Clinical Cancer Research最新文献

{"title":"Longitudinal Imaging Reveals Tumor Uptake and Prolonged Retention of Bispecific T Cell-Engaging Antibody in GBM via Passive and Active Mechanisms.","authors":"Yutian Feng, Benedikt Haupt, Truc T Huynh, Rebecca Meshaw, Angela Martin-Regalado, Aditi Thakur, Joseph T Duffy, Abdulaziz Alzeer, David A Siegel, Ashlynn Barnes, Dmitri Simberg, Michael R Zalutsky, Irina V Balyasnikova","doi":"10.1158/1078-0432.CCR-24-4194","DOIUrl":"10.1158/1078-0432.CCR-24-4194","url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to assess the dynamics of tumor-specific uptake, retention, and blood-tumor barrier penetration of our unique IL-13 receptor α-2 × CD3 bispecific T-cell engager (BTE) following systemic administration in mice with intracranial glioblastoma (GBM) xenografts.</p><p><strong>Experimental design: </strong>In vitro, BTE binding and accumulation were evaluated in glioma neurospheres. In in vivo studies, the BTEs labeled with either iodine-124 using residualizing chemistry or conjugated to Cy5 were used for longitudinal tracking in patient-derived xenograft models of GBM using PET/CT and confocal microscopy. The survival analysis in mice bearing intracranial GBM tumors was conducted to validate the findings from imaging studies.</p><p><strong>Results: </strong>In vitro, the BTE demonstrated target-specific binding and accumulation in IL-13 receptor α-2-expressing glioma spheres. In vivo, PET/CT imaging revealed that the BTE reached the tumor site within 3 hours after injection, achieving up to 4.8% ID/g, with sustained tumor retention for up to 24 hours, significantly higher than background levels in surrounding normal brain tissue. Confocal microscopy confirmed BTE presence in the tumor bed extravascular space with evidence of T cell-mediated BTE transport across the blood-tumor barrier. Despite its short plasma half-life, the BTE remained in the tumor microenvironment for at least 24 hours. Mice bearing GBM6 brain tumors treated with BTE for 3 to 4 days apart via the intravenous route showed a significant survival advantage over the control group.</p><p><strong>Conclusions: </strong>Our findings provide critical insights into the pharmacokinetics of BTE molecules in GBM. They demonstrate effective penetration and prolonged intratumoral retention following a single systemic dose, supporting further exploration of BTE treatment regimens for translation to clinical settings.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"3537-3549"},"PeriodicalIF":10.2,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multidimensional Analysis of B7 Homolog 3 RNA Expression in Small Cell Lung Cancer Molecular Subtypes.","authors":"Carl M Gay, Taofeek K Owonikoko, Lauren A Byers, Noura J Choudhury, Sajid Ahmed, Zachary Cain, Xiaozhong Qian, Matthew Brentnall, Simon Heeke, Ming Poi, Sharon Wu, Charles M Rudin","doi":"10.1158/1078-0432.CCR-24-3981","DOIUrl":"10.1158/1078-0432.CCR-24-3981","url":null,"abstract":"<p><strong>Purpose: </strong>B7 homolog 3 (B7-H3) is a promising target for antibody-drug conjugates, with ifinatamab deruxtecan demonstrating an objective response rate of 54.8% in previously treated extensive-stage small cell lung cancer (SCLC). This analysis aimed to characterize B7-H3 RNA expression with reference to SCLC molecular subtypes (SCLC-A, SCLC-N, SCLC-P, and SCLC-I) and immune-related parameters.</p><p><strong>Experimental design: </strong>Tumor RNA expression and mutational burden for 1,721 patients with SCLC were derived from a real-world database (Caris Life Sciences). A predominant molecular subtype was assigned based on RNA expression using a gene-ratio classifier. PD-L1 expression was assessed by IHC (antibody 22C3; positive cutoff: tumor proportion score ≥1%).</p><p><strong>Results: </strong>The predominant molecular subtype was SCLC-A in 848 (49.3%), SCLC-N in 202 (11.7%), SCLC-P in 142 (8.3%), SCLC-I in 291 (16.9%), and equivocal in 238 (13.8%) samples. B7-H3 expression was high and consistent among subtypes (q > 0.05), whereas DLL3 and SEZ6 expression each differed significantly (both q < 0.0001). PD-L1 positivity was similar across B7-H3 expression quartiles (range, 39.2%-46.5%). Median (95% confidence interval) B7-H3 expression was comparable between patients with and without prior immunotherapy [18.7 (16.5-21.2) and 17.3 (16.4-18.1) transcripts per million, respectively]. B7-H3 was not correlated with a T-cell signature but showed a strong correlation with HAVCR2/TIM3, CD86, PDCD1LG2/PD-L2, and M2 macrophages.