Pub Date : 2026-01-03DOI: 10.1186/s13045-025-01774-3
Stephen J F Chong,Rebecca Valentin,Jing Wang,Fen Zhu,Prafulla C Gokhale,Benjamin K Eschle,Filip Garbicz,Kartini Iskandar,Tomasz Sewastianik,Brienne C Y Toh,Johany Penailillo,Marisa O Peluso,Jeremy Zhang,Liam Hackett,Mary C Collins,Timothy Z Lehmberg,Ammar Adam,Li Zhang,Caroline M Armet,Matthew Rausch,Benjamin H Lee,Pamela M Holland,Vito J Palombella,Alison M Paterson,Li Ren Kong,Elisa Ten Hacken,Jennifer L Guerriero,Charles Herbaux,Catherine J Wu,Wee Joo Chng,Shazib Pervaiz,Carsten U Niemann,Ruben D Carrasco,Matthew S Davids
{"title":"CD47 blockade-driven necroptosis complements BCL-2 inhibition-driven apoptosis in lymphoid malignancies.","authors":"Stephen J F Chong,Rebecca Valentin,Jing Wang,Fen Zhu,Prafulla C Gokhale,Benjamin K Eschle,Filip Garbicz,Kartini Iskandar,Tomasz Sewastianik,Brienne C Y Toh,Johany Penailillo,Marisa O Peluso,Jeremy Zhang,Liam Hackett,Mary C Collins,Timothy Z Lehmberg,Ammar Adam,Li Zhang,Caroline M Armet,Matthew Rausch,Benjamin H Lee,Pamela M Holland,Vito J Palombella,Alison M Paterson,Li Ren Kong,Elisa Ten Hacken,Jennifer L Guerriero,Charles Herbaux,Catherine J Wu,Wee Joo Chng,Shazib Pervaiz,Carsten U Niemann,Ruben D Carrasco,Matthew S Davids","doi":"10.1186/s13045-025-01774-3","DOIUrl":"https://doi.org/10.1186/s13045-025-01774-3","url":null,"abstract":"","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"19 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893955","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}
Pub Date : 2025-12-22DOI: 10.1186/s13045-025-01749-4
Jia-Ming Wang,Hai-Yun Xie,Feng-Hao Zhang,Xuan Shu,Jin-Dan Luo,Li-Ping Xie,Jiang-Feng Li
Abnormal expression of kinesins has been observed in several types of cancer. The present study provided the first evidence that KIF26B could induce RNA m5C modification in bladder cancer (BCa). Detailly, KIF26B interacted with NSUN2 and recruited ubiquitinase STUB1 to promote K63-linked ubiquitination of NSUN2 at K511 site. K63-linked ubiquitination enabled NSUN2 to bind to KPNA1 and translocate into nucleus where it drove RNA m5C modification. Furthermore, KIF26B induced liquid-liquid phase separation (LLPS) of YBX1 and upregulated IL-6 expression through NSUN2/m5C/YBX1 axis. Secreted IL-6 then activated STAT3 signaling to promote transcription of kif26b through direct binding between STAT3 and kif26b promoter. IL-6 also recruited DLAT to acetylate NSUN2 at K229 site and increased association affinity between NSUN2 and KIF26B. Together, these established a KIF26B/NSUN2/m5C/IL-6 positive feedback loop, suggesting that targeting KIF26B may be a promising therapeutic strategy for BCa.
