Cancer research communications最新文献

{"title":"A Phase IB Study of Binimetinib and Palbociclib in Molecularly Selected Advanced Triple-Negative Breast Cancer.","authors":"Luis Manso, Rodrigo Sánchez-Bayona, Juan Antonio Guerra, Alfonso Cortés-Salgado, Juan Miguel Cejalvo, José A García-Saenz, Serafín Morales, Lucía González-Cortijo, Silvana Mourón, María J Bueno, Leonardo D Garma, Miguel Quintela-Fandino","doi":"10.1158/2767-9764.CRC-25-0428","DOIUrl":"10.1158/2767-9764.CRC-25-0428","url":null,"abstract":"<p><strong>Purpose: </strong>Advanced, pretreated triple-negative breast cancer (TNBC) has a dismal prognosis and lacks effective options beyond standard cytotoxics. We previously showed, via phosphoproteomic screening, that cyclin-dependent kinase 6 (CDK6) and ERK hyperactivation are linked to adverse outcomes and represent actionable targets. This prompted us to evaluate palbociclib and binimetinib in advanced TNBC after one or two prior therapies.</p><p><strong>Patients and methods: </strong>Patients with increased ERK and/or CDK6 activity were eligible. Treatment consisted in daily binimetinib (45 mg twice a day) plus palbociclib (100 mg daily, days 1-21) in 28-day cycles. Palbociclib escalation to 125 mg was allowed in cycle 2. The primary objective was to demonstrate a 2.5 month-long progression-free survival (PFS), a 50% increase over the reference PFS for cytotoxics (1.7 months). Whole-exome sequencing was performed in tumor samples of the efficacy population.</p><p><strong>Results: </strong>Fifty-one patients were screened, of whom 50 were biomarker-positive. Twenty-four initiated treatment between June 2021 and July 2022. Toxicity was frequent, consisting mainly in fatigue, diarrhea, neutropenia, and ocular effects, requiring frequent dose interruptions or reductions. The primary objective was not met (median PFS 50 days). However, a bimodal PFS pattern emerged, with 13% of the patients achieving disease control lasting 4 to 13 months. Whole-exome sequencing revealed a distinct mutational landscape among long-term responders compared with early progressors.</p><p><strong>Conclusions: </strong>In this biomarker-enriched TNBC population, the combination of palbociclib and binimetinib showed limited activity and notable toxicity. Whereas CDK6 and ERK hyperactivation confirmed their prognostic role, they did not predict treatment benefit. Exploratory genomic findings suggest the existence of a biologically distinct subset of patients with prolonged benefit, encouraging further investigation.</p><p><strong>Significance: </strong>Previous studies showed that patients with early TNBC with increased CDK4/6 and ERK activity are at high risk of relapse. Preclinical data also suggest the benefit of combined inhibition of CDK4/6 and MEK, and novel therapies are needed for TNBC in the advanced disease setting. Despite the rationale and a biomarker-driven design, this combination was toxic and showed limited efficacy. This combination should not be further developed in this disease.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1728-1737"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GALNT7 Stratifies dMMR/MSI Colorectal Cancer into Distinct Molecular Subsets Associated with Prognosis and PD-L1 Expression.","authors":"Hiroya Suzuki, Hirokazu Okayama, Shotaro Nakajima, Katsuharu Saito, Ryo Kanoda, Yuya Maruyama, Akira Matsuishi, Takuro Matsumoto, Misato Ito, Shun Chida, Wataru Sakamoto, Motonobu Saito, Zenichiro Saze, Tomoyuki Momma, Kosaku Mimura, Koji Kono","doi":"10.1158/2767-9764.CRC-25-0270","DOIUrl":"10.1158/2767-9764.CRC-25-0270","url":null,"abstract":"<p><p>Colorectal cancer with deficient mismatch repair (dMMR)/microsatellite instability (MSI) constitutes a distinct clinicopathologic and immunologic subtype, characterized by high sensitivity to immune checkpoint inhibitors. However, prognosis and therapeutic response vary considerably among dMMR/MSI colorectal cancers, underscoring the need for molecular markers to refine patient stratification. In this study, we systematically investigated cancer cell-intrinsic expression profiles of 188 glycosyltransferase genes by