Clinical Cancer Research最新文献

{"title":"Reprogramming of Cellular Plasticity via ETS and MYC Core-regulatory Circuits During Response to MAPK Inhibition in BRAF-mutant Colorectal Cancer.","authors":"Hey Min Lee, Zhao Zheng, Alexey Sorokin, Chi Wut Wong, Stefania Napolitano, Saikat Chowdhury, Preeti Marie Kanikarla, Anand K Singh, Veena Kochat, Christopher A Bristow, Sanjana Srinivasan, Michael Peoples, Emre Arslan, Jumanah Yousef Alshenaifi, Oscar E Villarreal, Van K Morris, John Paul Shen, Funda Meric-Bernstam, Abhinav K Jain, Natalie Wall Fowlkes, Amanda Anderson, David G Menter, Ajay Kumar Saw, Kunal Rai, Scott Kopetz","doi":"10.1158/1078-0432.CCR-25-4370","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-4370","url":null,"abstract":"<p><strong>Purpose: </strong>Aberrant enhancer dynamics play a critical role in the initiation and progression of colorectal cancer (CRC), particularly in the BRAFV600E-mutated metastatic subtype, which uniquely exhibits a strong epigenetic phenotype. Building on this epigenetic vulnerability, bromodomain 2, a reader of H3K27ac-marked enhancers, was found to be synthetically lethal with BRAF + EGFR inhibition.</p><p><strong>Experimental design: </strong>We evaluated the effectiveness of targeting aberrant enhancers with bromodomain and extraterminal (BET) + MAPK pathway inhibitors in patient-derived xenograft models of metastatic CRC, followed by comprehensive transcriptomic and chromatin profiling.</p><p><strong>Results: </strong>BET plus standard MAPK inhibitors demonstrated improved efficacy against BRAFV600E CRC and selective improvements against RAS-mutant CRC in vivo. This combination induced a more profound downregulation of the MAPK signaling pathway than MAPK inhibition alone. The loss of activation signal on H3K27ac-marked enhancers led to the dysregulation of core-regulatory circuitries, especially the MAPK downstream E26 transformation-specific transcription factor family and MYC. Single-nucleus RNA+ATAC sequencing distinguished differential transcriptomic and chromatin dynamics at the cell-type level. Profound downregulation of well-differentiated cell types confirmed deep inhibition of MAPK signaling and downstream transcription factors. Conversely, an abundance of dedifferentiated cell populations emerged after MAPK or combination inhibition, suggesting therapy-induced cell-state switching and adaptation.</p><p><strong>Conclusion: </strong>Our work demonstrates that BET inhibition improves MAPK signaling blockade through profound epigenetic reprogramming of core transcription factor circuits. These findings provide a preclinical rationale for the evaluation of BET + BRAF + EGFR inhibition in patients with treatment-refractory BRAFV600E metastatic CRC (NCT06102902).</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833735","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":"The Phase Ib IMPACT Trial of Intramuscular Personalized Neoantigen Synthetic Long Peptide Vaccines in Patients with Advanced Melanoma and Renal Cell Carcinoma.","authors":"Nussara Pakvisal, Piriya Wongkongkathep, Worawan Bunrasmee, Pimpayao Sodsai, Jirattha Siriluksana, Nittaya Boonnak, Tawanchay Sangcharoen, Bussaba Trakarnsanga, Shama Sukprakun, Peepattra Wantanasiri, Korn Chotirosniramit, Meghna Phanichkrivalkosil, Saharat Nanthawong, Prangwalai Chanchaem, Suwanan Mankhong, Sarinya Kumpunya, Suangson Supabphol, Nitiwat Sirijun, Krittanon Kongtragulsub, Phorutai Pearngam, Poorichaya Somparn, David Michael Payne, Boyang Zhao, Verayuth Praphanphoj, Natapol Pornputtapong, Sira Sriswasdi, Duangdao Wichadakul, Suleepon Uttamapinan, Pattama Angspatt, Ploytuangporn Wongchanapat, Nattaya Teeyapun, Sutima Luangdilok, Piyada Sitthideatphaiboon, Thiti Susiriwatananont, Nicha Zungsontiporn, Napa Parinyanitikul, Suebpong Tanasanvimon, Chanida Vinayanuwattikun, Andres Salazar, Nattiya Hirankarn, Virote Sriuranpong, Trairak Pisitkun","doi":"10.1158/1078-0432.CCR-25-4271","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-4271","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate safety and immunogenicity of intramuscularly delivered personalized neoantigen synthetic long peptide (SLP) vaccines in patients with advanced solid tumors.