an elevated risk of bone injury. We develop an optical bone densitometer (OBD) combined with deep learning to predict BMD in specific regions of human body. The OBD utilized a near-infrared light source to obtain photos with optical information from distal radius by emitting the light through the wrist, the relatively thin region of human body.To precisely capture the position of wrist, we employed U-net for biomedical image segmentation, which generates a mask for the original wrist image, leaving behind images without background noise for the subsequent deep learning analysis. The algorithm considers the preprocessed images and various physiological parameters to predict BMD in the target regions, thus providing a reliable result for both orthopedic surgeons and patients.
