Investigational New Drugs最新文献

{"title":"Targeting Myc through BET-PROTAC elicits potent anti-lymphoma activity in diffuse large B cell lymphoma.","authors":"Hui Wang, Ximei Wu, Jingjing Gao, Suchang Chen, ZiTao Zhou, Luyong Zhang, Bing Liu, Min Wei","doi":"10.1007/s10637-025-01535-6","DOIUrl":"https://doi.org/10.1007/s10637-025-01535-6","url":null,"abstract":"<p><p>Diffuse large B cell lymphoma (DLBCL) presents a great challenge in the clinic due to its poor prognosis. Prior research has identified c-Myc as a promising therapeutic target in DLBCL; however, direct targeting of c-Myc protein has proven challenging. The bromodomain and extraterminal (BET) protein family, which acts as transcriptional and epigenetic regulators, plays a crucial role in super-enhancer organization and transcriptional regulation of oncogenic drivers like c-Myc, offering an alternative approach. Recently developed BET proteolysis targeting chimera (PROTAC) compounds can rapidly and effectively degrade BET proteins and potentially offer a more durable effect than traditional BET inhibitors. In this work, we compared the anti-tumor activity of a BET PROTAC, ARV-825, with a BET inhibitor, JQ1, in DLBCL. Cell proliferation was assessed by CCK-8 assay, apoptosis was evaluated by Annexin V/PI staining, and the cell cycle was analyzed by staining DNA with propidium iodide (PI). Western blotting was used to determine the expression levels of BET family proteins and its downstream regulatory gene c-Myc, and the in vivo SCID mouse model implanted with SU-DHL-4 cells was used to analyze the in vivo drug efficacy. Our results showed that ARV-825 was superior to JQ1 in inhibiting DLBCL cell proliferation, inducing apoptosis, promoting cell cycle arrest, and prolonging survival. Notably, ARV-825 was more effective at downregulating c-Myc and BET protein levels than JQ1 in both in vitro and in vivo experiments. These evidences suggest that BET-PROTACs may offer a promising novel strategy for the clinical treatment of DLBCL.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Navigating antibody‒drug conjugates (ADCs): from metastatic to early breast cancer treatment strategies.","authors":"Tala Najdi, Lea Awad, Antoine Chartouni, Charbel Soueidy, Hampig Kourie","doi":"10.1007/s10637-025-01525-8","DOIUrl":"https://doi.org/10.1007/s10637-025-01525-8","url":null,"abstract":"<p><p>We are currently living in the era of precision medicine, and antibody‒drug conjugates (ADCs) represent promising advancements in targeted cancer therapy. While several ADCs have been investigated over the years, only three have gained FDA approval for breast cancer (BC): ado-trastuzumab emtansine (T-DM1/Kadcyla), trastuzumab deruxtecan (T-DXd/Enhertu), and sacituzumab govitecan (SG/Trodelvy). This review focuses on the three approved ADCs for BC, reviewing the trials that led to their approval and detailing the ongoing trials testing their clinical efficacy and safety profiles. We examine ongoing trials targeting both metastatic and early-stage patients. Notably, we explore trials incorporating investigational ADCs into early management strategies, addressing the unique challenges of biomarker identification, target toxicity, and cost-effectiveness. By summarizing the current landscape of FDA-approved and investigational ADCs, this study highlights the evolving nature of BC treatment. Preliminary findings from ongoing trials suggest that early integration of ADCs can lead to significant improvements in disease-free survival, reinforcing their role in personalized medicine. As research advances, ADCs are likely to become a cornerstone of breast cancer treatment, providing new hope for better patient outcomes.