</p><p><strong>Conclusions: </strong>B7-H3 showed consistent, high expression across SCLC molecular subtypes, whereas DLL3 and SEZ6 expression varied significantly. These data suggest that B7-H3-targeting antibody-drug conjugates may be active across SCLC subtypes, consistent with the high reported response rates.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"3476-3482"},"PeriodicalIF":10.2,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12351277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CH Mutations in 16,812 Advanced Cancer Patients-Response.","authors":"Daniel Magee, Robert Hahn-Lowry, George W Sledge, Matthew Oberley, Milan Radovich, David Spetzler","doi":"10.1158/1078-0432.CCR-25-1179","DOIUrl":"10.1158/1078-0432.CCR-25-1179","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"31 16","pages":"3597-3598"},"PeriodicalIF":10.2,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adapting Laser Interstitial Thermal Therapy (LITT) for the Treatment of Naturally Occurring Intracranial Tumors in Dogs.","authors":"Christopher L Mariani,Lucas P Wachsmuth,Alexa N Bramall,Danielle M Meritet,Jordan Hatfield,Vadim Tsvankin,Erin K Keenihan,Debra A Tokarz,Richard Tyc,Michael W Nolan,Peter E Fecci","doi":"10.1158/1078-0432.ccr-25-0570","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0570","url":null,"abstract":"PURPOSELaser interstitial thermal therapy (LITT) is a minimally invasive surgical intervention permitting thermal ablation of intracranial targets such as tumors, radiation necrosis or epileptogenic brain, including lesions that are deep, difficult to access or recurrent that would otherwise have few viable surgical options. Despite its advantages, LITT has several limitations, including restrictions on its effective treatment zone (approximately 3 cm) and a lack of specificity for tumor borders with healthy brain. Few viable animal models of appropriate size exist for studying LITT's impact on these disorders, or for optimizing the technology and obviating its current limitations. Pet dogs develop these same disorders at similar rates to humans. We hypothesized that LITT could be made feasible in dogs, creating a unique model for in vivo LITT research and development.EXPERIMENTAL DESIGNCanine cadaveric specimens and live dogs, including canine patients with spontaneously occurring intracranial gliomas, were used in this study. Commercially available equipment was used for neuronavigation (Curve, Brainlab) and to perform LITT (Neuroblate, Monteris Medical).RESULTSCanine cadavers and two end-of-life laboratory dogs allowed adaptation of the neuronavigation and LITT systems to dogs, with successful targeting and ablation of intracranial targets. Four canine patients with intracranial gliomas were subsequently successfully treated with these same technologies.CONCLUSIONSThis work establishes a a unique canine model for in vivo LITT research and development using commercially available systems, as well as creating a viable cutting-edge therapeutic intervention for pet dogs with intracranial lesions.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"7 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144825666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clonal hematopoiesis and inflammation predict hematologic toxicity and secondary myeloid malignancies after BCMA-directed chimeric antigen receptor T cell therapy.","authors":"Zachary M Avigan,Jerrel Catlett,Saoirse Bodnar,Darren Pan,Adolfo Aleman,Tianxiang Sheng,Erin Moshier,Adriana C Rossi,Shambavi Richard,Gurbakhash Kaur,Joshua Richter,Larysa J Sanchez,Cesar Rodriguez,Hearn Jay Cho,Shafinaz Hussein,Christian Salib,Lewis R Silverman,Sundar Jagannath,Samir Parekh,Santiago Thibaud","doi":"10.1158/1078-0432.ccr-25-1587","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1587","url":null,"abstract":"PURPOSEChimeric antigen receptor T cells (CAR-T) have demonstrated remarkable efficacy in multiple myeloma, but prolonged hematologic toxicity remains a common adverse event, and secondary myeloid malignancies are a significant safety concern.EXPERIMENTAL DESIGNWe evaluated 213 myeloma patients treated with B-cell maturation antigen (BCMA)-directed CAR-T at our center to characterize clinical, inflammatory, and myeloid clonal features associated with hematologic toxicity.RESULTSPatients with persistent grade ≥3 neutropenia or thrombocytopenia at day 100 (19%) had shorter progression-free