integrating single-cell, bulk, and cell line RNA sequencing datasets. This approach identified five glycosyltransferases, including GALNT7, expression of which differed consistently according to MSI status. The clinical and prognostic relevance of these glycosyltransferases was further analyzed across large-scale transcriptomic, proteomic, and IHC cohorts, comprising 662 dMMR/MSI and 3,483 proficient mismatch-repair (pMMR)/microsatellite-stable (MSS) colorectal cancers. A five-gene glycosyltransferase signature effectively distinguished MSI from MSS colorectal cancers across 18 datasets. Among the five genes, GALNT7 expression was robustly associated with favorable prognosis in four independent transcriptomic and IHC cohorts of dMMR/MSI colorectal cancers while showing little or no prognostic impact in pMMR/MSS colorectal cancers. Notably, GALNT7 expression was inversely correlated with PD-L1 expression at both the mRNA and protein levels in multiple datasets exclusively within dMMR/MSI colorectal cancers, but not in pMMR/MSS CRCs. Functional assays and lectin microarray analysis using MSI colorectal cancer cell lines revealed that GALNT7 knockdown enhanced IFNγ-induced PD-L1 expression without altering cell-surface glycosylation. In conclusion, GALNT7 expression stratified dMMR/MSI colorectal cancers into distinct subsets with differential tumor cell PD-L1 expression and diverse survival outcomes, highlighting its potential as a prognostic biomarker to guide treatment strategies.</p><p><strong>Significance: </strong>We identified glycosyltransferases with altered expression depending on MMR/MSI status. Our findings indicate the existence of two molecularly defined subtypes within dMMR/MSI colorectal cancers based on GALNT7 expression, characterized by differential tumor cell PD-L1 levels and distinct survival outcomes.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1530-1540"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12412012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144877063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic Impact of Immune-Related Adverse Events on Combination Immune Checkpoint/Tyrosine Kinase Inhibition for Metastatic Renal Cancer.","authors":"Bunpei Isoda, Masanobu Shiga, Shuya Kandori, Shota Takahashi, Akifumi Omiya, Tomoki Ishida, Kotoe Matsuda, Hiromichi Sakurai, Bryan J Mathis, Ken Tanaka, Manabu Komine, Masahiro Iinuma, Akira Joraku, Hiromitsu Negoro, Masakazu Tsutsumi, Takamitsu Inoue, Jun Miyazaki, Hiroyuki Nishiyama","doi":"10.1158/2767-9764.CRC-25-0337","DOIUrl":"10.1158/2767-9764.CRC-25-0337","url":null,"abstract":"<p><p>Immune checkpoint inhibitor (ICI) combinations and tyrosine kinase inhibitor (TKI) use are standard for metastatic renal cell carcinoma (mRCC), leading to improved outcomes. However, due to a lack of predictive biomarkers, the presence or absence of immune-related adverse events (irAE) is currently used as a predictive factor in clinical practice. To elucidate the impact of irAEs on efficacy, a cohort of patients with mRCC who received ICI-based combination therapy as initial treatment was analyzed. Patients were divided into two groups: those who received dual-ICI therapy (ICI-ICI, N = 55) or ICI and TKI therapy (ICI-TKI, N = 55). Subsequent to this initial categorization, each group was further subdivided based on the presence or absence of irAEs. In the ICI-ICI group, patients with irAEs exhibited significantly prolonged overall survival (OS) and progression-free survival [PFS; OS (median): not reached vs. 17.9 months, P = 0.03/PFS (median): 51.4 vs. 5.8 months, P < 0.01]. Conversely, no such correlation was observed between irAEs and OS/PFS in the ICI-TKI group. [OS (median): 26.3 months vs. not reached, P = 0.73/PFS (median): 16.8 months vs. 11.9 months, P = 0.38] Furthermore, treatment discontinuation due to AEs accounted for 65% (N = 32) in the ICI-ICI group and 57% (N = 24) in the ICI-TKI group, with a slightly higher tendency observed in the ICI-ICI group. These findings suggest that the prognostic impact of irAEs may differ depending on the treatment combination, and further basic research is needed to elucidate the underlying mechanisms.