Journal of Hematology & Oncology最新文献

{"title":"Cancer stem cell plasticity: mechanisms, immune microenvironment crosstalk, and therapeutic implications.","authors":"Jingyu Tan,Tao Wen,Jian Liu,Xiaoli Ru","doi":"10.1186/s13045-026-01828-0","DOIUrl":"https://doi.org/10.1186/s13045-026-01828-0","url":null,"abstract":"Cancer stem cells (CSCs) represent functionally defined and phenotypically plastic tumor cell populations implicated in therapeutic resistance, relapse, and metastasis. CSC plasticity is regulated through coordinated stemness signaling and epigenetic mechanisms. Canonical stemness-associated pathways, including Wnt, Notch, and Hedgehog, interact with epigenetic programs to maintain dynamic stem-like states and facilitate cellular adaptation to environmental and therapeutic stress. These regulatory networks are also associated with metabolic reprogramming and may support CSC survival under therapeutic and immune pressure. This review summarizes recent advances in our understanding of CSC plasticity, with a particular focus on the bidirectional interplay between CSCs and the tumor immune microenvironment. From a translational perspective, it further summarizes emerging strategies for targeting CSC plasticity in combination with immunotherapy, and discusses the present limitations and challenges of combination strategies. These observations may provide a conceptual framework for the development of more rational combination strategies, although their clinical benefit remains to be validated.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"22 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148416137","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":"Long-term follow-up of a phase 1/2 trial of anti-GDF-15 antibody visugromab plus anti-PD-1 antibody nivolumab in anti-PD-1/-L1 relapsed/refractory solid tumors.","authors":"Ignacio Melero,María de Miguel,Elena Garralda Cabanas,Guillermo de Velasco,Markus Joerger,Juan Martín-Liberal,Maria Reig,David König,Joerg Trojan,Maria-Elisabeth Goebeler,Martin Schuler,Guzman Alonso,Reinhard Dummer,Maria E Rodríguez-Ruiz,Ramón Yarza,Giulia Pretelli,Jorge Esteban-Villarubia,Kira-Lee Koster,Paula Sabat Viltro,Marco Sanduzzi-Zamparelli,Heinz Läubli,Christine Koch,Cyrus Sayehli,Tanja Gromke,Fabricio Racca,Egle Ramelyte,Peter R Galle,Andrea Necchi,Martin Reck,Zlatko Trajanoski,Hubert Hackl,Falk Gogolla,Jaclyn Billing,Teresa Sattmann,Jörg Wischhusen,Christine Schuberth-Wagner,Julia Akdemir,Felix S Lichtenegger,Alexandra Auckenthaler,Marlene Fox,Kathrin Klar,Petra Fettes,Mara Liebig,Aasim Amin,Sheena Sachdeva,Frank Hermann,Eugen Leo","doi":"10.1186/s13045-026-01818-2","DOIUrl":"https://doi.org/10.1186/s13045-026-01818-2","url":null,"abstract":"BACKGROUNDResistance to anti-PD-1/PD-L1 therapy is a major unmet need. Growth Differentiation Factor 15 (GDF-15) has been identified as a key resistance factor for anti-PD-1/PD-L1 immunotherapy. Visugromab, a neutralizing anti-GDF-15 antibody, plus the anti-PD-1 antibody nivolumab (V+N) was evaluated in the first-in-human phase 1/2a GDFATHER-01 trial in heavily pretreated participants with locally advanced/metastatic non-squamous non-small-cell lung cancer (nsq NSCLC), urothelial carcinoma (UC), or hepatocellular carcinoma (HCC), stringently defined as anti-PD-1/PD-L1-relapsed/refractory, and showed encouraging objective responses. This analysis reports long-term follow-up of these three phase 2 expansion cohorts of the GDFATHER-01 trial.METHODSSeventy-seven participants with nsq NSCLC (N=22), UC (N=27), and HCC (N=28) received visugromab (10 mg/kg) plus nivolumab (240 mg) every two weeks until disease progression or unacceptable toxicity.RESULTSObjective response rates (RECIST v1.1) were 18.2% for nsq NSCLC (4/22; 95%CI 5.2-40.3), 18.5% for UC (5/27; 95%CI 6.3-38.1), and 14.3% for HCC (4/28; 95%CI 4.0-32.7). Median duration of response (DoR) was 32.2 months (95%CI 5.5-38.0), 28.8 months (95%CI 7.4-39.4), and 19.4 months (95%CI 5.8-39.7; with protracted recruitment), respectively, with 7/13 responses (53.8%) ongoing. Confirmed complete response or complete metabolic response (CR or CMR) among responders was 61.5% (8/13), with 7/8 