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retrospective analysis of clinical features of pembrolizumab induced psoriasis.","authors":"Ming Shu, Zhiqiang Fan, Bin Huang, Chunjiang Wang","doi":"10.1007/s10637-025-01536-5","DOIUrl":"https://doi.org/10.1007/s10637-025-01536-5","url":null,"abstract":"<p><p>To explore the clinical features of pembrolizumab induced psoriasis to provide reference for the optimal treatment of immune checkpoint inhibitor-induced psoriasis. Clinical reports of pembrolizumab induced psoriasis were collected by searching the database until January 31, 2025. The clinical data extracted from the collected articles were retrospectively analyzed. A total of 42 patients were included, 76.2% male, with a median age of 69 years (range 28, 83). These patients included 21 (50.0%) patients with new-onset psoriasis and 21 (50.0%) patients with pre-existing psoriasis. The duration of onset of psoriasis was 8 weeks (range 0.4, 108), and the duration of onset of new psoriasis was longer than that of preexisting psoriasis (9 weeks vs. 7.2 weeks). Plaque psoriasis (38.1%) and psoriatis vulgaris (33.3%) were the most commonly reported phenotypes. After discontinuation or continuation of medication, 90.5% of patients experienced partial or complete improvement of skin symptoms after receiving topical, biologics, and oral systemic treatments. Pembrolizumab induced psoriasis can lead to various types of psoriasis, mainly in elderly and male patients. The pathogenesis and optimal treatment of Pembrolizumab in psoriasis require further investigation.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of potent CRBN-recruiting epidermal growth factor receptor (EGFR) degraders in vitro.","authors":"Wenbo Hu, Jinmei He, Tianyu Xie, Mengjia Zhou, Mingxia Liu, Xin Wang","doi":"10.1007/s10637-025-01539-2","DOIUrl":"https://doi.org/10.1007/s10637-025-01539-2","url":null,"abstract":"<p><p>Epidermal Growth Factor Receptor (EGFR), a transmembrane receptor tyrosine kinase (RTK) belonging to the ErbB family, initiates cancer-promoting pathways upon binding with epidermal growth factor (EGF). This activation leads to increased cellular proliferation, inhibition of apoptosis, invasion, and neovascularization. EGFR plays a critical role in non-small cell lung cancer (NSCLC) and is targeted by EGFR tyrosine kinase inhibitors (TKIs). However, resistance to these inhibitors often develops over time, complicating treatment strategies. Proteolysis-targeting chimeras (PROTACs) represent a novel class of drugs that induce targeted protein degradation by promoting ubiquitination upon binding, resulting in degradation via the 26S proteasome. This innovative strategy potentially addresses the drug resistance associated with small molecule inhibitors and holds promise for the treatment of NSCLC. In this paper, we designed and synthesized a series of small molecule PROTACs targeting EGFR utilizing WZ4002, known for its mutation selectivity, as the warhead. These compounds were evaluated for their antiproliferative activity against A549 and NCl-H1975 cell lines, with WZ4002 serving as a control drug. Most compounds exhibited moderate to strong activity against NCl-H1975 cells, with comparatively weaker effects on A549 cells. Among the tested compounds, HJM- 17 and HJM- 19 emerged as the most potent against NCl-H1975 cells. Further analysis through protein immunoblotting revealed that HJM- 17 effectively reduced the expression of EGFR^L858R/T790M. These active compounds lay the groundwork for future studies focused on EGFR-targeting PROTACs.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glasdegib combined with chemotherapy in the treatment of patients with acute myeloid leukemia: a comprehensive meta-analysis.","authors":"Abdelaziz A Awad, Ahmed Yasser Shaban, Fatma Mohammed, Mohamed Mahmoud Marey, Mohamed A Aldemerdash, Ahmed W Abbas, Omar Saeed, Abdelrahman Saeed, Mahmoud M Elhady, Israa Sharabati, Mohamed Hamed, Ahmed R A Abou-Shanab, Ahmed Bahnasy, Hussien Ahmed H Abdelgawad","doi":"10.1007/s10637-025-01528-5","DOIUrl":"https://doi.org/10.1007/s10637-025-01528-5","url":null,"abstract":"<p><strong>Background: </strong>Acute myeloid leukemia (AML) is characterized by clonal expansion of myeloid precursors, often accompanied by poor prognostic outcomes in older populations due to molecular heterogeneity and resistance to conventional chemotherapeutic agents. Glasdegib, a potent inhibitor of the Hedgehog signaling pathway, has emerged as a targeted agent that enhances chemosensitivity and demonstrates favorable pharmacodynamic profiles in combination regimens. This systematic review evaluates the clinical efficacy and safety of Glasdegib-based therapies in the management of AML.