</p><p><strong>Significance: </strong>In patients with mRCC who received ICI-ICI, the occurrence of irAEs was associated with improved survival outcomes, whereas no such association was observed in patients who received ICI-TKI. This suggests that irAEs may reflect the favorable immune response specific to ICI-ICI therapy, whereas differences in the tumor microenvironment, particularly involving neutrophils, in ICI-TKI patients may influence treatment response.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1681-1689"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12446605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145001995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPSai: A Clinically Validated AI Tool for Tissue of Origin Prediction during Routine Tumor Profiling.","authors":"Hassan Ghani, Anthony Helmstetter, Jennifer R Ribeiro, Todd Maney, Stephanie Rock, Rebecca A Feldman, Jeff Swensen, Farah Abdulla, David B Spetzler, Elena Florento, Ari M Vanderwalde, Patricia Pittman, Milan Radovich, Jaclyn Hechtman, Casey Bales, George W Sledge, Myra M George, David Bryant, Jim P Abraham, Matthew J Oberley","doi":"10.1158/2767-9764.CRC-25-0171","DOIUrl":"10.1158/2767-9764.CRC-25-0171","url":null,"abstract":"<p><p>A subset of cancers present with unclear or potentially incorrect primary histopathologic diagnoses, including cancers of unknown primary (CUP). We aimed to develop and validate an artificial intelligence (AI) tool, Genomic Probability Score AI (GPSai™), which predicts tumor tissue of origin in CUP and flags potential misdiagnoses for additional workup during routine molecular testing. The GPSai model was trained on whole exome and whole transcriptome data from 201,612 cases submitted for tumor profiling at Caris Life Sciences. Retrospective (N = 21,549) and prospective (N = 76,271) validations were performed. The clinical impact was evaluated over 8 months of live testing and through physician surveys. GPSai demonstrated 95.0% accuracy in non-CUP cases and reported on tumor tissue of origin in 84.0% of CUP and 96.3% of non-CUP cases. During the initial 8 months of implementation, GPSai changed the diagnosis on 704 patients (0.88% of all profiled cases), which were supported by orthogonal evidence including imaging, IHC, mutational signatures, hallmark fusions, or viral reads. Diagnosis changes prompted changes in targeted therapy eligibility based on level 1 clinical evidence in 86.1% of cases (n = 606/704). A majority (89.7%; n = 87/97) of physician responses indicated acceptance of the GPSai results, and 53.6% (n = 52/97) of responses stated that the results prompted a change in treatment plan. GPSai accurately identifies tumor tissue of origin and has the potential for clinical impact in a small but meaningful subset of patients with CUP or pathologically ambiguous tumors. Our results support the integration of this AI tool into routine molecular testing to improve diagnostic accuracy and guide subsequent therapeutic decisions.</p><p><strong>Significance: </strong>Our findings show that GPSai, a deep learning-based tool, can support the identification of primary tumor sites with high accuracy in conjunction with orthogonal evidence. Its integration into routine tumor profiling furthermore allows simultaneous biomarker identification. Analysis of real-world implementation of GPSai shows that it enhances diagnostic accuracy, including resolution of CUP cases, and prompts clinically relevant therapeutic recommendation changes without requiring additional specimen.