ongoing. In addition, 46.2% (6/13) of responders achieved a deeper response on V+N per RECIST v1.1 than with the prior anti-PD-(L)1 therapy; median DoR on V+N was 28.8 months (95%CI 7.4-38.0) versus 12.0 months (95%CI 8.0-24.0) on initial anti-PD-1/PD-L1 treatment. V+N was generally well tolerated.CONCLUSIONSIn heavily pretreated, advanced/metastatic participants with nsq NSCLC, UC, or HCC who were anti-PD-1/PD-L1-relapsed/refractory, V+N achieved deep and durable objective responses. The observed DoR, depth of response, and CR+CMR rate among responders exceeded those reported for their initial anti-PD-1/PD-L1 therapy. These findings suggest that GDF-15 blockade with visugromab can overcome resistance and enhance the magnitude and durability of anti-PD-1/PD-L1 responses, and warrant further exploration in randomized trials.REGISTRYClinicalTrials.gov, TRN: NCT04725474, Registration date: 25 January 2021; EudraCT, TRN: 2020-002103-19, Registration date 16 Dec 2020.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"64 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148416140","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":"From tumor targeting to tumor accessibility: surface-engineered bacteria as precision living therapeutics for translational medicine.","authors":"Liyuan Qiao,Leyang Wu,Yihan Xiao,Jiahui Qiu,Xinyue Qiao,Xiao Dong,Chengxuan Lei,Wanru Wang,Yuzi Zhao,Zichun Hua","doi":"10.1186/s13045-026-01827-1","DOIUrl":"https://doi.org/10.1186/s13045-026-01827-1","url":null,"abstract":"The concept of bacterial therapy dates back over a century to clinical observations that incidental infections could induce tumor regression. Recent advances in genetic engineering and synthetic biology have since transformed bacteria into versatile living therapeutics with significant preclinical potential against diseases such as cancer, inflammatory disorders, and metabolic conditions. However, clinical translation faces considerable hurdles. Here, we provide a clinically oriented perspective on the translational gap in bacterial therapy. Drawing inspiration from the success of antibody-drug conjugates in achieving precise payload delivery, we highlight an emerging paradigm of \"precision living therapeutics\" enabled by bacterial surface engineering. we propose the concept of \"Tumor accessibility\" for the first time, and identify its insufficiency as a critical bottleneck in current therapeutic applications. We then systematically summarize recent advances in bacterial surface engineering, encompassing physical, chemical, and biological strategies, with a focus on their capacity to evade immune clearance, enhance tumor colonization, and improve therapeutic performance. Chemical approaches primarily involve covalent conjugation, including the SpyTag/SpyCatcher system and bioorthogonal click chemistry-based metabolic labeling. Physical strategies center on cell membrane encapsulation and surface coatings such as layer-by-layer encapsulation. Biological strategies include cell camouflage and genetic modulation of surface structures, display of functional biomolecules, and affinity-based systems such as biotin-streptavidin interactions. Finally, we discuss integrative strategies that combine surface-engineered bacteria with conventional treatment modalities, including physical therapy, chemotherapy, and immunotherapy. We propose that future clinical translation of bacterial therapy should shift from localized modification design to a holistic consideration of systemic accessibility.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"37 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148400705","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":"Long-term control of peritoneal metastases following claudin 18.2-targeted CAR T-Cell therapy in advanced gastric cancer","authors":"Chang Liu, Hongxi Zeng, Jiarui Li, Panpan Zhang, Dan Liu, Miao Zhang, Ran Xue, Jifang Gong, Xiaotian Zhang, Yu Sun, Lin Shen, Changsong Qi","doi":"10.1186/s13045-026-01826-2","DOIUrl":"https://doi.org/10.1186/s13045-026-01826-2","url":null,"abstract":"Gastric cancer with peritoneal metastasis has a poor prognosis and limited treatment