</p><p><strong>Methods: </strong>Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched four electronic databases (PubMed, Scopus, Cochrane Library, and Web of Science) to identify eligible studies reported up to August 2024. Using R version R.4.4.1, we reported outcomes as pooled proportions and confidence intervals (CIs). The survival data were extracted from Kaplan-Meier curves and reconstructed.</p><p><strong>Results: </strong>The pooled two-year overall survival for Glasdegib plus chemotherapy was 30% (95% CI [27-34%], I² = 0%). Subgroup analysis showed rates of 36% (95% CI [30-42%], Cytarabine and Daunorubicin), 27% (95% CI [20-36%], Low-Dose Cytarabine), and 25% (95% CI [20-31%], Azacitidine. Median survival times were highest for Glasdegib plus Cytarabine and Daunorubicin at 17.6 months (95% CI [15.6-21.9]), followed by 10.4 months (95% CI [8.22-12.3]) for Glasdegib plus Azacitidine, and 7.89 months (95% CI [5.47-11.5]) for Glasdegib plus Low-Dose Cytarabine. Safety analysis revealed varied adverse event rates for Glasdegib plus chemotherapy, with febrile neutropenia (37%), nausea (47%), vomiting (32%), and QT prolongation (44%) being the most commonly reported.</p><p><strong>Conclusion: </strong>Glasdegib combined with chemotherapy demonstrates promising efficacy in improving survival outcomes for AML patients, particularly in combination with Cytarabine and Daunorubicin. While adverse events were common, they were generally manageable, supporting Glasdegib as a viable therapeutic option. Further research is warranted to optimize treatment regimens and evaluate long-term safety and quality-of-life outcomes.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":"43 2","pages":"405-424"},"PeriodicalIF":3.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase 1 study of HP518, a PROTAC AR degrader in patients with mCRPC: results on safety, pharmacokinetics, and anti-tumor activity.","authors":"Arun A Azad, Howard Gurney, Craig Underhill, Lisa Horvath, Mark Voskoboynik, Xinghai Li, Ivan King, Lisa Shao, Yiyun Dai, Frank Perabo","doi":"10.1007/s10637-025-01533-8","DOIUrl":"https://doi.org/10.1007/s10637-025-01533-8","url":null,"abstract":"<p><p>HP518 is an oral PROteolysis TArgeting Chimera (PROTAC) protein degrader targeting the wild-type androgen receptor (WT-AR) and mutant AR ligand-binding domain (AR-LBD). A multicenter, first-in-human, open-label Phase 1 dose escalation study was conducted in patients with metastatic castration-resistant prostate cancer (mCRPC) to evaluate the safety, pharmacokinetics, and anti-tumor activity of HP518. Twenty-two patients with mCRPC with disease progression on at least 1 novel androgen receptor pathway inhibitor (ARPI) and ≤ 1 line of chemotherapy received HP518 once daily orally in sequential cohorts. Patients were not selected for AR-LBD mutations. Objectives were to assess safety, tolerability, maximum tolerated dose, pharmacokinetics (PK), as well as efficacy by PSA₅₀ response and radiographic response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and Prostate Cancer Working Group 3 (PCWG3) criteria. Exploratory objectives included genomic profiling using cell-free DNA. The majority of treatment-emergent adverse events (TEAEs) were Grade 1 or 2. The most common AEs were nausea and vomiting, fatigue, constipation, diarrhea, and decreased appetite. Only one (vomiting) out of 10 serious adverse events (SAE) was considered drug-related. No patient experienced a dose-limiting toxicity (DLT), and no AEs led to dose reduction or study discontinuation. Following multiple dosing of HP518, the PK appeared to plateau showing a less than dose-proportional relationship between exposure and dosage. Two patients demonstrated a partial response, and three patients showed a PSA50 response. In this initial Phase 1 study, HP518 demonstrated an acceptable safety profile and responses in a limited subset of mCRPC patients with progression after ARPI warranting further investigation. ClinicalTrials.gov Identifier: NCT05252364.