</p><p><strong>Patients and methods: </strong>In this Phase I trial, 12 patients with advanced melanoma (n=9) or renal cell carcinoma (n=3) who lacked access to further reimbursed standard therapies at enrollment received intramuscular neoantigen SLP vaccines with poly-ICLC. Each vaccine contained ~20 predicted neoantigen peptides. Adverse events were monitored throughout vaccination and follow-up. Immune profiling was performed at baseline and predefined post-vaccination time points.</p><p><strong>Results: </strong>Intramuscular neoantigen vaccination was well tolerated, with only grade 1-2 local pain or fever and no immune-mediated toxicities. All participants developed de novo T-cell responses, which were detectable as early as one week post-vaccination in most patients. On average, 53% of peptides per patient were immunogenic, inducing both CD8⁺ and CD4⁺ neoantigen-specific responses. Patients previously treated with immune checkpoint inhibitors (ICIs) had higher baseline immunity but achieved comparable post-vaccination responses to ICI-naïve patients. IFN-γ-dominant CD8⁺ and TNF-α-dominant CD4⁺ responses were observed, along with increased effector memory differentiation. Two patients with higher CD8⁺ TEMRA proportions were the longest survivors. Tumor biopsies revealed enhanced CD8⁺ infiltration, and epitope spreading occurred in two evaluable cases. Analysis of 239 peptides showed greater immunogenicity for dual MHC I/II-binding, cysteine-containing, and in-frame indel- or low-VAF- derived mutations, while proline substitutions reduced responses.</p><p><strong>Conclusions: </strong>Intramuscular neoantigen SLP vaccination with poly-ICLC is safe and induces rapid, mutation-specific T-cell immunity with robust CD8⁺ effector responses. These findings support intramuscular administration as a promising strategy for peptide-based cancer vaccines.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833740","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":"Enfortumab vedotin plus pembrolizumab as first-line treatment in recurrent or metastatic head and neck squamous cell carcinoma: results from EV-202 cohort 9.","authors":"Paul L Swiecicki, Glenn J Hanna, Jessica L Geiger, Takao Fujisawa, Missak Haigentz, Yoshitaka Honma, Justine Y Bruce, Kaoru Tanaka, Kei Muro, Priyanka Bhateja, Jason Kaplan, Shubin Liu, Seema Gorla, Michele Wozniak, Ryan Dillon, Salaheldin Hamed, Changting Meng, Marya F Chaney, Ari J Rosenberg","doi":"10.1158/1078-0432.CCR-25-4650","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-4650","url":null,"abstract":"<p><strong>Purpose: </strong>To assess safety and efficacy of enfortumab vedotin (EV) and pembrolizumab as first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC).</p><p><strong>Patients and methods: </strong>In this open-label, multicohort, phase 2 study (NCT04225117), the R/M HNSCC cohort (cohort 9) received EV (1.25 mg/kg IV) on days 1, 8 and pembrolizumab (200 mg IV) on day 1 in 21-day cycles. Eligible patients had R/M HNSCC, programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1, and no prior systemic therapy in R/M setting. Primary endpoint was investigator-assessed confirmed objective response rate (cORR) per RECIST v1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.</p><p><strong>Results: </strong>The primary analysis included 41 patients. Of these, 39.0% had PD-L1 CPS 1-19 and 61.0% had CPS ≥20. Median (IQR) nectin-4 expression H-score was 185.0 (110.0-255.0). In patients with oropharyngeal squamous cell carcinoma (n=14), 78.6% had p16-positive disease. Median follow-up for OS was 11.0 months. Sixteen patients achieved a response and cORR was 39.0% (95% CI: 24.2-55.5). Complete response rate was 9.8%. DOR was not estimable, and estimated 6-month DOR rate was 81.7% (95% CI: 42.0-95.4). Median PFS was 5.1 months (95% CI: 3.5-NE). Grade 3 treatment-related adverse events were reported in 41.5% of patients; most commonly, maculopapular rash (7.3%).