options. Claudin 18.2 (CLDN18.2) CAR T therapy has shown activity in advanced gastric cancer, but its role in peritoneal disease remains insufficiently characterized. Here, we report three patients with gastric cancer and peritoneal metastasis from a phase I trial of satri-cel (NCT03874897), all with high CLDN18.2 expression. All three patients experienced clinical and radiologic benefit after treatment and achieved durable peritoneal disease control. After CLDN18.2-targeted CAR T-cell therapy, one patient underwent conversion surgery 8 months after infusion. After resection of subsequent bilateral ovarian metastases, no further disease progression was observed, corresponding to long-term control of peritoneal metastases. The other two patients achieved overall survival of 44 and 35 months, respectively. Although circulating CAR T-cells became nearly undetectable in peripheral blood by around day 30 after infusion, CAR T-cell infiltration was still detected in resected gastric or ovarian tumor tissues months later. These findings support substantial and durable activity of CLDN18.2 CAR T-cell therapy in gastric cancer with peritoneal metastasis.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"167 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148355629","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":"Antibody-oligonucleotide conjugates: design principles, intracellular delivery, and translational opportunities.","authors":"Yuqian Li,Xinlin Liu,Fuyuan Zhang,Rong Fu,Daqiang Zhao,Li Ye,Yi Zhun Zhu","doi":"10.1186/s13045-026-01824-4","DOIUrl":"https://doi.org/10.1186/s13045-026-01824-4","url":null,"abstract":"Antibody-oligonucleotide conjugates (AOCs) have emerged as a promising therapeutic platform that integrates the targeting capability of antibodies with the gene-regulatory potential of oligonucleotide payloads. By enabling cell or tissue selective delivery, AOCs may extend oligonucleotide therapeutics beyond liver predominant distribution and broaden intervention strategies for intracellular targets that have historically been difficult to drug. However, their therapeutic performance is not determined by target binding alone, but also by productive intracellular delivery, including receptor mediated uptake, endosomal trafficking, payload release, and functional access to cytoplasmic or nuclear compartments. In this review, we summarize the key design principles governing AOCs performance, including target biology, antibody formats, oligonucleotide payload classes, chemical modifications, linker design, conjugation strategies, and critical quality attributes. We further discuss the intracellular fate of AOCs and highlight endosomal escape as a major rate limiting step that often constrains biological activity despite efficient cellular uptake. In addition, we review current translational progress, with particular emphasis on neuromuscular disorders, as well as emerging applications in oncology, central nervous system diseases, and other indications. Finally, we outline major challenges and future directions that are likely to shape the next generation of AOCs therapeutics.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"42 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148393635","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":"Emerging artificial intelligence advances in oncology: latest updates from the 2026 AACR annual meeting.","authors":"Yan-Ruide Li,Zhengyao Shao,Haochen Nan","doi":"10.1186/s13045-026-01823-5","DOIUrl":"https://doi.org/10.1186/s13045-026-01823-5","url":null,"abstract":"Advances presented at the 2026 American Association for Cancer Research (AACR) Annual Meeting highlight a shift from standalone artificial intelligence (AI) models to integrated, agentic systems across oncology. Platforms such as Synapse enable large-scale data coordination, supporting interoperable and reproducible research. Building on this foundation, conversational and multi-agent AI tools (e.g., DrBioRight, GP CoPilot, Isabl AI Agent) allow natural language interaction with multimodal cancer data, lowering technical barriers. Agentic frameworks for real-world data (RWD) transformation, including clinical document abstraction, cohort extraction, and social determinants of health (SDOH) analysis, demonstrate high accuracy and scalability, while self-critical systems improve reliability. Clinically, AI shows growing impact through validated imaging biomarkers, enhanced trial matching, and scalable cohort identification. In parallel, multi-agent systems are accelerating therapeutic discovery, including CAR-T development and immunotherapy target identification. Collectively, these advances position AI as an active, collaborative partner in cancer research and precision oncology.