survival (p=.0003) and overall survival (p<.0001), and amongst those with continued remissions, 64% developed prolonged high-grade cytopenias beyond one year. While baseline inflammation is a risk factor for hematologic toxicity, underlying clonal hematopoiesis (CH) modulated this risk, and the combination of CH and elevated ferritin was highly predictive of delayed recovery (adjusted HR 0.38, p=.006). Serum cytokine analysis in patients with delayed myeloid recovery showed a signature of persistent inflammation and endothelial dysfunction. Finally, 9% developed secondary myeloid diseases, including 5% with high-grade myelodysplastic syndrome (MDS) requiring therapy a median of 14.5 months post-CAR-T. MDS was associated with clonal expansion of underlying TP53-mutated CH from a median variant allele frequency of 3.4% pre-CAR-T to 44.0%. While patients with baseline TP53-mutated CH exhibited clonal evolution and a high incidence of MDS (67%), other CH mutations did not show similar expansion after CAR-T (p>.99).CONCLUSIONSThis study underscores the impact of hematologic toxicity and CH on BCMA CAR-T outcomes and suggests a potential role of CAR-T in influencing TP53 clonal dynamics and myeloid disease development.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"26 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144825665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 Clinical Study and In Vivo Findings with PT-112, a Novel Immunogenic Cell Death-Inducing Small Molecule, in Relapsed or Refractory Multiple Myeloma.","authors":"Taxiarchis Kourelis,Sikander Ailawadhi,Dan T Vogl,Sarah E Gibson,Meaghen E Sharik,Megan T Du,Tyler D Ames,Christina Y Yim,Johan Baeck,Matthew R Price,Jose M Jimeno,Marta Chesi,P Leif Bergsagel","doi":"10.1158/1078-0432.ccr-24-2574","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2574","url":null,"abstract":"PURPOSEPT-112 is a novel immunogenic cell death (ICD)-inducing small molecule under Phase 2 development in several cancer types. It inhibits ribosome biogenesis and causes organelle stresses, leading to selective ICD in cancer cells. The possibility of PT-112's pyrophosphate moiety driving high drug concentrations to bone sites of disease led to an interest in PT-112 use in multiple myeloma. Here, we present findings from Phase I and in vivo studies for PT-112 in relapsed or refractory multiple myeloma (RRMM).EXPERIMENTAL DESIGNPT-112 biodistribution was analyzed in mice via laser ablation inductively coupled plasma mass spectrometry. Activity of PT-112 was assessed in de novo and variant Vk*MYC multiple myeloma mouse models as monotherapy or combination therapies. M-spike levels and survival were measured. A Phase I dose escalation study of PT-112 monotherapy was conducted using 3+3 design in heavily pretreated RRMM patients with exhausted available therapies.RESULTSIn vivo biodistribution imaging revealed high concentrations in bone, kidney, lung, skin, and liver. PT-112 was active in Vk*MYC multiple myeloma mouse models, alone and in combination. Phase I data showed that PT-112 monotherapy was safe and well-tolerated, establishing a recommended Phase 2 dose of 360 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Confirmed responses and other signals of activity were observed.CONCLUSIONSThese results suggest a lack of cross-resistance with standard of care and support the translational value of the Vk*MYC model system. Further clinical investigation of PT-112 is warranted in multiple myeloma.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"745 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144825669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased ErbB2 signaling is an early adaptation to androgen signaling inhibition and persists in castration resistant prostate cancer.","authors":"Jude Owiredu,Betul Ersoy-Fazlioglu,Larysa Poluben,Carla Calagua,Christopher Dennehy,Anastasia-Maria Stavridi,Liyang Wang,Olga Voznesensky,Fang Xie,Huihui Ye,Yue Sun,David J Einstein,Xin Gao,Charlene Mantia,Mary-Ellen Taplin,William J Muller,Steven P Balk,Joshua W Russo","doi":"10.1158/1078-0432.ccr-22-3683","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-22-3683","url":null,"abstract":"PURPOSEErbB2 activity is increased in a subset of prostate cancer (PCa), but the gene is rarely amplified. This study sought to identify mechanisms driving increased ErbB2 activity and their role in progression to castration resistant prostate cancer (CRPC).EXPERIMENTAL DESIGNErbB2 