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":"43 2","pages":"435-445"},"PeriodicalIF":3.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A phase I dose-escalation and expansion study of RMX1002, a selective E-type prostanoid receptor 4 antagonist, as monotherapy and in combination with anti-PD-1 antibody in advanced solid tumors.","authors":"Dan Liu, Jifang Gong, Jian Zhang, Yongqian Shu, Hao Wu, Tianshu Liu, Yanhua Xu, Lijia Zhang, Min Li, Xichun Hu, Lin Shen","doi":"10.1007/s10637-025-01512-z","DOIUrl":"10.1007/s10637-025-01512-z","url":null,"abstract":"<p><p>RMX1002 (grapiprant) is a selective E-type prostanoid receptor 4 (EP4) antagonist and a promising candidate for cancer therapy, potentially enhancing anti-tumor immune responses. This study aimed to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of RMX1002 as monotherapy and in combination with anti-PD-1 antibody toripalimab for advanced solid tumors. This multicenter, phase I trial enrolled patients with histologically or cytologically confirmed advanced solid tumors. This study included three phases: Ia (dose-escalation of RMX1002 monotherapy from 200 to 650 mg BID), Ib (dose-escalation from 500 to 650 mg BID in combination with toripalimab), and Ic (dose-expansion of 500 mg BID with toripalimab). Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. A total of 45 patients were enrolled (17 in phase Ia, 12 in phase Ib, and 16 in phase Ic). No dose-limiting toxicity was reported, and the MTD was not reached. Overall, 21 patients experienced RMX1002-related adverse events with CTCAE grade ≥ 3. Pharmacokinetics revealed rapid absorption of RMX1002 with the maximum concentration (C_max) reached within 2 to 5 h, and dose-dependent increases in C_max and area under the concentration-time curve. The increase in urinary metabolite of PGE2 suggested the inhibition of EP4 signaling pathway. The best response was stable disease, reported in 64.7%, 28.6%, and 18.8% of patients in phase Ia, Ib, and Ic, respectively. RMX1002 was well tolerated and showed a best response of stable disease. RMX1002 500 mg BID with toripalimab 240 mg every 3 weeks is the recommended dose for future trials.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"250-261"},"PeriodicalIF":3.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"US FDA-accelerated approvals and subsequent withdrawals: influence on Japanese clinical oncology practice guidelines.","authors":"Hayase Hakariya, Akihiko Ozaki, Tetsuya Tanimoto","doi":"10.1007/s10637-025-01524-9","DOIUrl":"10.1007/s10637-025-01524-9","url":null,"abstract":"<p><p>The US (US) Food and Drug Administration (FDA)-accelerated approval pathway facilitates early access to oncology drugs based on surrogate endpoints, with required confirmatory post-marketing trials. However, regulatory decisions vary globally, with some drugs withdrawn in the US remaining approved in Japan. We conducted a cross-sectional analysis of Japanese professional society guidelines, evaluating recommendations for seven accelerated approval cancer drugs withdrawn from the US market but retained in Japan. We assessed for level of evidence and level of treatment preference ratings with consensus across guidelines issued by the corresponding Japanese professional societies. Four of the seven drugs (57%) were recommended as highly or moderately preferred treatment options in Japanese guidelines: gemtuzumab ozogamicin for acute myeloid leukemia, gefitinib for EGFR-positive non-small cell lung cancer, bevacizumab for HER2-negative metastatic breast cancer, and atezolizumab with nab-paclitaxel for PD-L1-positive triple-negative breast cancer. Detailed analysis of regulatory history and background of guideline recommendation revealed discrepancies in the assessment of clinical benefits: gemtuzumab ozogamicin failed to demonstrate benefits amid safety concerns, while gefitinib, bevacizumab, and atezolizumab were more controversial, although they did not demonstrate improved overall survival in post-marketing trials. Despite regulatory withdrawal in the US due to unproven clinical benefits, drugs retained in Japan received positive guideline recommendations. This finding highlights regional variations in regulatory decisions and different approaches to benefit-risk assessments, suggesting a need for improved transparency in Japan's regulatory decisions and guideline recommendations, with clearer justifications for endorsing drugs that are considered to have unproven clinical benefits in the US.