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"204 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148379900","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":"Dual-modular-nanobody CAR-T cell technical platform against the solid tumor microenvironment.","authors":"Yangzi Li,Xuan Wang,Shangkun Zhang,Tao Peng,Zihan Gong,Haodong Jiang,Xianing Huang,Shenxia Xie,Heng Liu,Fengzhen Mo,Tongcun Zhang,Xiaomei Yang,Xiaobing Jiang,Xiaoling Lu","doi":"10.1186/s13045-026-01821-7","DOIUrl":"https://doi.org/10.1186/s13045-026-01821-7","url":null,"abstract":"BACKGROUNDCAR-T therapy is effective in hematologic cancers but faces challenges in solid tumors due to antigen heterogeneity and an immunosuppressive tumor microenvironment (TME). Systemic CTLA-4 blockade enhances immunity but often causes severe adverse events. To overcome these limitations, we developed a dual-modular nanobody-based CAR-T platform targeting fibroblast activation protein (FAP) on cancer-associated fibroblasts and locally releasing an anti-CTLA-4 nanobody within the tumor stroma.METHODSFAP/CTLA-4 dual-module CAR-T cells were generated and assessed in vitro for antigen-specific cytotoxicity, cytokine release, and exhaustion. Antitumor efficacy was evaluated in xenograft models, measuring tumor growth, survival, and T-cell infiltration (Ethics Approval Number: 202001011). One patient with refractory glioblastoma received intrathecal infusion; clinical response, cerebrospinal fluid (CSF) cytokines (Ethics Approval Number 2022-0553-01), and safety were monitored. Tumor and immune microenvironment changes were analyzed via transcriptomic sequencing and multiplex immunofluorescence staining.RESULTSIn vitro, engineered CAR-T cells showed potent cytotoxicity, cytokine production, and reduced exhaustion. In vivo, they induced tumor regression, prolonged survival, and increased T-cell infiltration. In the glioblastoma patient, intrathecal administration resulted in disease stabilization, elevated CSF cytokines, and a favorable safety profile. Transcriptomic sequencing and multiplex immunofluorescence staining indicated TME remodeling toward an immunologically active state.CONCLUSIONSFAP/CTLA-4 DMN CAR-T overcomes the immunosuppressive solid tumor microenvironment through localized immunomodulation, demonstrating promising efficacy in preclinical models and a patient with refractory glioblastoma.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"11 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148372688","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":"KRAS inhibition is an effective therapy for appendiceal adenocarcinoma.","authors":"Saikat Chowdhury, Ichiaki Ito, Vinay K Pattalachinti, Abdelrahman M G Yousef, Mahmoud M G Yousef, Sacha El Khoury, Nicholas Hornstein, Ashlee Nichole Seldomridge, David Hong, Micheal J Overman, Melissa W Taggart, Wai Chin Foo, Beth Helmink, Keith F Fournier, John Paul Shen","doi":"10.1186/s13045-026-01817-3","DOIUrl":"10.1186/s13045-026-01817-3","url":null,"abstract":"<p><strong>Background: </strong>Appendiceal adenocarcinoma (AA) is a rare cancer with limited treatment options. KRAS is the most commonly mutated gene in AA and a promising therapeutic target, but its preclinical and translational relevance in AA remains unclear.</p><p><strong>Methods: </strong>We evaluated KRAS^G12D-specific (MRTX1133) and pan-KRAS inhibitor (RMC-6236) in KRAS^mut organoid and PDX models of AA. Tumor-intrinsic and microenvironmental responses were characterized using multi-omics profiling. Clinical outcomes were also assessed in cohort of 15 patients with AA treated with KRAS inhibitors.