signaling was interrogated with a combination of immunohistochemistry (IHC), reverse-phase protein array, and RNA sequencing in cell lines, xenografts, and clinical tumors at various stages of castration resistance. Sensitivity to ErbB2 inhibitors was tested in vitro and in vivo.RESULTSErbB2 activation, identified by IHC with an antibody against phosphorylated ErbB2, was present in ~26% of residual tumors in radical prostatectomies (RPs) after neoadjuvant androgen signaling inhibition (ASI) and in advanced CRPC. The ErbB3/ErbB2 activating ligand NRG1 was found by IHC in ~75% of neoadjuvant-treated tumors. NRG1 mRNA was rapidly increased by ASI in PCa cells and xenografts and was increased in post-ASI data sets. Overexpression of an active ERBB2 splice variant (d16ERBB2) was also increased rapidly after ASI in PCa cells and was found in a subset of CRPC. ErbB2 signaling in all models remained sensitive to the covalent ErbB2 inhibitor neratinib, which enhanced responses to castration and suppressed the growth of castration-resistant xenografts with ErbB2 activation.CONCLUSIONSIncreased ErbB2 signaling is a rapid adaptation to ASI and contributes to castration resistance. Increases in NRG1 and d16ERBB2 contribute to increased ErbB2 signaling. Potent ErbB2 antagonists may enhance responses to ASI in castration-sensitive PCa, and ErbB2 phosphorylation may be a biomarker for tumors that will respond in CRPC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"19 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144825698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of BMS-986365, a first-in-class dual androgen receptor ligand-directed degrader (AR LDD) and antagonist, for the treatment of advanced prostate cancer.","authors":"Surendra Nayak,John D Norris,Massimo Ammirante,Emily Rychak,Suzanne E Wardell,Debbie Liao,Brandon Toyama,Raju Kandimalla,Andy Christoforou,Toshiya Tsuji,Ken Liu,Minerva Tran,Joseph Meiring,Samantha Reiss,Joseph R Piccotti,Joshua M Baughman,Celia Fontanillo,Marwa Khater,Deborah S Mortensen,Brian Cathers,Neil Bence,Daniel W Pierce,Veronique Plantevin-Krenitsky,Dana Rathkopf,Joshua D Hansen,Lawrence G Hamann,Rama Krishna Narla,Vivek K Arora,Donald P McDonnell,Mark Rolfe,Shuichan Xu","doi":"10.1158/1078-0432.ccr-25-0471","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0471","url":null,"abstract":"PURPOSEBMS-986365, a heterobifunctional AR LDD, was designed as a potent cereblon-dependent degrader and competitive antagonist of AR to overcome resistance to ARPIs in metastatic prostate cancer (PC).EXPERIMENTAL DESIGNIn vitro impact of BMS-986365-induced AR degradation on AR activity and PC cell proliferation was evaluated. Intrinsic agonistic and antagonist activities of BMS-987365 were assessed. In vivo anti-tumor activity of BMS-986365 was compared with enzalutamide in cell line- or patient-derived PC models.RESULTSBMS-986365 is a potent, rapid, and selective degrader of AR wildtype and most clinically relevant mutants. Degradation of both wildtype and mutant AR is the key driver of BMS-986365 efficacy, with additional antagonism of residual AR activity enabled through occupancy of its ligand-binding domain. Compared with enzalutamide, BMS-986365 more efficiently inhibits AR target gene transcription and AR-dependent proliferation of PC cell lines. While enzalutamide increased AR protein in mCRPC models, BMS-986365 maintained low levels of AR protein despite increased AR transcript levels. In vivo, BMS-986365 demonstrated on‑target activity, degrading AR, suppressing AR signaling, and inhibiting growth in validated cell line- and patient-derived xenograft models of castration-sensitive PC and advanced and/or therapy-resistant CRPC. Clinically, BMS-986365 reduced prostate‑specific antigen in patients with mCRPC post ARPI, including patients with wildtype AR.CONCLUSIONSThe preclinical observations, coupled with clinical data, strongly support the potential for BMS-986365 to overcome ARPI-resistant disease regardless of AR mutational status. These findings establish BMS-986365 as a first-in-class, dual AR degrader and competitive antagonist, likely to emerge as an important tool in the armamentarium to treat PC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"4 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ARID1A loss plus CD8+ T cell infiltration associate with favorable clinical outcomes in urothelial carcinoma.","authors":"Zhaopei Liu,Lingkai Zhang,Kaifeng Jin,Han Zeng,Xiaohe