{"title":"Aberrant KIF26B expression promotes bladder cancer progression through driving NSUN2 nuclear localization.","authors":"Jia-Ming Wang,Hai-Yun Xie,Feng-Hao Zhang,Xuan Shu,Jin-Dan Luo,Li-Ping Xie,Jiang-Feng Li","doi":"10.1186/s13045-025-01749-4","DOIUrl":"https://doi.org/10.1186/s13045-025-01749-4","url":null,"abstract":"Abnormal expression of kinesins has been observed in several types of cancer. The present study provided the first evidence that KIF26B could induce RNA m5C modification in bladder cancer (BCa). Detailly, KIF26B interacted with NSUN2 and recruited ubiquitinase STUB1 to promote K63-linked ubiquitination of NSUN2 at K511 site. K63-linked ubiquitination enabled NSUN2 to bind to KPNA1 and translocate into nucleus where it drove RNA m5C modification. Furthermore, KIF26B induced liquid-liquid phase separation (LLPS) of YBX1 and upregulated IL-6 expression through NSUN2/m5C/YBX1 axis. Secreted IL-6 then activated STAT3 signaling to promote transcription of kif26b through direct binding between STAT3 and kif26b promoter. IL-6 also recruited DLAT to acetylate NSUN2 at K229 site and increased association affinity between NSUN2 and KIF26B. Together, these established a KIF26B/NSUN2/m5C/IL-6 positive feedback loop, suggesting that targeting KIF26B may be a promising therapeutic strategy for BCa.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"21 1","pages":"110"},"PeriodicalIF":28.5,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801322","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}
CLL1-targeted chimeric antigen receptor T (CAR-T) cell therapy has shown clinically meaningful activity in relapsed/refractory acute myeloid leukemia (R/R AML). This updated phase I study enrolled 38 adults with R/R AML to evaluate the safety and efficacy of this treatment according to the prespecified protocol. Treatment-related adverse events included grade 3/4 cytokine release syndrome (CRS) in 17 patients (44.74%) and grade 4 immune effector cell-associated neurotoxicity syndrome (ICANS) in 1 patient (2.63%). Persistent cytopenia (all grades) was observed in all patients, with a median time to neutrophil recovery of 45 days. At a median follow-up of 24.87 months, the objective response rate (ORR) was 73.68% (28/38), and the minimal residual disease-negative complete response rate (MRD-CR) was 42.11%. Median progression-free survival (PFS) and overall survival (OS) were 9 months (95%CI 3.03-14.47) and 12.17 months (95%CI 3.03-24.87), respectively. The two-year PFS and OS rates were 47.94% (95%CI: 32.00%-63.83%) and 51.43% (95%CI 35.51%-67.32%), respectively. These results indicate a clinically relevant antitumor efficacy and a manageable safety profile of CLL1-targeted CAR-T cell therapy in adults with R/R AML.Registry: www.chictr.org.cn , TRN: ChiCTR2000041054, Registration date: 17 December 2020.
{"title":"Updated data of CLL1 CAR-T cell therapy in adult patients with relapsed/refractory acute myeloid leukemia.","authors":"Xiaomei Zhang,Wenyi Lu,Wenjun Zhang,Xiaoyuan He,Yu Zhang,Xin Jin,Meng Zhang,Yingshuai Wang,Xuwen Guan,Rui Zhang,Bing Wang,Hairong Lyu,Xia Xiao,Xue Bai,Yedi Pu,Juanxia Meng,Haibo Zhu,Zhao Wang,Huan Zhang,Cuicui Lyu,Hongkai Zhang,Aibin Liang,Mingfeng Zhao","doi":"10.1186/s13045-025-01764-5","DOIUrl":"https://doi.org/10.1186/s13045-025-01764-5","url":null,"abstract":"CLL1-targeted chimeric antigen receptor T (CAR-T) cell therapy has shown clinically meaningful activity in relapsed/refractory acute myeloid leukemia (R/R AML). This updated phase I study enrolled 38 adults with R/R AML to evaluate the safety and efficacy of this treatment according to the prespecified protocol. Treatment-related adverse events included grade 3/4 cytokine release syndrome (CRS) in 17 patients (44.74%) and grade 4 immune effector cell-associated neurotoxicity syndrome (ICANS) in 1 patient (2.63%). Persistent cytopenia (all grades) was observed in all patients, with a median time to neutrophil recovery of 45 days. At a median follow-up of 24.87 months, the objective response rate (ORR) was 73.68% (28/38), and the minimal residual disease-negative complete response rate (MRD-CR) was 42.11%. Median progression-free survival (PFS) and overall survival (OS) were 9 months (95%CI 3.03-14.47) and 12.17 months (95%CI 3.03-24.87), respectively. The two-year PFS and OS rates were 47.94% (95%CI: 32.00%-63.83%) and 51.43% (95%CI 35.51%-67.32%), respectively. These results indicate a clinically relevant antitumor efficacy and a manageable safety profile of CLL1-targeted CAR-T cell therapy in adults with R/R AML.Registry: www.chictr.org.cn , TRN: ChiCTR2000041054, Registration date: 17 December 2020.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"6 1","pages":"112"},"PeriodicalIF":28.5,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771432","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}
Pub Date : 2025-12-12DOI: 10.1186/s13045-025-01766-3
Yuanxiang Wang,Susu Xiao,Wei Yu,Bo Han,Gang Guo