</p><p><strong>Conclusion: </strong>EV with pembrolizumab demonstrated promising clinical activity as first-line treatment in patients with PD-L1 CPS ≥1 R/M HNSCC. Safety results reinforced the manageable tolerability profile of EV with pembrolizumab.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833522","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":"Benralizumab relieves Eosinophil-Related Cutaneous Adverse Events from Cancer Therapy: A Nonrandomized Phase 2 Trial.","authors":"Mario E Lacouture, Alexander Pan, Tara Maier, Anna Chen, George Dranitsaris, Neil J Shah, Chau Dang, Devika Gajria, Allison Gordon, Neil Iyengar, Pedram Razavi, Mark Robson, Ezra Rosen, Serena Wong, Ucalene Harris, Kwami Ketosugbo, Cindy Bravo, Manu Jain, Alina Markova","doi":"10.1158/1078-0432.CCR-25-2764","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-2764","url":null,"abstract":"<p><strong>Purpose: </strong>Eosinophil-related cutaneous adverse events (ercAEs) are common following systemic cancer therapies and often impact health-related quality of life (HRQoL). Here we investigate the efficacy and safety of benralizumab for ercAEs following systemic cancer therapies.</p><p><strong>Patients and methods: </strong>This single-arm, single-center, open-label, phase 2 trial (NCT04552288) in patients with cancer and systemic therapy-associated ercAEs, was performed from September 2020 to October 2023. Benralizumab 30 mg was administered subcutaneously in the approved dosing of q4w (x3), followed by q8w (x3). The primary endpoint was clinical response (reduction in ercAEs to CTCAE grade ≤1 by Week 4). Secondary endpoints included, HRQoL, rash body surface area (rash-BSA), eosinophil levels, and AEs.</p><p><strong>Results: </strong>At baseline (N = 47), ercAEs were related to PI3K inhibitors in 47%, checkpoint inhibitors in 21%, tyrosine kinase inhibitors in 9%, and antibody-drug conjugates in 9%; ercAEs were grade 2 and 3 in 49% and 51% of patients, respectively. Of the 42 patients evaluable for the primary endpoint, 76% patients (n = 32/42) responded to treatment by Week 4; median ercAE grade decreased from 2 to 1 (P < .0001). Patients exhibited improved HRQoL, reduced mean rash-BSA, and decreased peripheral eosinophils. All patients with ercAEs following alpelisib (n = 18) or enfortumab vedotin (n = 4) responded by Week 4 (both P < .05). Most AEs were mild to moderate and likely unrelated to benralizumab.</p><p><strong>Conclusions: </strong>Benralizumab demonstrated favorable efficacy and safety against grade 2/3 ercAEs following systemic cancer therapies. Further investigation in larger placebo-controlled trials is warranted.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834374","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":"Transcriptomic Subgroups in Soft Tissue Tumors Correlate with Morphologic Subtype, Genomic Features, and Outcome.","authors":"Jakob Hofvander, Jan Köster, Saskia Sydow, Paul Piccinelli, Fredrik Vult von Steyern, Panagiotis Tsagkozis, Asle Hesla, Linda Magnusson, Jenny Nilsson, Fredrik Mertens","doi":"10.1158/1078-0432.CCR-25-3740","DOIUrl":"10.1158/1078-0432.CCR-25-3740","url":null,"abstract":"<p><strong>Purpose: </strong>Soft tissue tumors (STT) are highly heterogeneous neoplasms with more than 100 recognized subtypes, many of which lack reliable diagnostic or prognostic markers. We aimed to evaluate the clinical utility of transcriptome sequencing [RNA sequencing (RNA-seq)] in classifying STTs and identifying prognostically relevant subgroups.