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"311-317"},"PeriodicalIF":3.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patient-derived tumor organoids for cancer immunotherapy: culture techniques and clinical application.","authors":"Ningning Yao, Na Jing, Jianzhong Lin, Wenxia Niu, Wenxing Yan, Hongqin Yuan, Zeyi Xiong, Qing Hou, Xiaxi Qiao, Quanming Liu, Jianzhong Cao, Ning Li","doi":"10.1007/s10637-025-01523-w","DOIUrl":"https://doi.org/10.1007/s10637-025-01523-w","url":null,"abstract":"<p><p>Cancer immunotherapy has revolutionized tumor treatment. However, robust and effective testing platforms remain lacking, especially for the selection of the optimized therapy at the patient-specific level. Unlike conventional treatment evaluations, testing platforms for cancer immunotherapy must incorporate not only tumor cells but also the tumor microenvironment (TME), including immune components. Recently, emergence of patient-derived tumor organoids (PDTOs), an in vitro preclinical model, has provided a novel approach for studying tumor evolution and assessing treatment responses, and shows great potential when coculturing with immune cells to study the mechanisms of immunotherapy efficacy and resistance. However, traditional organoid technology is limited in capturing the full impact of the TME on tumor behaviors due to the absence of stromal components. To circumvent these restrictions, complex organoid cocultures with immune cells, cancer-associated fibroblasts and vasculatures are developed. In this review, we summarized recent advances in PDTO culture techniques for modeling the TME and explored the application of complex tumor organoids in cancer immunotherapy.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":"43 2","pages":"394-404"},"PeriodicalIF":3.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bispecific antibody targeting CD155 mediates T-cell immunotherapy against human gynecological malignancies.","authors":"Li Ma, Juan Ma, Dingqing Feng, Xin Xue","doi":"10.1007/s10637-025-01529-4","DOIUrl":"https://doi.org/10.1007/s10637-025-01529-4","url":null,"abstract":"<p><p>T cells are crucial regulators in cancer treatment due to their cytotoxic ability. Recently, immunotherapies based on bispecific antibodies (Bi-Ab) have achieved remarkable effects in cancer treatment, attributed to their capability of recruiting and activating T cells to kill tumors. In the present study, we investigated whether CD155 is an effective target for T-cell-mediated immunotherapy against human gynecological malignancies. We demonstrated that CD155 is expressed on common gynecological tumor cells, including cervical, uterine, and ovarian cancers. Next, we evaluated the specific cytotoxic activity of T cells armed with CD155Bi-Ab (CD155Bi-T cells) against tumor cells. Compared with control T cells treated with separate anti-CD155 and anti-CD3 mAbs, CD155Bi-T cells exhibited significant cytotoxicity against CD155-positive gynecological tumor cells. Specifically, in the luciferase assay, the cytotoxicity of CD155Bi-T cells was 2.67-fold higher than that of control T cells at an effector/target ratio of 5:1, indicating a significant enhancement in tumor-killing activity. This enhanced cytotoxic activity was further supported by increased expression of activation markers (CD69 and 4 - 1BB), higher production of T-cell-derived cytokines (IL- 2, IFN-γ, and TNF-α), and elevated levels of the cell-killing mediators (perforin and granzyme B). Taken together, our findings demonstrate that CD155 is a promising target for gynecological tumors, and CD155Bi-T cells hold significant potential for immunotherapy against CD155⁺ gynecological malignancies.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":"43 2","pages":"318-327"},"PeriodicalIF":3.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}