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1477-1489"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12399951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug-Drug Interaction Liabilities with BTK Inhibitor TL-895.","authors":"Jack C Stromatt, Eman A Ahmed, Thomas Drabison, Mahesh R Nepal, Anika T Chowdhury, Shelley J Orwick, Daelynn R Buelow, Eric D Eisenmann, Kevin M Huang, Alex Sparreboom, Sharyn D Baker","doi":"10.1158/2767-9764.CRC-25-0265","DOIUrl":"10.1158/2767-9764.CRC-25-0265","url":null,"abstract":"<p><p>TL-895 is an orally administered protein kinase inhibitor in clinical development for the treatment of B-cell malignancies and various other blood and autoimmune disorders. In the early stages of drug development, limited data are available to assess off-target engagement and drug-drug interaction (DDI) liabilities, which may have profound effects on drug safety and efficacy. In this context, we characterized the kinase interaction profile of TL-895 and determined that the agent inhibits Bruton's tyrosine kinase (BTK) and bone marrow kinase on chromosome X (BMX), with more potent inhibition of BMX than BTK in a kinase assay (IC50: 0.53 vs. 3.02 nmol/L) and a bioluminescence resonance energy transfer (BRET) assay (IC50: 1.6 vs. 6.8 nmol/L). We used in vitro and in vivo models to assess DDI liabilities and identified TL-895 as a substrate of the hepatic uptake transporter OATP1B1 and the enzyme CYP3A4. In vivo, coadministration of TL-895 did not increase plasma concentrations of the endogenous and xenobiotic OATP1B1 substrates chenodeoxycholic acid 24-acyl-β-D-glucuronide, pravastatin, and gilteritinib, which indicates that TL-895 is an unlikely perpetrator of OATP1B1-mediated DDIs. Consistent with hepatic microsomal studies, we found that plasma concentrations of TL-895 were increased by 1.8- and 4.6-fold, respectively, in male and female mice lacking all CYP3A isoforms. The pharmacokinetic profile of TL-895 was not significantly sexually dimorphic or strain-dependent at drug doses producing human-equivalent measures of systemic exposure. These collective findings signify an important contribution of OATP1B1 and CYP3A4 to the in vivo handling of the dual BTK/BMX inhibitor TL-895 and suggest the agent is an unlikely perpetrator of potentially deleterious DDIs in polypharmacy regimens.</p><p><strong>Significance: </strong>TL-895 is an investigational second-generation BTK inhibitor for the treatment of B-cell malignancies. We found that TL-895 undergoes hepatocellular uptake by OATP1B-type transporters in advance of extensive CYP3A-mediated metabolism but is unlikely to perpetrate pharmacokinetic DDIs that could compromise drug safety in the context of polypharmacy regimens.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1621-1630"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12426595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144980478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Utilizing Serum-Derived Lipidomics with Protein Biomarkers and Machine Learning for Early Detection of Ovarian Cancer in the Symptomatic Population.","authors":"Brendan M Giles, Rachel Culp-Hill, Robert A Law, Charles M Nichols, Mattie Goldberg, Enkhtuya Radnaa, Maria Wong, Connor Hansen, Moises Zapata, Collin Hill, Kian Behbakht, Benjamin G Bitler, Emma J Crosbie, Chloe E Barr, Anna Jeter, Vuna S Fa, Violeta Beleva Guthrie, Leonardo N Hagmann, Emily C Kubota, James Robert White, Abigail McElhinny","doi":"10.1158/2767-9764.CRC-25-0140","DOIUrl":"10.1158/2767-9764.CRC-25-0140","url":null,"abstract":"<p><p>Ovarian cancer is the fifth leading cause of cancer-related deaths among women. Most patients are diagnosed at late stage (III/IV), resulting in a 5-year survival rate below 30%. This is driven by the presentation of vague abdominal symptoms that confound diagnosis at early stages (I/II) and a shortage of robust biomarkers. We are taking a novel approach for earlier ovarian cancer detection, leveraging lipids as biomarkers. We utilized untargeted ultrahigh pressure liquid chromatography-mass spectrometry to analyze sera from two large, independent cohorts (N = 433 and N = 399) designed to reflect the symptomatic population, including individuals with benign adnexal masses, early- and late-stage ovarian cancer, gastrointestinal disorders, and otherwise healthy women seeking care for symptoms. We identified a significantly altered lipid profile in ovarian cancer and early-stage ovarian cancer specifically across both cohorts compared with controls. We also profiled select protein biomarkers (cancer antigen 125, human epididymis protein 4, β-2 folate receptor α, and mucin 1) and, utilizing machine