Journal of Hematology & Oncology最新文献

{"title":"Plasma biomarkers predicting development of lung cancer 5 years before diagnosis.","authors":"Kostas A Papavassiliou, Athanasios G Papavassiliou","doi":"10.1186/s13045-026-01838-y","DOIUrl":"https://doi.org/10.1186/s13045-026-01838-y","url":null,"abstract":"","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"19 1","pages":""},"PeriodicalIF":47.8,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148760052","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":"Correction: First in human phase 1 study of DT2216, a selective BCL-xL degrader, in patients with relapsed/refractory solid malignancies.","authors":"Daruka Mahadevan, Minal Barve, Devalingam Mahalingam, Jay Parekh, Michael Kurman, James Strauss, Larry Tremaine, Robert Hromas, Joshua Sills, John McCulloch, John Harkey, Stacy Suberg, Lisa Zimmerman, Guangrong Zheng, Daohong Zhou","doi":"10.1186/s13045-026-01837-z","DOIUrl":"10.1186/s13045-026-01837-z","url":null,"abstract":"","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"19 1","pages":""},"PeriodicalIF":47.8,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148706765","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":"The KRAS targeting revolution in metastatic pancreatic cancer: insights from the landmark RASolute-302 trial and emerging allele-specific strategies at ASCO 2026.","authors":"Serena Pillozzi, Elisa Giommoni, Giulia Petroni, Daniele Rossini, Daniele Lavacchi, Marco Brugia, Andrea Galli, Lorenzo Antonuzzo","doi":"10.1186/s13045-026-01834-2","DOIUrl":"10.1186/s13045-026-01834-2","url":null,"abstract":"<p><p>Survival in metastatic pancreatic ductal adenocarcinoma (mPDAC) has long been limited by a dismal second-line therapeutic ceiling dictated by conventional chemotherapy. However, breakthrough data from the ASCO 2026 Annual Meeting and the publication of the phase III RASolute-302 trial mark a definitive shift toward targeted KRAS inhibition. This correspondence highlights how the first-in-class pan-RAS (ON) inhibitor daraxonrasib (RMC-6236) virtually doubled median overall survival (13.2 vs. 6.6 months) and progression-free survival compared to chemotherapy in second-line mPDAC, establishing a new standard of care. Concurrently, we evaluate emerging allele-specific strategies from ASCO 2026 designed to optimize target engagement and safety. These include the selective KRAS G12D inhibitor DN022150 and promising horizontal combinations pairing the G12D inhibitor HRS-4642 with either the anti-PD-L1 antibody adebrelimab or a Nectin-4-targeted antibody-drug conjugate (ADC). Furthermore, we address the KRAS G12C cohort where farnesyl transferase co-inhibition (darlifarnib plus adagrasib) successfully bypasses adaptive resistance. Ultimately, the therapeutic landscape of mPDAC is transitioning toward tailored genomic frameworks. Future success will rely on optimizing the clinical sequencing or combination of pan-RAS and allele-specific agents, guided by real-time liquid biopsies, to permanently dismantle resistance and transform mPDAC into a manageable molecular entity.</p>","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"19 1","pages":""},"PeriodicalIF":47.8,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13453085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148697681","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 1 trial of CD123-directed chimeric antigen receptor T-cell therapy in adults with relapsed/refractory acute myeloid leukemia or blastic plasmacytoid dendritic cell neoplasm.","authors":"Lihua E Budde, Marissa M Del Real, Joo Song, Tracey Stiller, Yan Wang, Ahmed Aribi, Karamjeet Sandhu, Ryotaro Nakamura, Emanuela C Marcucci, Jian J Wu, Kenneth Ng, Mary C Clark, Brent Wood, Jamie R Wagner, Jinny Paul, Christine E Brown, Anthony Stein, Guido Marcucci, M Suzette Blanchard, Joycelynne Palmer, Stephen J Forman","doi":"10.1186/s13045-026-01833-3","DOIUrl":"10.1186/s13045-026-01833-3","url":null,"abstract":"<p><strong>Background: </strong>Patients with relapsed acute myeloid leukemia (AML), particularly following allogeneic stem cell transplant (alloHCT), have extremely limited therapeutic options. CD123 is an AML-associated antigen and represents an attractive target for immunotherapy. We report outcomes of a phase 1 trial evaluating CD123-targeting chimeric antigen receptor (CAR) T cells in patients with relapsed/refractory (r/r) AML or blastic plasmacytoid dendritic cell neoplasm (BPDCN).