</p><p><strong>Results: </strong>MRTX1133 was highly effective for KRAS^G12D organoids (IC50 = 4.1 nM); both KRAS^G12D and KRAS^G12V organoids were sensitive to RMC-6236 (IC50 = 4.4 nM vs. 0.5 nM, respectively). In PDX models of peritoneal carcinomatosis from AA, MRTX1133 reduced tumor growth in the KRAS^G12D model TM00351, and RMC-6236 reduced tumor growth in KRAS^G12V model AAPDX-16. Pathologic evaluation showed dramatically reduced tumor cellularity, proliferation, and pERK expression as well as induction of apoptosis. Gene Set Enrichment Analysis (GSEA) demonstrated consistent downregulation of E2F targets and RAS/ERK signaling across both models, confirming on-target KRAS inhibition, alongside upregulation of EMT (Epithelial-to-Mesenchymal Transition), suggesting a shared resistance-associated transcriptional program. Interferon-alpha and interferon-gamma signaling were significantly upregulated following pan-KRAS inhibition, implicating TME (Tumor Microenvironment) immunomodulation as a downstream consequence of KRAS inhibition in AA. scRNA-seq analysis of the TME showed a dramatic shift from normal to inflammatory cancer-associated fibroblasts (CAFs) following KRAS inhibition. Upregulation of interferon alpha and gamma pathways was also observed, suggesting that KRAS inhibition can activate innate immune response in the setting of peritoneal metastases. Among 15 patients treated with KRAS inhibitors (8 G12D, 5 G12C, 2 pan-KRAS), all evaluable pateints had a biochemical response by serum markers and clinical benefit by imaging criteria (1 CR, 1 PR, 12 SD).</p><p><strong>Conclusions: </strong>While effective suppression of RAS/ERK signaling by KRAS inhibitors reduces tumor growth, adaptive activation of EMT pathway may mediate resistance in KRAS^mut AA. Additionally, KRAS inhibition remodels TME and may enhance innate immune signaling. These findings support the continued clinical development of KRAS inhibitors in AA and provide a rationale for combination strategies targeting resistance pathways and stromal remodeling.</p>","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":" ","pages":""},"PeriodicalIF":47.8,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13536544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148375849","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":"Large language model-guided CAR-T in silico platform for cytokine optimization in liver cancer with low antigen density.","authors":"Haochen Nan,Xinyuan Shen,Youcheng Yang,Shubing Wang,Yan-Ruide Li","doi":"10.1186/s13045-026-01822-6","DOIUrl":"https://doi.org/10.1186/s13045-026-01822-6","url":null,"abstract":"CAR-T cell therapy has shown remarkable success in hematologic malignancies but remains limited in solid tumors such as liver cancer due to antigen heterogeneity, low target antigen density, and an immunosuppressive tumor microenvironment (TME). Cytokine engineering can enhance CAR-T persistence and effector function; however, the optimal cytokine payload may vary depending on tumor type, target antigen expression level, and microenvironmental context, making systematic experimental comparison time-consuming and labor-intensive. Here, we applied a large language model (LLM)-based CAR-T in silico platform to systematically evaluate cytokine engineering strategies, including IL-2, IL-7, IL-12, IL-15, and IL-18, in glypican-3 (GPC3)-targeted CAR-T cells for liver cancer. We used cytokine selection as a biologically grounded benchmark to test whether the platform could recover known CAR-T cell-relevant cytokine biology and support future novel predictions. Computational predictions identified IL-15 as the most effective enhancer, particularly against tumor cells with low GPC3 expression. Guided by these results, we generated cytokine-armored GPC3 CAR-T cells and performed in vitro and in vivo validation. IL-15-engineered CAR-T cells exhibited superior proliferation, persistence, and serial cytotoxicity against GPC3-low liver cancer cells. In human liver cancer xenograft models, IL-15-enhanced CAR-T cells achieved improved tumor control compared with conventional and other cytokine-engineered CAR-T cells. The recovery of IL-15 served as a positive benchmark supporting the validity of the LLM-guided CAR-T in silico workflow. Collectively, this study establishes an LLM-guided framework, schema-constrained for rational cytokine selection in CAR-T engineering and identifies IL-15 as a potent enhancer for targeting antigen-low liver cancers.