learning-based modeling, identified a proof-of-concept multiomic model consisting of less than 20 top-performing lipid and protein features. This model was trained on cohort 1 and tested on cohort 2, achieving AUCs of 92% (95% confidence interval, 87%-95%) for distinguishing ovarian cancer from controls and 88% (95% confidence interval, 83%-93%) for distinguishing early-stage ovarian cancer from controls. These findings demonstrate the clinical utility and robustness of lipids as proof-of-concept diagnostic biomarkers for early ovarian cancer within the clinically complex symptomatic population, particularly when applied in a multiomic approach.</p><p><strong>Significance: </strong>Patients with ovarian cancer endure delayed diagnosis and poor outcomes. We profiled lipids in two cohorts and integrated them with proteins in machine learning. This enabled early-stage detection in a complex range of controls.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1516-1529"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144838723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Minimal Impact of COVID-19 on One-Year Mortality on US Patients with Cancer Diagnosed Early during the Pandemic.","authors":"Anne-Michelle Noone, Nadia Howlader, Angela B Mariotto, Yoon Duk Hong, Ruth M Pfeiffer","doi":"10.1158/2767-9764.CRC-25-0286","DOIUrl":"10.1158/2767-9764.CRC-25-0286","url":null,"abstract":"<p><p>Patients with cancer diagnosed early in the COVID-19 pandemic may have been particularly vulnerable due to immunosuppression caused by their cancer. The objective was to assess cause of death due to COVID-19, cancer, and other causes among patients with cancer during the pandemic. We thus examined causes of death (cancer, COVID-19, other causes) among patients with cancer diagnosed in 2020 (N = 503,128) compared with 2018 (N = 537,006) in the Surveillance, Epidemiology, and End Results-22. We focused on 1-year cause-specific mortality by cancer type, stage, and age at diagnosis. In a counterfactual analysis, we estimated the number and proportions of patients with cancer dying of cancer or other competing causes if COVID-19 were eliminated as a possible cause of death. Among 2020 patients with cancer, 15.8% died of cancer, 3.3% from other causes, and 0.7% from COVID-19. Among those who died, COVID-19 mortality was 9%, 7.6%, 2.8%, 2.8%, and 1.2% of all deaths for prostate, breast, colorectal, lung, and pancreatic cancers, respectively. In a counterfactual analysis assuming that COVID-19 had not occurred, similar percentages would have died of cancer or other causes, except for lung and pancreatic cancers. In summary, cancer was the leading cause of death in 2020, but COVID-19 did not have a large influence on competing-cause mortality. These findings inform healthcare strategies to mitigate excess mortality among patients with cancer during future healthcare disruptions.</p><p><strong>Significance: </strong>These findings show that, among patients with cancer, cancer remains a leading cause of death during the COVID-19 pandemic. These results underscore the importance of cancer care even amid other public health emergencies.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1642-1650"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12434678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144980830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase I, Open-Label, Dose Escalation Study of Enoblituzumab in Children and Young Adults with B7-H3-Expressing Relapsed or Refractory Solid Tumors.","authors":"Kenneth B DeSantes, Kimberly A McDowell, Paul M Sondel, Paul R Hutson, Rosandra N Kaplan, Julie R Park, Meenakshi G Hegde, Crystal L Mackall, John M Maris","doi":"10.1158/2767-9764.CRC-25-0293","DOIUrl":"10.1158/2767-9764.CRC-25-0293","url":null,"abstract":"<p><strong>Purpose: </strong>This multicenter, phase I, cohort expansion study was performed to characterize the safety, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of enoblituzumab in children with relapsed/refractory tumors expressing B7-H3 above a predetermined threshold.