Bacterial therapy represents a promising strategy for cancer treatment, in which tumor regression can be achieved through bacteria-mediated immunotherapy. The mechanisms involve disrupting cellular metabolism, inducing apoptosis, delivering therapeutic agents, and enhancing anticancer immune responses. Naturally occurring bacteria possess inherent advantages in biocompatibility and self-propulsion. Facultative anaerobic species, such as Salmonella, can increase tumor accumulation by more than tenfold through the enhanced permeability and retention (EPR) effect. However, the application of native bacterial therapy is limited by its toxicity and unstable colonization in vivo at disease sites. The negatively charged bacterial surface and abundant functional groups enable surface modifications through ionic interactions or covalent bonding. These approaches include modifying lipopolysaccharides and capsules that trigger in vivo toxicity, or coating bacteria with exogenous nanomaterials to achieve detoxification and construct drug delivery platforms. Furthermore, gene editing and synthetic genetic circuit strategies allow the precise engineering of bacteria to improve tumor targeting, reduce pathogenicity, and endow them with novel anticancer functions. This review discusses the routes of bacterial administration, surface engineering strategies, synthetic circuit design, and clinical translation in bacteria-mediated cancer immunotherapy. It comprehensively summarizes the historical progress, advantages, and distinctive features of bacterial therapy, with a particular emphasis on recent advances in synthetic gene circuit design. Finally, the review highlights the clinical translation prospects and existing challenges of bacteria-mediated tumor therapy, aiming to ensure biosafety, prevent unintended immune responses, and promote large-scale clinical applications in cancer treatment.
{"title":"Engineering bacteria for enhanced tumor therapy: from surface modification to synthetic genetic circuits.","authors":"Yuanxiang Wang,Susu Xiao,Wei Yu,Bo Han,Gang Guo","doi":"10.1186/s13045-025-01766-3","DOIUrl":"https://doi.org/10.1186/s13045-025-01766-3","url":null,"abstract":"Bacterial therapy represents a promising strategy for cancer treatment, in which tumor regression can be achieved through bacteria-mediated immunotherapy. The mechanisms involve disrupting cellular metabolism, inducing apoptosis, delivering therapeutic agents, and enhancing anticancer immune responses. Naturally occurring bacteria possess inherent advantages in biocompatibility and self-propulsion. Facultative anaerobic species, such as Salmonella, can increase tumor accumulation by more than tenfold through the enhanced permeability and retention (EPR) effect. However, the application of native bacterial therapy is limited by its toxicity and unstable colonization in vivo at disease sites. The negatively charged bacterial surface and abundant functional groups enable surface modifications through ionic interactions or covalent bonding. These approaches include modifying lipopolysaccharides and capsules that trigger in vivo toxicity, or coating bacteria with exogenous nanomaterials to achieve detoxification and construct drug delivery platforms. Furthermore, gene editing and synthetic genetic circuit strategies allow the precise engineering of bacteria to improve tumor targeting, reduce pathogenicity, and endow them with novel anticancer functions. This review discusses the routes of bacterial administration, surface engineering strategies, synthetic circuit design, and clinical translation in bacteria-mediated cancer immunotherapy. It comprehensively summarizes the historical progress, advantages, and distinctive features of bacterial therapy, with a particular emphasis on recent advances in synthetic gene circuit design. Finally, the review highlights the clinical translation prospects and existing challenges of bacteria-mediated tumor therapy, aiming to ensure biosafety, prevent unintended immune responses, and promote large-scale clinical applications in cancer treatment.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"150 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732709","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}
Mitochondria, the powerhouse of the cell, orchestrate a plethora of critical functions, including energy production, metabolic regulation, programmed cell death, and signal transduction. Their pivotal role in the pathogenesis of numerous diseases underscores their significance. Among the various regulatory mechanisms, RNA modifications emerge as a dominant posttranscriptional modulator of gene expression, increasingly recognized for their profound impact on mitochondrial functions. Groundbreaking discoveries have unveiled compelling links between RNA modifications and oxidative phosphorylation, regulated cell death-particularly cuproptosis-and antitumor immunity, underscoring RNA modifications' vital role and untapped potential in mitochondrial biology, cancers and aging-related diseases. In this Review, we comprehensively catalog the primary RNA modifications modifiers and their small-molecule inhibitors that influence mitochondrial functions. We explore the latest research delineating RNA modifications' involvement in mitochondria-related glucose metabolism, regulated cell death, and mitochondrial dynamics, presenting an intricate regulatory network. Furthermore, we investigate the intriguing intersection of RNA modifications and mitochondria-related antitumor immunity, highlighting prospective therapeutic targets to enhance immunotherapy outcomes. This review not only accentuates the critical importance of RNA modifications in mitochondrial function but also paves the way for novel therapeutic strategies in disease treatment.
