Investigational New Drugs最新文献

{"title":"MicroRNA nanoformulation: a promising approach to anti-tumour activity.","authors":"Abhishesh Kumar Badal, Arnab Nayek, Ruby Dhar, Subhradip Karmakar","doi":"10.1007/s10637-025-01534-7","DOIUrl":"10.1007/s10637-025-01534-7","url":null,"abstract":"<p><p>Cancer is a major cause of morbidity and mortality, making it one of the most debilitating diseases in our time. Despite advancements in therapeutic strategies, the development of chemoresistance and the occurrence of secondary tumours pose significant challenges. While several promising anti-tumour agents have been identified, their clinical utility is often limited due to toxicity and associated side effects. MicroRNAs (mi-RNAs) are critical regulators of gene expression, and their altered levels are closely linked to cancer development and progression. Although some microRNAs have shown potential as biomarkers for cancer detection, their integration into routine clinical practice has yet to be realized. Numerous candidate microRNAs exhibit therapeutic potential for cancer treatment; however, further research is needed to create efficient, patient-compliant, and customized drug delivery systems. In recent decades, various nanotechnology platforms have successfully transitioned to clinical trials, particularly in the field of RNA nanotechnology. Several RNA nanoparticles have been developed to address key challenges in vivo for targeting cancer, demonstrating favourable biodistribution characteristics. Studies have shown that RNA nanoparticles, characterized by precise stoichiometry and homogeneity, can effectively target tumour cells while avoiding aggregation in normal, healthy tissues following systemic injection. Animal models have demonstrated that RNA nanoparticles can deliver therapeutics such as siRNA and anti-microRNA, effectively inhibiting tumour growth. Using nanoparticles conjugated with antibodies and/or peptides enhances the targeted delivery and sustained release of microRNAs and anti-microRNAs, which may reduce the required therapeutic dosage and minimize systemic and cellular damage. This review focuses on developing microRNA nanoformulations to improve cellular uptake, bioavailability, and accumulation at tumour sites, assessing their potential anti-tumour efficacy against various types of malignancies. The significance of these advancements in clinical oncology cannot be overstated.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"504-524"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144020186","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":"TP53 and DNA-PK as potential biomarkers for enhanced efficacy of Olaparib in colorectal cancer.","authors":"Do Yeon Kim, Hyeseon Yun, Ji-Eun You, Yoon Sun Park, Yea Seong Ryu, Dong-In Koh, Jae-Sik Shin, Dong-Hoon Jin","doi":"10.1007/s10637-025-01544-5","DOIUrl":"10.1007/s10637-025-01544-5","url":null,"abstract":"<p><p>Olaparib is selected based on the presence of BRCA mutations in patient populations; however, further investigation is still required regarding its effect on restoring homologous recombination (HR) through the inactivation of non-homologous end joining (NHEJ). Therefore, identifying regulators of NHEJ could increase the sensitivity of cancer cells to Olaparib by inhibiting DNA damage repair is a major focus of current research. Loss of DNA-dependent protein kinase (DNA-PK), which is a major components of NHEJ, compromises DNA damage repair, and the resulting increase in DNA damage burden may heighten reliance on poly (ADP-ribose) polymerase (PARP)-dependent DNA repair in cancer cells, rendering them more susceptible to PARP inhibitor therapy. However, DNA-PK alone is not sufficient to enhance the effectiveness of Olaparib, so various adjuvant and combination therapies are being explored. We classified colorectal cancer (CRC) cells based on their sensitivity to Olaparib and found that they were categorized according to TP53 status. Here, we examine the role of DNA-PK in the response to Olaparib, emphasizing its relationship with TP53 status. Our findings indicate that the inhibition of DNA-PK enhances sensitivity to Olaparib and induces phosphorylation of p53 exclusively in cells with TP53 wild-type (WT). Furthermore, using CRC patient-derived cells (PDC) and patient-derived xenograft (PDX) model, we show that the sensitivity of Olaparib is determined TP53 and DNA-PK genotypes. These findings highlight TP53 and DNA-PK as potential predictive biomarkers for optimizing PARP inhibitor-based therapy in CRC.