Yang Shen

T‐cell receptor–like chimeric antigen receptor T cells targeting mesothelin: A first‐in‐human dose‐escalation trial for platinum‐resistant advanced ovarian cancer

Abstract Background Ovarian cancer remains a formidable therapeutic challenge due to late diagnosis, high recurrence rates, and limited treatment options. Mesothelin (MSLN) is highly expressed in ovarian cancer, making it a promising target for immunotherapy. Given this target profile, the authors developed a novel T‐cell receptor (TCR)‐like chimeric antigen receptor (CAR) T‐cell therapy targeting MSLN, designated KT127. Methods A first‐in‐human, dose‐escalation trial of KT127 was conducted following preclinical evaluation in vitro and in vivo. A combination of rapid titration and a standard “3 + 3” dose‐escalation design was implemented. Eleven patients received KT127 at doses ranging from 1 × 10 6 to 2 × 10 7 cells/kg following lymphodepletion. The primary objectives were to assess the safety and tolerability of KT127. Secondary objectives included overall survival, disease control rate (DCR), and progression‐free survival as efficacy measures. Quality of life (QOL) was assessed using the European Organisation for Research and Treatment of Cancer QLQ‐OV28 questionnaire. Results No dose‐limiting toxicities, cytokine release syndrome, or immune effector cell‐associated neurotoxicity syndrome were observed. The DCR was 80% (95% confidence interval, 44.4%–97.5%). QOL assessments indicated improvement in abdominal/gastrointestinal symptoms post‐treatment ( p  = .037), with no significant deterioration in other domains. Proteomic analysis identified differential expression of kallikrein‐related peptidases (KLK13, KLK14) and chemokine CXCL17 at baseline, potentially linked to treatment outcomes. Conclusions This study highlights that KT127 has a manageable safety profile and shows preliminary biological activity in patients with advanced ovarian cancer, particularly those who have failed multiple lines of therapies.

Dual-target CAR-T therapy for ovarian cancer: synergistic targeting of MSLN and B7H3 enhances anti-tumor efficacy and overcomes antigen heterogeneity

Ovarian cancer (OC) remains a lethal malignancy with limited treatment options owing to antigen heterogeneity and an immunosuppressive tumor microenvironment (TME). Here, we designed a unique chimeric Antigen Receptor T-Cell (CAR-T) construct (B4M3) that integrates an anti-MSLN scFv linked to the CD3ζ activation domain and an anti-B7H3 scFv linked to the 4-1BB co-stimulatory domain. In vitro, B4M3 CAR-T cells exhibited robust cytotoxicity against OC cell lines with enhanced degranulation (CD107a) and efficient tumor cell killing, even at low effector-to-target ratios. In vivo, B4M3 CAR-T cells significantly inhibited tumor growth and prolonged survival and demonstrated superior tumor infiltration and persistence in OC xenograft models. Imaging mass cytometry (IMC) revealed that B4M3 treatment reshaped the TME, increased cytotoxic T lymphocyte (CTL) infiltration, and reduced regulatory T cells (Tregs). Mechanistically, B4M3 therapy upregulated TGF-β, promoting Th17 differentiation and CTL recruitment, thereby enhancing anti-tumor immunity. Our findings demonstrate that B4M3 CAR-T cells effectively address antigen heterogeneity and enhance therapeutic efficacy in OC, thereby offering a promising strategy for solid tumor immunotherapy.

Development of model for identifying homologous recombination deficiency (HRD) status of ovarian cancer with deep learning on whole slide images