</p><p><strong>Experimental design: </strong>We performed RNA-seq on 704 tumors representing 56 histologic subtypes, integrating global gene expression (GGE) profiles, fusion transcript detection, genomic features, and clinicopathologic data. Unsupervised clustering and machine learning approaches were used to refine tumor classification and identify prognostic transcriptomic signatures.</p><p><strong>Results: </strong>We identified more than 200 pathogenic gene fusion transcripts, including 40 not previously described. Strong GGE profiles were seen for many morphologic subtypes, especially for those characterized by specific gene fusions. Sarcomas with complex genomes, such as myxofibrosarcoma, undifferentiated pleomorphic sarcoma, and leiomyosarcoma (LMS), showed less distinct GGE profiles, and for LMS, subclusters correlating with genomic profiles were seen. On the basis of GGE profiles and other data, the diagnosis was changed in 5.7% of the cases. Comparison with follow-up data identified transcriptional subclusters among sarcomas with complex genomes that correlated with metastasis-free survival.</p><p><strong>Conclusions: </strong>Transcriptomic profiling enhances diagnostic precision, uncovers novel oncogenic fusions, and provides prognostic information in STTs. Still, the results of the current study suggest that, due to the morphologic and clinical diversity of these tumors, multicenter collaborative studies are needed to fully explore the potential of RNA-seq in STTs.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1825-1834"},"PeriodicalIF":10.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13133608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146141242","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":"Proactive Brain Screening Using Contrast-Enhanced Brain CT Scans in HER2+ Metastatic Breast Cancer.","authors":"Gaia Griguolo, Michele Bottosso, Giusy Landa, Giorgio Bonomi, Federica Miglietta, Maria Cristina Guarascio, Marina La Commare, Francesca Zanghì, Terlisa Sheppard, Carlo Alberto Giorgi, Cristina Falci, Christine Hodgdon, Francesca Caumo, Maria Vittoria Dieci, Valentina Guarneri","doi":"10.1158/1078-0432.CCR-25-3557","DOIUrl":"10.1158/1078-0432.CCR-25-3557","url":null,"abstract":"<p><strong>Purpose: </strong>According to recent EANO-ESMO guidelines, proactive brain imaging can be considered in asymptomatic patients with HER2+ metastatic breast cancer (mBC) because of high risk of developing brain metastases. However, optimal imaging modality and timing remain unclear. We retrospectively assessed the impact of contrast-enhanced CT screening on symptomatic brain metastases in patients with HER2+ mBC.</p><p><strong>Experimental design: </strong>Consecutive patients newly diagnosed with HER2+ mBC treated with trastuzumab-pertuzumab plus taxane (2014-2024) were retrospectively identified. Brain screening was defined as at least one contrast-enhanced brain CT scan per year without neurologic symptoms during the first 2 years after diagnosis.</p><p><strong>Results: </strong>Among 148 identified patients, 73 underwent brain screening and 75 did not. The median number of annual brain CT scans during the first 2 years was 2.0 (IQR, 1.2-2.5) and 0.0 (IQR, 0-0.5) in the screening and nonscreening groups, respectively. Thirty (20.3%) patients developed brain metastases during the first 2 years. The cumulative brain metastasis incidence was significantly higher in patients undergoing screening (30.6% vs. 12.3%, Gray's P = 0.004), but symptomatic brain metastases were significantly lower in patients undergoing screening (0% vs. 9.5%, Gray's P = 0.012). Patients undergoing screening had better preserved performance status at brain metastasis diagnosis (P = 0.002) and a numerical trend toward fewer brain metastases (P = 0.057). Treatment patterns after brain metastasis diagnosis were similar, although whole-brain radiotherapy was used less often in the screening group (14.3% vs. 44.4%, P = 0.073).