</p><p><strong>Methods: </strong>This was a single center, open-label, phase 1 dose escalation study enrolling patients with either CD123-positive r/r AML (Arm 1) or BPDCN (Arm 2). Patients received autologous or donor-derived allogeneic CD123 CAR T cells following lymphodepletion. The co-primary objectives were to examine safety and anti-tumor activity using an activity-constrained for toxicity design and to determine the recommended phase 2 dose. Secondary objectives included assessments of progression-free and overall survival.</p><p><strong>Results: </strong>We enrolled 41 patients, of whom 21 patients (n = 19 on Arm 1 and n = 2 on Arm 2) received CD123 CAR T-cell infusion. The median age of treated AML patients was 45 years (range: 20-71); the two BPDCN patients were aged 24 and 75 years. Among AML patients, 17 (89%) had undergone prior alloHCT. AML patients received 50 × 10⁶ (n = 2), 200 × 10⁶ (n = 6), or 500 × 10⁶ (n = 11) CAR T cells; BPDCN patients received 100 × 10⁶ CAR T cells. There was no dose-limiting toxicity, prolonged myelosuppression, or graft-versus-host disease. Fourteen (74%) AML patients developed grade ≤ 3 cytokine release syndrome (CRS) and 11 (58%) experienced grade ≤ 2 neurotoxicity. Fifteen of 19 treated AML patients were evaluable for disease response for overall best response, of whom 4 (26.7%) had best response of complete remission, including 2 with incomplete count recovery. Neither patient with BPDCN developed CRS but both experienced grade 1 neurotoxicity. One of 2 BPDCN patients achieved CR and relapsed at 3 months. CAR T cell expansion was dose-dependent, but persistence was limited.</p><p><strong>Conclusions: </strong>CD123-directed CAR T-cell therapy is feasible and demonstrates a favorable safety profile in patients with r/r AML and BPDCN, including those with prior alloHCT. Although the estimated overall complete remission rate was modest, these findings provide a foundation for further optimization of CD123 CAR T-cell design, patient selection, and combination strategies.</p><p><strong>Trial registration: </strong>This trial was registered at ClinicalTrials.gov as NCT02159495.</p>","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"19 1","pages":""},"PeriodicalIF":47.8,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13536854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874492","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 modular γδ TCR-T platform combining KRAS pMHC targeting with re-dosable mRNA engager redirection.","authors":"Ángel Ramírez-Fernández, Adham S Bear, Elahe Kamali, Robert Bartoszek, Matthew Ho, Gregory M Chen, Devin Dersh, Laura Córdoba-Espejo, Jiageng Liu, Mosha Deng, Miriam Velasco-Sidro, Ankita Jain, Julia Han Noll, Caitlin R Hopkins, Owen Koucky, Janna Minehart, Alexander J Dimitri, Erik Williams, Maya Lavorando, Alejandro Segura-Tudela, John Scholler, Julie Barber-Rotenberg, Julie K Jadlowsky, Daniel J Powell, Anne Chew, Vanessa E Gonzalez, Donald L Siegel, Bruce L Levine, Michael T Lotze, Carl H June, James L Riley, Robert H Vonderheide, Friederike Herbst, Joseph A Fraietta","doi":"10.1186/s13045-026-01836-0","DOIUrl":"10.1186/s13045-026-01836-0","url":null,"abstract":"<p><p>Solid tumors often evade TCR-engineered αβ T cells when antigen expression varies or when the restricting Human Leukocyte Antigen (HLA) allele is lost. γδ T cells, in contrast, detect cellular dysregulation through non-peptide/Major Histocompatibility Complex (MHC) cues, including phosphoantigens and stress ligands, and can be developed as allogeneic therapies. Although intratumoral γδ T cell signatures are associated with improved outcome across cancers, γδ recognition itself is broad and still selected within the thymus just as αβ T cell receptors (TCRs) are. It does not, however, anchor specificity to a defined driver-mutation pMHC epitope. We therefore asked whether a high-affinity, co-receptor-independent αβ TCR could graft oncogenic-driver specificity onto γδ T cells while leaving the endogenous γδ TCR intact. We knocked the KRASG12V/HLA-A*11:01 TCR A11v into primary human γδ T cells. Engineered cells co-expressed the transgenic αβ TCR and the endogenous γδ TCR and lysed KRASG12V/HLA-A*11:01⁺ tumor cells in vitro and in vivo. To cover potential resistance through loss of HLA-A*11:01, we delivered an mRNA lipid nanoparticle (LNP) encoding a secreted mesothelin×CD3 (M5) bispecific T cell engager (TCE). LNP-M5 produced circulating TCE that redirected γδ A11v T cells and polyclonal bystander T cells to kill mesothelin⁺ targets, accompanied by development of higher γδ A11v T cell counts in vivo. In humanized mice bearing mixed HLA-A*11:01⁺ and HLA-A*11:01 - KRASG12V tumors, γδ A11v T cells produced transient control, whereas adding LNP-M5 yielded complete responses and prolonged survival. Thus, this two-part therapy couples invariant driver targeting to tunable redirection and addresses loss of the restricting HLA allele, a central escape route for TCR-based therapy. It provides an off-the-shelf reagent to enable KRAS-anchored treatment with the ability to redeliver the reagent.</p>","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"19 1","pages":""},"PeriodicalIF":47.8,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13536626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874451","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":"CD20 expression dynamics in adult B-cell acute lymphoblastic leukemia and impact on anti-CD20 treatment.","authors":"Monika Szczepanowski,Johanna Richter,Sonja Bendig,Lorenz Bastian,Miriam Kelm,Veronika Beck,Thomas Beder,Guranda Chitadze,Michaela Kotrová,Johannes Duell,Christoph Faul,Johannes Gärtner,Alina Hartmann,Britta Kehden,Eva Maria Murga Penas,Martin Neumann,Matthias Ritgen,Wiebke Schrader,Björn Steffen,Heiko Trautmann,Andreas Viardot,Thomas Burmeister,Claudia D Baldus,Stefan Schwartz,Nicola Gökbuget,Monika Brüggemann","doi":"10.1186/s13045-026-01832-4","DOIUrl":"https://doi.org/10.1186/s13045-026-01832-4","url":null,"abstract":"BACKGROUNDBaseline CD20 expression ≥ 20% in B-cell acute lymphoblastic leukemia (B-ALL) has been associated with poorer outcomes, which improved after rituximab introduction into frontline therapy for CD20-positive cases. We investigated the clinical and biological significance of this threshold by monitoring early dynamics of CD20 expression.METHODSIn the GMALL 08/2013 trial, adults with B-ALL received a cyclophosphamide/dexamethasone prephase, followed by Induction and Consolidation I, which included four rituximab doses in BCR::ABL1-negative patients, irrespective of CD20 status. CD20 expression was measured by standardized multiparametric flow cytometry in 274 patients in bone marrow and blood at diagnosis and in blood after prephase. IG/TR based measurable residual disease (MRD) was correlated with baseline bone marrow or the highest CD20-positive blast percentage recorded throughout prephase. The historical GMALL 07/2003 cohort treated without rituximab served for comparison.RESULTSBaseline CD20 expression was significantly higher in blood than in bone marrow and increased further during prephase. In paired baseline samples, 6/76 c-/pre-B ALL cases (7.9%) were CD20-negative by bone marrow (< 20%) but positive in blood. In paired blood samples, 14/106 patients crossed the 20% threshold after prephase (12/86 c-/pre-B ALL, 13.9% and 2/20 pro-B ALL, 10.0%). Among 182 BCR::ABL1-negative patients, highest recorded CD20 across all time points classified 76 (41.8%) as < 20% and 106 (58.2%) as ≥ 20%. Higher CD20 expression was associated with improved MRD response under rituximab. Among MRD-evaluable patients after Induction I (n = 161), molecular complete remission (MolCR) was achieved in 10.6% of patients with CD20 expression < 20% compared with 30.5% of those with CD20 expression ≥ 20%. After Consolidation I (n = 159), corresponding MolCR rates were 50.0% and 72.6%, respectively. Associations were weaker when only baseline CD20 bone marrow status was considered. No association with MRD response was observed in GMALL 07/2003 patients treated without rituximab, suggesting a treatment-driven effect in GMALL 08/2013.CONCLUSIONSCD20 expression in adult B-ALL varies from diagnostic bone marrow to blood and post-prephase measurements. The highest recorded CD20% value better predicts early MRD responses under rituximab. Post-prephase CD20 reassessment in blood identifies additional patients with eligibility for rituximab.REGISTRYClinicalTrials.gov, TRN: NCT02881086 (2016-08-23); NCT00198991 (2005-09-12).","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"52 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148522121","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":"Clinical benefit of PD-1 antibody plus chemotherapy in advanced HER2 negative gastric or gastro-oesophageal junction adenocarcinoma according to PD-L1 levels: Post-hoc analysis of RATIONALE-305 and pooled analysis of individual patient-level data.","authors":"Ming-Yu Lai,Hao-Xiang Wu,Ming-Ming He,Wen-Long Guan,Sheng Xu,Han Hu,Ya-Ling Xu,Feng-Hua Wang,Rui-Hua Xu,Miao-Zhen Qiu","doi":"10.1186/s13045-026-01830-6","DOIUrl":"https://doi.org/10.1186/s13045-026-01830-6","url":null,"abstract":"While multiple phase III trials have established the survival benefit of adding a programmed cell death protein 1 (PD-1) antibody to first-line chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-negative advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, evidence across different programmed cell death ligand 1 (PD-L1) expression levels remains limited, preventing definitive conclusions about the superiority of combination therapy in certain subgroups. We firstly performed a post-hoc analysis of the RATIONALE-305 trial, finding only marginal benefit in the 1 ≤ tumor area positivity (TAP) < 5 and 1 ≤ combined positive score (CPS) < 5 subgroups. Subsequently, we performed a pooled analysis of individual patient-level data from RATIONALE-305 and four additional phase III trials (CheckMate 649, KEYNOTE-062, KEYNOTE-859, and ORIENT-16). The pooled analysis demonstrated that adding a PD-1 antibody to chemotherapy significantly improved overall survival in patients with intermediate PD-L1 levels (1 ≤ CPS < 10: HR, 0.84; 95% CI, 0.75-0.93), including the lower intermediate subset (1 ≤ CPS < 5: HR, 0.85; 95% CI, 0.75-0.97), but not in the CPS < 1 subgroup (HR, 0.96; 95% CI, 0.82-1.14). Progression-free survival results were consistent with those for overall survival, and improvements in objective response rate were observed across all subgroups. In conclusion, this study provides novel evidence that the combination therapy is superior to chemotherapy alone in patients with advanced HER2-negative G/GEJ adenocarcinoma and PD-L1 CPS ≥ 1.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"178 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148522120","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":"Copper homeostasis and cuproptosis rewire the tumor microenvironment: mechanisms, immune modulation, and therapeutic opportunities.","authors":"Guoqing Li,Wenlong Wang","doi":"10.1186/s13045-026-01831-5","DOIUrl":"https://doi.org/10.1186/s13045-026-01831-5","url":null,"abstract":"Copper, an essential trace element with dual functions in cancer progression, drives tumor growth via oncogenic signaling, metabolic plasticity, and extracellular matrix remodeling. By contrast, copper overload triggers cuproptosis, a form of mitochondrial proteotoxic cell death mediated by the FDX1/LIPT1/DLAT/Fe-S regulatory axis. To date, a unified theoretical framework integrating copper metabolism, tumor microenvironment (TME) remodeling, and antitumor immunity remains lacking. In this review, we reframe the TME as a structured copper ecosystem in which both cellular components and the extracellular matrix are modulated by copper, and propose a contextual copper signaling network, in which copper-mediated tumor cell fate is determined by the labile copper pool, the metabolic state, and tumor cellular heterogeneity. We further delineate a unified causal chain linking cuproptosis-driven immunogenicity and cGAS-STING activation to immune cell activation and PD-L1 modulation. Therapeutically, copper chelation and cuproptosis induction strategies have demonstrated promising efficacy, and combining cuproptosis induction with existing antitumor therapies may reverse therapeutic resistance and enhance treatment efficacy. Future studies need to validate cuproptosis-related signatures as predictive biomarkers for precision oncology and refine copper-targeted therapies to minimize systemic toxicities.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"32 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148476285","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":"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}