{"title":"Mitochondria at the intersections of RNA modifications and metabolism reprogramming implications in cell death, tumor microenvironment, and immunotherapy.","authors":"Jiaxun Zhang,Haoxuan Zhang,Leifeng Chen,Yuze Wu,Jiaming Xie,Yannan Yang,Aaron Chen,Akezhouli Shahatiaili,Shan Muhammad,Wenhui Yang,Yingli Sun,Yibo Gao","doi":"10.1186/s13045-025-01762-7","DOIUrl":"https://doi.org/10.1186/s13045-025-01762-7","url":null,"abstract":"Mitochondria, the powerhouse of the cell, orchestrate a plethora of critical functions, including energy production, metabolic regulation, programmed cell death, and signal transduction. Their pivotal role in the pathogenesis of numerous diseases underscores their significance. Among the various regulatory mechanisms, RNA modifications emerge as a dominant posttranscriptional modulator of gene expression, increasingly recognized for their profound impact on mitochondrial functions. Groundbreaking discoveries have unveiled compelling links between RNA modifications and oxidative phosphorylation, regulated cell death-particularly cuproptosis-and antitumor immunity, underscoring RNA modifications' vital role and untapped potential in mitochondrial biology, cancers and aging-related diseases. In this Review, we comprehensively catalog the primary RNA modifications modifiers and their small-molecule inhibitors that influence mitochondrial functions. We explore the latest research delineating RNA modifications' involvement in mitochondria-related glucose metabolism, regulated cell death, and mitochondrial dynamics, presenting an intricate regulatory network. Furthermore, we investigate the intriguing intersection of RNA modifications and mitochondria-related antitumor immunity, highlighting prospective therapeutic targets to enhance immunotherapy outcomes. This review not only accentuates the critical importance of RNA modifications in mitochondrial function but also paves the way for novel therapeutic strategies in disease treatment.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"26 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717997","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}
BACKGROUNDConsolidation durvalumab following no progression on concurrent chemoradiotherapy (cCRT) is standard of care for unresectable stage III non-small-cell lung cancer (NSCLC). However, in clinical practice many patients receive sequential CRT (sCRT). The PACIFIC-5 trial aimed to evaluate the efficacy and safety of consolidation durvalumab for unresectable stage III NSCLC following no progression on cCRT or sCRT.METHODSThis randomised, double-blind, placebo-controlled, phase III trial enrolled patients aged ≥ 18 years with unresectable stage III NSCLC, regardless of PD-L1 expression or sensitising EGFR or ALK aberrations, without disease progression after cCRT or sCRT. Patients were randomised (2:1) to durvalumab 1500 mg or placebo intravenously every 4 weeks (stratified by tumour PD-L1 expression and prior treatment) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was progression-free survival (PFS) by blinded independent central review in the modified intention-to-treat population (mITT). Secondary endpoints included overall survival (OS) in the mITT and safety. The safety analysis set include patients who received at least one dose of study treatment.RESULTSOf 407 patients randomised to receive durvalumab (n = 272) or placebo (n = 135), 405 received at least one dose of durvalumab (n = 271) or placebo (n = 134). The mITT comprised 381 patients randomised to durvalumab (n = 252) or placebo (n = 129). Durvalumab showed statistically significant improvement in PFS versus placebo in the mITT (median [95% confidence interval {CI}], 14.0 [10.9-18.0] vs. 6.5 [5.4-13.8] months; hazard ratio [95% CI], 0.75 [0.58-0.99]; p = 0.038). There was a trend toward improved OS with durvalumab versus placebo in the mITT (median [95% CI], 38.3 [28.9-42.8] vs. 32.5 [20.6-40.4] months; hazard ratio [95% CI], 0.87 [0.66-1.17]; p = 0.346 [interim analysis]). Among the safety analysis set, maximum grade 3 or 4 adverse events of any cause occurred in 26.9% (73/271) and 23.9% (32/134) and 1.5% (4/271) and 0% (0/134) had treatment-related adverse events leading to death for durvalumab and placebo, respectively.CONCLUSIONSPACIFIC-5 met its primary endpoint of improved PFS after either cCRT or sCRT. Follow-up for overall survival is ongoing.TRIAL REGISTRATIONNCT03706690.