</p><p><strong>Conclusions: </strong>Brain screening with CT scans was associated with fewer symptomatic brain metastases and better performance status at brain metastasis diagnosis, supporting proactive imaging in HER2+ mBC. Prospective studies are warranted to define optimal timing and imaging modalities.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1790-1798"},"PeriodicalIF":10.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13133600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146141194","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":"Tumor Matrix Proteoglycan Accumulation and Processing Alter T-cell Effector Function and the Response to Immunotherapy in Patients with Oligometastatic Colorectal Cancer.","authors":"Dustin A Deming, Sean G Kraus, Joshua Brand, Katherine A Johnson, Daniel Abbott, Jeremy Kratz, Anita A Turk, Philip Emmerich, Evie Carchman, Sam J Lubner, Noelle K LoConte, Nataliya V Uboha, Somak Chaudhuri, Ruchi Shah, Anna Field, Elizabeth Field, Cheri A Pasch, David H Kim, Sharon Weber, Charles Heise, Elise Lawson, Cristina Sanger, Kristina Matkowskyj, Fotis Asimakopoulos, Jens Eickhoff, Huy Q Dinh, Michael F Bassetti","doi":"10.1158/1078-0432.CCR-25-2780","DOIUrl":"10.1158/1078-0432.CCR-25-2780","url":null,"abstract":"<p><strong>Purpose: </strong>Versican (VCAN) is an immunoregulatory matrix proteoglycan that, when cleaved, releases an immunostimulatory fragment, versikine. In this study, we evaluate the impact of VCAN on immune surveillance and immunotherapy response in a prospective clinical trial.</p><p><strong>Patients and methods: </strong>T-cell function was assayed in the setting of VCAN. Normal and matched tissues were acquired from 243 patients across colorectal cancer stages. A phase Ib clinical trial enrolled 15 subjects with microsatellite stable oligometastatic colorectal cancer and examined the safety and efficacy of the sequential combination of stereotactic body radiotherapy, pembrolizumab, and resection (NCT02837263). The outcomes were correlated with the VCAN status and circulating immune phenotype by single-cell RNA sequencing.</p><p><strong>Results: </strong>VCAN significantly accumulates in 59% of colorectal cancers and is heavily proteolyzed [VCAN proteolytic predominant (VPP)] in 27% (40% of oligometastatic colorectal cancers). VCAN decreased CD8+ T-cell trafficking (P < 0.01) and activated CD8+ T-cell effector function [decreased IL2RA (P < 0.05), PD-1 (P < 0.05), and granzyme B (GZMB; P < 0.001)]. The clinical trial met the primary endpoint with a 1-year recurrence-free survival (RFS) of 60%. Of those enrolled, 40% had the VPP phenotype, which was associated with a trend toward improved RFS (P = 0.053), and all are still alive with a median follow-up of 4.1 years. The VPP phenotype was associated with enhanced circulating CD8+ T-cell effector function at baseline, which was further enhanced with study treatment.</p><p><strong>Conclusions: </strong>VCAN limits T-cell trafficking and effector function, and its proteolysis correlates with an effector phenotype of circulating CD8+ T cells, greater tumor-infiltrating lymphocytes, and improved clinical outcomes with this immunotherapy-based clinical trial treatment.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1707-1723"},"PeriodicalIF":10.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146164377","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":"Subcutaneously Administered Tislelizumab in Locally Advanced or Metastatic Non-Small Cell Lung Cancer: Pharmacokinetics and Safety Results from the BGB-A317-103 Phase I Study.","authors":"Minjiang Chen, Iurie Bulat, Marina Maglakelidze, Ning Li, Zhaohong Chen, Weixiang Kong, Yong Li, Jian Fang, Jing Zhang, Junping Zhang, Bin Wang, Jinfeng Ma, Yuping Sun, Qiming Wang, Xiong Chen, Xiangyu Liu, Tian Yu, William D Hanley, Nageshwar Budha, Hanying Li, Xiao Lin, Ziru Niu, Lubna Jamal, Ramil Abdrashitov, Mengzhao Wang","doi":"10.1158/1078-0432.CCR-25-2173","DOIUrl":"10.1158/1078-0432.CCR-25-2173","url":null,"abstract":"<p><strong>Purpose: </strong>Tislelizumab, an anti-PD-1 monoclonal antibody, is approved for various indications intravenously. Subcutaneous delivery offers potential advantages in convenience and resource utilization. BGB-A317-103 assessed pharmacokinetics, safety, and efficacy of subcutaneous tislelizumab in treatment-naïve patients with advanced or metastatic non-small cell lung cancer.