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"80 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148365147","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":"Short ramp-up glofitamab halves mortality risk after anti-CD19 CAR T-cell therapy failure in patients with diffuse large B-cell lymphoma: final results of the LYSA BiCAR phase 2 trial with a pre-specified external control arm.","authors":"Guillaume Cartron,Isabelle Chaillol,Roch Houot,Yassine Al Tabaa,Fabien Le Bras,Loïc Ysebaert,Sylvain Choquet,Fabrice Jardin,Jacques-Olivier Bay,François-Xavier Gros,Franck Morschhauser,Cédric Rossi,Thomas Gastinne,Catherine Thieblemont,Magalie Joris,Laure Ricard,Caroline Regny,Laurianne Drieu La Rochelle,Pierre Feugier,Ambroise Marcais,Romain Ould-Ammar,Karin Tarte,Camille Laurent,Pierre Sesques","doi":"10.1186/s13045-026-01816-4","DOIUrl":"https://doi.org/10.1186/s13045-026-01816-4","url":null,"abstract":"BACKGROUNDFailure after anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in diffuse large B-cell lymphoma (DLBCL) is associated with poor survival and there is no established standard of care. We previously reported the phase 2 LYSA BiCAR trial of short-ramp-up glofitamab after CAR T-cell failure. Here, we present the final survival results and a pre-specified external comparative effectiveness analysis against a contemporary control arm constructed from academic data.METHODSBiCAR is a multicenter, single-arm trial in adults with CD20-positive DLBCL refractory to, or in first relapse/progression after anti-CD19 CAR T-cell therapy. Participants received obinutuzumab pretreatment followed by intravenous glofitamab with an accelerated step-up to 30 mg within 8 days, then 30 mg every 21 days for up to 11 cycles. For comparative analyses, we constructed an external control arm from patients included in the French DESCAR-T registry and the ALYCANTE phase 2 trial who experienced CAR T-cell failure, who subsequently started non-bispecific systemic therapy, met key BiCAR eligibility criteria, and initiated treatment within a ±1-month window around the BiCAR treatment period. To minimise datasource bias, both arms, glofitamab (BICAR) and control, were constructed from individual patient data from the DESCAR-T registry and the ALYCANTE trial. A propensity score including major prognostic variables was estimated and applied using stabilized inverse probability of treatment weighting with multiple imputation. Additional weighting schemes and restrictions were applied in sensitivity analyses, and restricted mean survival time (RMST) was evaluated by treatment arm.RESULTSAmong 47 enrolled BiCAR patients, 46 received glofitamab. At a median follow-up of 30.4 months, median overall survival (OS) was 17.3 months, and the 2-year OS rate was 38.3%. For comparative effectiveness, 45 glofitamab-treated patients and 133 controls formed the analysis cohort. In the primary weighted analysis, median OS was 19.6 months for glofitamab and 7.6 months for controls, with a hazard ratio for death of 0.49 (95% CI, 0.31-0.79; P = 0.007). Multiple sensitivity analyses yielded consistent estimates. Glofitamab significantly improved the RMST of 5 months (P = 0.007) over a 2-year follow-up.CONCLUSIONSIn this robust comparative effectiveness study, short-ramp-up glofitamab administered at first relapse or progression after CAR T-cell failure significantly increases the chance of survival compared to contemporaneous non-bispecific salvage therapies, supporting its use as a preferred option for eligible patients with DLBCL who fail anti-CD19 CAR T-cell therapy.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT04703686.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"446 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148372731","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}