Homologous recombination deficiency (HRD) refers to the dysfunction of homologous recombination repair (HRR) at the cellular level. The assessment of HRD status has the important significance for the formulation of treatment plans, efficacy evaluation, and prognosis prediction of patients with ovarian cancer. This study aimed to construct a deep learning-based classifier for identifying tumor regions from whole slide images (WSIs) and stratify the HRD status of patients with ovarian cancer (OC). The deep learning models were trained on 205 H&E-stained sections which contained 205 ovarian cancer patients, 64 were found to have HRD status while 141 had homologous recombination proficiency (HRP) status from two institutions Memorial Sloan Kettering Cancer Center (MSKCC) and Zhongda Hospital, Southeast University. The framework includes tumor regions identification by UNet + + and subtypes of ovarian cancer classifier construction. Referring to the EasyEnsemble, we classified the HRP patients into three distributed subsets. These three subsets of HRP patients were combined with the HRD patients to establish three new training groups for subsequent model construction. The three models were integrated into a single model named Ensemble Model. The UNet + + algorithm segmented tumor regions with 81.8% accuracy, 85.9% recall, 83.8% dice score and 68.3% IoU. The AUC of the Ensemble Model was 0.769 (Precision = 0.800, Recall = 0.727, F1-score = 0.762) in the study. The most discriminative features between HRD and HRP comprised S_mean_dln_obtuse_ratio, S_mean_dln_acute_ratio and mean_Graph_T-S_Betweenness_normed. The models we constructed enables accurate discrimination between tumor and non-tumor tissues in ovarian cancer as well as the prediction of HRD status for patients with ovarian cancer.

Identification of CXCL13 as a Promising Biomarker for Immune Checkpoint Blockade Therapy and PARP Inhibitor Therapy in Ovarian Cancer

Ovarian cancer has poor response rates to immune checkpoint blockade (ICB) therapy, despite the use of genomic sequencing to identify molecular targets. Homologous recombination deficiency (HRD) is a conventional indicator of genomic instability (GI) and has been used as a marker for targeted therapies. Indicators reflecting HRD status have shown potential in predicting the efficacy of ICB treatment. Public databases, including TCGA, ICGC, and GEO, were used to obtain data. HRD scores, neoantigen load, and TMB were obtained from the TCGA cohort. Candidate biomarkers were validated in multiple databases, such as the Imvigor210 immunotherapy cohort and the open-source single-cell sequencing database. Immunohistochemistry was performed to further validate the results in independent cohorts. CXCL10, CXCL11, and CXCL13 were found to be significantly upregulated in HRD tumors and exhibited prognostic value. A comprehensive analysis of the tumor immune microenvironment (TIME) revealed that CXCL13 expression positively correlated with neoantigen load and immune cell infiltration. In addition, single-cell sequencing data and clinical trial results supported the utility of CXCL13 as a biomarker for ICB therapy. Not only does CXCL13 serve as a biomarker reflecting HRD status, but it also introduces a potentially novel perspective on prognostic biomarkers for ICB in ovarian cancer.

Cancer-associated fibroblast-secreted FGF7 as an ovarian cancer progression promoter

Abstract Background Ovarian cancer (OC) is distinguished by its aggressive nature and the limited efficacy of current treatment strategies. Recent studies have emphasized the significant role of cancer-associated fibroblasts (CAFs) in OC development and progression. Methods Employing sophisticated machine learning techniques on bulk transcriptomic datasets, we identified fibroblast growth factor 7 (FGF7), derived from CAFs, as a potential oncogenic factor. We investigated the relationship between FGF7 expression and various clinical parameters. A series of in vitro experiments were undertaken to evaluate the effect of CAFs-derived FGF7 on OC cell activities, such as proliferation, migration, and invasion. Single-cell transcriptomic analysis was also conducted to elucidate the interaction between FGF7 and its receptor. Detailed mechanistic investigations sought to clarify the pathways through which FGF7 fosters OC progression. Results Our findings indicate that higher FGF7 levels correlate with advanced tumor stages, increased vascular invasion, and poorer prognosis. CAFs-derived FGF7 significantly enhanced OC cell proliferation, migration, and invasion. Single-cell analysis and in vitro studies revealed that CAFs-derived FGF7 inhibits the ubiquitination and degradation of hypoxia-inducible factor 1 alpha (HIF-1α) via FGFR2 interaction. Activation of the FGF7/HIF-1α pathway resulted in the upregulation of mesenchymal markers and downregulation of epithelial markers. Importantly, in vivo treatment with neutralizing antibodies targeting CAFs-derived FGF7 substantially reduced tumor growth. Conclusion Neutralizing FGF7 in the medium or inhibiting HIF-1α signaling reversed the effects of FGF7-mediated EMT, emphasizing the dependence of FGF7-mediated EMT on HIF-1α activation. These findings suggest that targeting the FGF7/HIF-1α/EMT axis may offer new therapeutic opportunities to intervene in OC progression.