</p><p><strong>Patients and methods: </strong>BGB-A317-103 is an open-label, multicenter, phase I study. In part 1 (dose/injection site exploration), patients received subcutaneous tislelizumab (abdomen or thigh injections; 300 mg) in two of the first three cycles and intravenous tislelizumab (200 mg) in the remaining cycle, followed by intravenous tislelizumab thereafter. In part 2 (dose expansion), patients received 300 mg of subcutaneous tislelizumab in the thigh in all cycles. Both parts included chemotherapy during the first four to six cycles. Pharmacokinetics, bioavailability, efficacy, immunogenicity, and safety were assessed.</p><p><strong>Results: </strong>At data cutoff (December 6, 2024), in part 1 (N = 39), subcutaneous administration yielded higher trough concentrations than intravenous [geometric means: 23.1 μg/mL (thigh), 19.5 μg/mL (abdomen), and 14.8 μg/mL (intravenously)]. Estimated bioavailability was 85.6% for thigh and 72.4% for abdomen. In part 2 (N = 22), subcutaneous tislelizumab in the thigh showed consistent pharmacokinetics with part 1. Preliminary analysis showed an overall response rate of 44.4%; the median duration of response and median progression-free survival were not reached. Tislelizumab's safety profile was consistent with previous studies, with no new signals or injection-site reactions.</p><p><strong>Conclusions: </strong>Subcutaneous tislelizumab demonstrated high bioavailability after thigh and abdomen injections. Safety and efficacy were consistent with previous tislelizumab plus chemotherapy studies, warranting further investigation of subcutaneous tislelizumab.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1678-1685"},"PeriodicalIF":10.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13133601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146164426","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":"A Phase II Study of Docetaxel and Pembrolizumab plus Interleukin 12 Gene Therapy in Nonmetastatic, Anthracycline-Refractory Triple-Negative Breast Cancer (INTEGRAL).","authors":"Polly Niravath, Ivonne Uzair, Kai Sun, Hanh Mai, Jian Guan, Mailin Li, Jenying Deng, Wei Qian, Jianying Zhou, Liliana Guzman, Kelsey Banaglorioso, Rabia Hashmani, Sunil Mathur, Jenny Chang","doi":"10.1158/1078-0432.CCR-25-2649","DOIUrl":"10.1158/1078-0432.CCR-25-2649","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate the safety and efficacy of combining intratumoral IL12 gene therapy with docetaxel and pembrolizumab in high-risk patients with early-stage triple-negative breast cancer (TNBC) refractory to anthracycline-based neoadjuvant chemotherapy.</p><p><strong>Patients and methods: </strong>In this single-arm, open-label phase II trial, patients with stages I to III TNBC and residual disease after anthracycline therapy received neoadjuvant docetaxel (100 mg/m2 i.v.) and pembrolizumab (200 mg i.v.) every 3 weeks for four cycles. Intratumoral injections of adenoviral-mediated interleukin 12 (ADV/IL12) gene therapy were administered 3 days prior to cycles 2 to 4. The primary endpoint was pathologic complete response (pCR). Secondary endpoints were safety and toxicity assessments. Correlative analyses included immune profiling and cytokine measurement.</p><p><strong>Results: </strong>Eight patients were enrolled; half received ADV/IL12 at a starting dose of 5 × 1011 viral particles (VP) in 2 mL volume, injected into the breast tumor. Owing to adverse events (AE), the remaining four patients received 3 × 1011 VPs. The trial was terminated early because of toxicity, with 87.5% of patients experiencing grade ≥3 AEs, including two treatment-related deaths. Only one (12.5%) patient who received a lower dose of ADV/IL12 achieved a pCR. Elevation of CCL4 levels was observed exclusively in the patient who achieved pCR.