</p><p><strong>Patients and methods: </strong>Samples from 101 patients were screened for B7-H3 expression. Twenty-five patients with relapsed/refractory B7-H3-expressing solid tumors were enrolled in the trial with a median age of 14.8 years (range, 6-24 years). Enoblituzumab was administered intravenously weekly at 10 or 15 mg/kg.</p><p><strong>Results: </strong>B7-H3 expression was documented in 96% of evaluable tumors by IHC. The maximum administered dose of enoblituzumab was the protocol-specified maximum dose of 15 mg/kg as no dose-limiting toxicities were observed. Patients received a median of 6.5 doses (range 1-24), and the main toxicities encountered were infusion-related reactions. Pharmacokinetic studies showed that drug plasma concentrations fit a linear two-compartment model with a mean elimination half-life of 67 days. No objective tumor responses were documented.</p><p><strong>Conclusions: </strong>B7-H3 is expressed on a high fraction of pediatric solid tumors spanning many different disease histologies. Enoblituzumab was well tolerated at a weekly dose of 15 mg/kg and induced inflammatory reactions in some patients though no objective responses were observed. Further testing of enoblituzumab in combination with other agents, or the use of other B7-H3-directed therapeutics, should be considered for children with relapsed solid tumors.</p><p><strong>Significance: </strong>This phase I clinical trial is the first study to evaluate the feasibility and safety of administering enoblituzumab to pediatric patients with relapsed solid tumors. We demonstrated that B7-H3 is highly expressed across a wide variety of tumor histologies. Enoblituzumab could be safely administered at a dose of 15 mg/kg. However, no objective responses were observed, suggesting that alternative strategies to target B7-H3 for children with relapsed tumors should be considered.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1574-1583"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12421222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144838671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IPH5201, an Anti-CD39 mAb, as Monotherapy or in Combination with Durvalumab in Advanced Solid Tumors.","authors":"John Powderly, Martina Imbimbo, Antoine Italiano, Patricia Martin-Romano, Meredith McKean, Teresa Macarulla, Eduardo Castañón Alvarez, Benedito A Carneiro, Raymond Mager, Vicky Barnhart, Steven Eck, Elina Murtomaki, Arsène-Bienvenu Loembé, Yun He, Zachary A Cooper, Eric Tu, Chunling Fan, Agnes Boyer Chamard, Carine Paturel, Paula G Fraenkel, Antoine Hollebecque","doi":"10.1158/2767-9764.CRC-25-0361","DOIUrl":"10.1158/2767-9764.CRC-25-0361","url":null,"abstract":"<p><strong>Purpose: </strong>Blocking enzymatic activity of cluster of differentiation 39 (CD39) with IPH5201 may promote antitumor immunity by increasing immunostimulatory ATP and reducing immunosuppressive adenosine levels in the tumor microenvironment. This first-in-human, phase 1 study evaluated IPH5201 as monotherapy or in combination with durvalumab (anti-PD-L1) in patients with advanced solid tumors.</p><p><strong>Patients and methods: </strong>The study consisted of two consecutive dose-escalation parts: IPH5201 monotherapy (100, 300, 1,000, and 3,000 mg) every 3 weeks and IPH5201 (300, 1,000, and 3,000 mg) + durvalumab 1,500 mg every 3 weeks. The primary endpoint was to evaluate safety and tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, and immunogenicity.</p><p><strong>Results: </strong>Overall, 38 patients received IPH5201 monotherapy and 19 received IPH5201 + durvalumab, with a median duration of follow-up of 7.6 months (range, 1.0-23.7). The most common cancer types were pancreatic (42.1%), non-small cell lung (19.3%), and colorectal (17.5%) cancers. The most common treatment-related adverse events were infusion-related reactions and fatigue. There were no adverse event-related deaths, and the maximum tolerated dose was not reached. Overall, 23/57 patients (40.4%) had stable disease as their best overall response. IPH5201 exhibited a linear pharmacokinetic profile and an estimated terminal half-life of 8 to 9 days at higher doses. On-treatment tumor biopsies revealed decreased CD39 ATPase activity in 5/7 patients, including all evaluable patients receiving the maximum dose of IPH5201 3,000 mg every 3 weeks.