Su,Yawei Ding,Jiaxing Sun,Yuzhen Wu,Hailong Liu,Yu Zhu,Le Xu,Weijuan Zhang,Zewei Wang,Yuan Chang,Jiejie Xu","doi":"10.1158/1078-0432.ccr-25-0816","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0816","url":null,"abstract":"PURPOSEARID1A, encoding a component of the SWI/SNF complex, is frequently mutated in urothelial carcinoma (UC). However, its specific impacts on clinical outcomes and CD8+ T cell functions in UC remain poorly understood.EXPERIMENTAL DESIGNThe clinical relevance of ARID1A loss and CD8+ T cell infiltration was evaluated in three cohorts (ZSHS, n = 135, FUSCC, n = 118, IMvigor210, n = 274). Immune microenvironment profiling was performed via IHC in the ZSHS cohort and transcriptomics in the IMvigor210 cohort. The Shanghai-sequencing cohort (n = 134) provided genomic characterization of ARID1A-loss patients.RESULTSARID1A loss did not affect the overall survival and CD8+ T cell infiltration in both ZSHS and FUSCC cohorts. Only in ARID1A-loss UC, high infiltration of CD8+ T cells yielded favorable outcomes (ZSHS cohort, Log-rank P = 0.010; FUSCC cohort, Log-rank P = 0.015). Moreover, ARID1A loss CD8 high patients displayed improved survival following adjuvant chemotherapy (Log-rank P = 0.015) and PD-1/PD-L1 blockade (Log-rank P = 0.020). In ARID1A-loss UC, the enhanced antitumor function of CD8+ T cells might be affected by tertiary lymphoid structures. Further, ARID1A loss CD8 high patients exhibited an antitumor immune contexture characterized by decreased immune suppressive cells such as DC-SIGN+ TAMs, PDPN+ cells, and TGF-β+ cells, as well as lower expression of checkpoints like B7-H3 and B7-H4.CONCLUSIONSThe combination of ARID1A loss plus CD8+ T cell infiltration indicated a favorable prognosis and responsiveness to both chemotherapy and immunotherapy. These findings provide valuable insights for developing novel therapeutic strategies and improving treatment stratification for UC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"15 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Camizestrant in combination with three globally approved CDK4/6 inhibitors in women with ER+, HER2- advanced breast cancer: Results from SERENA-1.","authors":"Richard D Baird,Begoña Bermejo de Las Heras,Manuel Ruiz-Borrego,Christos Vaklavas,Irene Moreno,Mafalda Oliveira,Anne Armstrong,Nicholas Turner,Jason Incorvati,Chris J Twelves,Eva Ciruelos,Erika Hamilton,Manish R Patel,Peter Kabos,Carmela Ciardullo,Teresa Klinowska,Justin P O Lindemann,Alastair M Mathewson,Christopher J Morrow,Andy Sykes,Jincheng Yang,Bairu Zhang,Ivan Victoria","doi":"10.1158/1078-0432.ccr-25-1198","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1198","url":null,"abstract":"PURPOSEThis trial investigated safety and tolerability of camizestrant with CDK4/6 inhibitors (CDK4/6i), in women with ER+, HER2- advanced breast cancer.PATIENTS AND METHODSSERENA-1 (NCT03616587) is a Phase 1, multi-part, open-label study in women with refractory ER+, HER2- advanced breast cancer. Patients received oral once-daily camizestrant 75 or 150 mg plus abemaciclib; camizestrant 75, 150, or 300 mg plus palbociclib; or camizestrant 75 mg plus ribociclib 400 or 600 mg. Safety/ tolerability, pharmacokinetics, efficacy, and impact on ESR1m ctDNA was assessed.RESULTSBy September 16, 2024 (data cut-off), 53 patients had received camizestrant plus abemaciclib, 78 plus palbociclib, and 60 plus ribociclib. Patients had a median of 2 (range 0-7) prior regimens for advanced disease; 83% had received a prior CDK4/6i and 59% prior fulvestrant. The most common TEAE for camizestrant 75 mg (Phase 3 dose) plus each CDK4/6i were diarrhoea (with abemaciclib [87.5%]), and neutropenia (with palbociclib [80%] and ribociclib [32.1% for 400 mg, 53.1% for 600 mg]). Median camizestrant tmax was ~4 hours post dose across combinations, with an estimated half-life of 9.5-17 hours. No clinically meaningful drug-drug interactions. were evident. In this heavily pre-treated population, CBR24 was 49.5% and median PFS was 7.4 months (95% CI: 5.3-9.3), with anti-tumor activity across all combinations, including patients previously treated with CDK4/6i and/or fulvestrant, with or without ESR1m.CONCLUSIONCamizestrant is well-tolerated, with anti-tumor activity in combination with CDK46i. These results support evaluation of camizestrant 75 mg plus standard CDK4/6i doses in Phase 3 trials.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"11 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}