</p><p><strong>Conclusions: </strong>The combination of docetaxel, pembrolizumab, and intratumoral ADV/IL12 is associated with high systemic toxicity and minimal efficacy. These results underscore the need for cautious dose optimization and patient selection when integrating immunopotentiating cytokines into neoadjuvant regimens. Translational insights from this study inform safer design of future IL12-based strategies in immune-refractory TNBC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1697-1706"},"PeriodicalIF":10.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13012616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146141184","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":"Association of Circulating T Cell and Tumor Microenvironment Profiles with Immune Checkpoint Blockade Outcomes in Sarcoma.","authors":"Evan Rosenbaum, Fiona Ehrich, Mohammad Yosofvand, Martina Bradic, Jasme Lee, Mathew Adamow, Sujana Movva, Ciara M Kelly, Viswatej Avutu, Lauren B Banks, Jason E Chan, Ping Chi, Mark A Dickson, Mrinal M Gounder, Mary L Keohan, Robert G Maki, Damon R Reed, Paige Fuentes, Paige Collins, Rhoena Desir, Allison Reiner, Oleg Baranov, Konstantin Chernyshov, Nikita Kotlov, Ajay Subramanian, Everett J Moding, Li-Xuan Qin, Phillip Wong, William D Tap, Cristina R Antonescu, Katherine S Panageas, Ronglai Shen, Sandra P D'Angelo","doi":"10.1158/1078-0432.CCR-25-3419","DOIUrl":"10.1158/1078-0432.CCR-25-3419","url":null,"abstract":"<p><strong>Purpose: </strong>Immune checkpoint blockade (ICB) benefits only a subset of patients with sarcoma. Biomarkers of response and resistance are needed to help guide patient selection.</p><p><strong>Experimental design: </strong>We analyzed peripheral blood and tumor samples from patients with sarcoma treated in five ICB-based clinical trials. Baseline peripheral blood mononuclear cells (PBMC) underwent 11-color flow cytometry to define T-cell immunotypes. Baseline tumor tissue underwent RNA sequencing (RNA-seq) to classify tumors into four tumor microenvironment (TME) subtypes using consensus clustering of 29 functional gene expression signatures. Associations between immune features and clinical outcomes were assessed. A deep learning model was applied to baseline hematoxylin and eosin (H&E) slides to detect and quantify lymphoid aggregates in patients with available RNA-seq.</p><p><strong>Results: </strong>Among 178 patients with PBMC available for analysis, a proliferative (PRO) circulating T-cell immunotype was associated with poorer overall survival (OS) than lymphocyte-activation gene 3 (LAG)- or LAG+ immunotypes. RNA-seq from 67 tumors identified an immune-enriched/nonfibrotic TME subtype associated with a higher response rate, longer progression-free survival, and longer OS compared with immune-enriched/fibrotic, immune-depleted, and fibrotic subtypes. Automated analysis of 48 baseline H&E slides identified lymphoid aggregates in five tumors; four were classified as immune-enriched and two of these responded to ICB.</p><p><strong>Conclusions: </strong>Patients with sarcoma and a PRO circulating T-cell immunotype had inferior outcomes to ICB, whereas those with an immune-enriched/nonfibrotic TME had superior outcomes. Automated analysis of H&E slides showed promise in identifying patients with an immune-enriched TME. These findings support the use of a multimodal approach to identify predictors of response to immunotherapy in sarcoma.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1777-1789"},"PeriodicalIF":10.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13014529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146164416","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}