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"656-668"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144077716","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":"Peptide YY fragment PYY1-36 disrupts mitochondrial biogenesis via RBM43-dependent PGC-1α translation inhibition.","authors":"Benkun Liu, Fucheng Zhou, Bowen Shi, Yubo Yan, Yanbo Wang, Junfeng Wang, Yaoguo Lang, Shidong Xu","doi":"10.1007/s10637-025-01545-4","DOIUrl":"10.1007/s10637-025-01545-4","url":null,"abstract":"<p><p>Mitochondrial dysfunction is a key driver of cancer progression, with therapies increasingly targeting metabolic weaknesses. Peptide YY (PYY), a gastrointestinal hormone, regulates cellular activity, but its influence on mitochondrial health in lung cancer remains poorly understood. We explored how PYY1-36, a bioactive fragment of PYY, affects mitochondrial stability in NCI-H1581 lung cancer cells. Using dose-response experiments, we measured oxidative stress by tracking lactate dehydrogenase (LDH) release, mitochondrial ROS levels, and oxidative DNA damage (8-OHdG). Energy production was evaluated through ATP levels, oxygen consumption rates (OCR), and Complex I activity. We also analyzed mitochondrial biogenesis markers (NRF1, TFAM, PGC-1α) and the RNA-binding protein RBM43 via qPCR and immunoblotting. Dose-dependent tests showed that PYY1-36 triggers mitochondrial oxidative damage, marked by higher LDH release and ROS spikes. These changes aligned with sharp drops in ATP production and disrupted respiratory function. Notably, PYY1-36 reduced mitochondrial mass and biogenesis, supported by weaker MitoTracker Red signals and lower mtDNA/nDNA ratios. Key regulators NRF1 and TFAM were strongly suppressed, pointing to widespread mitochondrial failure. Intriguingly, PYY1-36 blocked PGC-1α protein synthesis without altering mRNA levels, suggesting a post-transcriptional control mechanism. PYY1-36 also boosted RBM43 levels. Knocking down RBM43 reversed PYY1-36's effects on PGC-1α and mitochondrial health. Our findings reveal RBM43 as a central player in PYY1-36-induced mitochondrial dysfunction through its suppression of PGC-1α translation. Targeting RBM43 could unlock new strategies to tackle metabolic chaos in lung cancer.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"669-678"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12310810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127587","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":"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":"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":2.7,"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":2.7,"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":"Clinical features, treatment, and prognosis of nivolumab induced immune encephalitis.","authors":"Zhaoquan Wu, Haibo Lei, Ronghui Li, Xiang Liu, Chunjiang Wang","doi":"10.1007/s10637-025-01522-x","DOIUrl":"10.1007/s10637-025-01522-x","url":null,"abstract":"<p><p>Immune encephalitis (IE) is an immune-mediated adverse events (irAEs) linked to nivolumab therapy, and its clinical characteristics remain unclear. This study aimed to analyze the clinical patterns of nivolumab-induced IE to inform diagnosis, treatment, and prevention strategies. We conducted a retrospective analysis of nivolumab-induced IE by reviewing case reports from the database until October 31, 2024. Among the 86 patients (53.5% male), the median age was 64 years (range 17, 83). The median time to the onset of IE was 38 days (range 4, 1430), and the median treatment cycle was 2 cycles (range 1, 18). The most prevalent symptoms included altered mental status (38.4%) and fever (37.2%). Cerebrospinal fluid analysis revealed elevated protein levels, normal glucose, and pleocytosis. Antineuronal antibodies were present in 29.1% of patients. MRI findings typically showed T2/FLAIR hyperintense signals in 52.3%. EEG results indicated diffuse slowing (16.3%). Following drug discontinuation and treatment, 86% of patients exhibited recovery or improvement, while 5.8% unfortunately succumbed to the condition. IE represents a rare yet severe irAEs associated with nivolumab. Clinicians must remain vigilant for signs of IE in patients undergoing nivolumab treatment. Diagnostic tests for nivolumab-induced IE generally do not reveal specific abnormalities. For individuals diagnosed with IE, it is crucial to initiate systemic steroid treatment without delay.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"293-300"},"PeriodicalIF":3.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597090","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":"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}