Combination therapy for platinum-resistant ovarian cancer: a novel at-home regimen with envafolimab, lenvatinib, and etoposide

Abstract Background Effective and tolerable treatment for patients with platinum-resistant recurrent ovarian cancer remains a great challenge in clinical practice. This study aimed to evaluate the efficacy and safety of envafolimab, the first subcutaneously administered programmed death ligand 1 (PD-L1) inhibitor, combined with lenvatinib and etoposide in patients with platinum-resistant recurrent ovarian cancer. Methods This was an open-label, single-arm, phase 2 trial (ENLEN-OC-001). Patients with platinum-resistant recurrent ovarian cancer were eligible for inclusion who were administered envafolimab subcutaneously on day 1 and lenvatinib and etoposide orally on days 1-14, with 21 days as a cycle. After 6-10 cycles, envafolimab and lenvatinib were taken as maintenance therapy until intolerable toxicity, disease progression, withdrawal of consent, or finishing 24 months of treatment. The primary endpoint was objective response rate (ORR), and the secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results Of the screened 28 patients, 21 were included, with 18 being assessed for the efficacy and safety. The ORR was 44.4% (95% CI 21.5%-69.2%), and the DCR was 83.3% (95% CI 58.6%-96.4%). The median PFS was 10.2 months (95% CI 5.6-not applicable [NA]), and the median OS was 21.3 months (95% CI 6.8-NA). The most common grade 3/4 adverse events were leukopenia (27.8%) and thrombocytopenia (16.7%). No serious adverse events or treatment-related deaths were reported. No changes were observed in the depression, anxiety, and quality of life following treatment. Conclusion Envafolimab combined with lenvatinib and etoposide showed promising efficacy and tolerable safety for patients with platinum-resistant recurrent ovarian cancer. ClinicalTrials.gov identifier NCT05422183

Efficacy and Safety of Anlotinib in Overall and Disease-Specific Advanced Gynecological Cancer: A Real-World Study

Anlotinib is a novel oral small-molecule multi-target tyrosine kinase inhibitor that has been approved for treating non-small cell lung cancer. However, its efficacy and safety among patients with advanced gynecological cancer have not been comprehensively evaluated. We conducted this study to address this issue in the real-world setting. Data from patients treated with Anlotinib for persistent, recurrent or metastatic gynecological cancer were collected from 17 centers from August 2018. The database lock-time was on March 2022. Anlotinib was administered orally on days 1-14 every 3 weeks until disease progression, severe toxicity occurred, or death. In this study, disease-specific advanced gynecological cancer was mainly referred to cervical, endometrial, and ovarian cancer. The outcomes included objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). A total of 249 patients were analyzed, with a median follow-up of 14.5 months. The overall ORR and DCR were 28.1% [95% confidence interval (CI) 22.6% to 34.1%] and 80.7% (95% CI 75.3% to 85.4%), respectively. Specifically, the ORR varied from 19.7% to 34.4% and the DCR differed from 81.7% to 90.0% in disease-specific advanced gynecological cancer. The median PFS was 6.1 months and ranged from 5.6 to 10.0 months in the overall and disease-specific advanced gynecological cancer, respectively. Larger cumulative dosage of Anlotinib (>700 mg) was in general associated with longer PFS in the overall and disease-specific advanced gynecological cancer. The most common adverse event related to Anlotinib treatment was pain/arthralgia (18.3%). In conclusion, Anlotinib holds promise in treating patients with advanced gynecological cancer including its disease-specific types, with reasonable efficacy and tolerable safety.

Envafolimab, Lenvatinib Combined With VP-16 in Platinum-resistant Recurrent Epithelial Ovarian Cancer

This study is a single-arm, open-label, exploratory clinical study, the main purpose is to evaluate the combination of envafolimab, lenvatinib VP-16 in the treatment of platinum-resistant recurrent epithelial ovarian cancer，primary fallopian tube cancer and primary peritoneal carcinoma.