</p><p><strong>Conclusions: </strong>IPH5201 as monotherapy, or in combination with durvalumab, was well tolerated at pharmacologically active doses that induced reduction of intratumoral CD39 enzymatic activity and showed preliminary evidence for disease stabilization.</p><p><strong>Significance: </strong>The adenosine pathway is a source of emerging targets in cancer immunotherapy. IPH5201 is a mAb that targets the adenosine pathway by blocking human CD39 enzymatic activity. In this first-in-human, phase 1 study, IPH5201 as monotherapy or in combination with durvalumab was well tolerated with a manageable safety profile in patients with advanced solid tumors. Preliminary evidence for disease stabilization and reduction of tumoral CD39 enzymatic activity were observed.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1690-1700"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12451260/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144980713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical Evaluation of Folate Receptor-α Chimeric Antigen Receptor T Cells Exhibits Highly Efficient Antitumor Activity against Osteosarcoma.","authors":"Michelle Choe, Danielle Kirkey, Isabel Lira, Grace Hawkins, Melia Blankenfeld, Sarah Menashe, Rhonda E Ries, Brianna Wrightson, Christina Root, Cyd N McKay, Jack H Peplinski, Raisa Glabman, Lara E Davis, Sanjay V Malhotra, Richard Gorlick, Elizabeth T Loggers, Soheil Meshinchi","doi":"10.1158/2767-9764.CRC-25-0086","DOIUrl":"10.1158/2767-9764.CRC-25-0086","url":null,"abstract":"<p><p>Metastatic and relapsed osteosarcoma remains difficult to treat despite advanced surgical techniques, intensified chemotherapy, and targeted therapies. Adoptive immunotherapies such as chimeric antigen receptor (CAR) T cells are in their nascent stage but remain a viable therapeutic strategy for patients with aggressive solid tumors such as osteosarcoma. Folate receptor-α (FOLR1) has been functionally implicated in osteosarcoma pathophysiology, providing rationale as a potential therapeutic target. We recently advanced a FOLR1-specific CAR T-cell product (FH FOLR1-CART) into a trial in infant acute myeloid leukemia (NCT06609928) and now evaluate this CAR construct against osteosarcoma. We provide comprehensive FOLR1 transcript and protein expression profile in patients with osteosarcoma, cell lines, and patient-derived xenografts, substantiating its significance as a therapeutic target. We further evaluate the in vitro and in vivo efficacy of FH FOLR1-CART in both standard and patient-derived osteosarcoma cell lines and xenograft models. FOLR1 transcript is expressed in the overwhelming majority of osteosarcoma primary patient specimens, osteosarcoma cell lines, and patient-derived models. FH FOLR1-CART exhibits robust in vitro activation and potent cytotoxicity against FOLR1-expressing osteosarcoma cell lines and primary osteosarcoma patient samples. More importantly, FH FOLR1-CART demonstrates potent antitumor activity in both localized and metastatic in vivo cell-derived and patient-derived xenograft models, with complete tumor eradication. These results demonstrate a potential therapeutic option for patients with advanced osteosarcoma. FH FOLR1-CART is advancing to an early-phase trial in relapsed/refractory osteosarcoma at Fred Hutchinson Cancer Center and Seattle Children's Hospital.</p><p><strong>Significance: </strong>FOLR1 expression has previously been implicated in the pathogenesis of treatment-resistant osteosarcoma. This report demonstrates FOLR1 expression by most osteosarcoma tumors and provides preclinical evidence of robust antitumor activity both in vitro and in vivo against xenograft osteosarcoma models exhibited by FH FOLR1-CART. These data support ongoing efforts for clinical translation of FH FOLR1-CART to an early-phase clinical trial for patients with aggressive osteosarcoma.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1701-1713"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}