{"title":"PACIFIC-5: a phase III clinical trial of consolidation durvalumab in patients with unresectable stage III NSCLC and no progression after concurrent or sequential chemoradiotherapy.","authors":"Yi-Long Wu,Lin Wu,Nan Bi,Timucin Cil,Hong Ge,Zhengfei Zhu,Chih-Liang Wang,Wei Zhang,Dongqing Lv,E Mingyan,Jianguo Sun,Yi Pan,Maciej Krzakowski,Mustafa Dikilitas,Mehmet Ali Nahit Sendur,Young-Chul Kim,Yanjiao Yang,Rui Mao,Biao Zhang,Luhua Wang","doi":"10.1186/s13045-025-01768-1","DOIUrl":"https://doi.org/10.1186/s13045-025-01768-1","url":null,"abstract":"BACKGROUNDConsolidation durvalumab following no progression on concurrent chemoradiotherapy (cCRT) is standard of care for unresectable stage III non-small-cell lung cancer (NSCLC). However, in clinical practice many patients receive sequential CRT (sCRT). The PACIFIC-5 trial aimed to evaluate the efficacy and safety of consolidation durvalumab for unresectable stage III NSCLC following no progression on cCRT or sCRT.METHODSThis randomised, double-blind, placebo-controlled, phase III trial enrolled patients aged ≥ 18 years with unresectable stage III NSCLC, regardless of PD-L1 expression or sensitising EGFR or ALK aberrations, without disease progression after cCRT or sCRT. Patients were randomised (2:1) to durvalumab 1500 mg or placebo intravenously every 4 weeks (stratified by tumour PD-L1 expression and prior treatment) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was progression-free survival (PFS) by blinded independent central review in the modified intention-to-treat population (mITT). Secondary endpoints included overall survival (OS) in the mITT and safety. The safety analysis set include patients who received at least one dose of study treatment.RESULTSOf 407 patients randomised to receive durvalumab (n = 272) or placebo (n = 135), 405 received at least one dose of durvalumab (n = 271) or placebo (n = 134). The mITT comprised 381 patients randomised to durvalumab (n = 252) or placebo (n = 129). Durvalumab showed statistically significant improvement in PFS versus placebo in the mITT (median [95% confidence interval {CI}], 14.0 [10.9-18.0] vs. 6.5 [5.4-13.8] months; hazard ratio [95% CI], 0.75 [0.58-0.99]; p = 0.038). There was a trend toward improved OS with durvalumab versus placebo in the mITT (median [95% CI], 38.3 [28.9-42.8] vs. 32.5 [20.6-40.4] months; hazard ratio [95% CI], 0.87 [0.66-1.17]; p = 0.346 [interim analysis]). Among the safety analysis set, maximum grade 3 or 4 adverse events of any cause occurred in 26.9% (73/271) and 23.9% (32/134) and 1.5% (4/271) and 0% (0/134) had treatment-related adverse events leading to death for durvalumab and placebo, respectively.CONCLUSIONSPACIFIC-5 met its primary endpoint of improved PFS after either cCRT or sCRT. Follow-up for overall survival is ongoing.TRIAL REGISTRATIONNCT03706690.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"127 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696642","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}
Immunotherapy has revolutionized the landscape of cancer treatment, yet its efficacy is often limited by drug resistance, the immunosuppressive tumor microenvironment (TME), and the "undruggable" nature of key immunoregulatory proteins. Targeted protein degradation (TPD) technology, which harnesses cellular degradation machinery to eliminate disease-associated proteins, is emerging as a transformative strategy in the field of tumor immunotherapy. This review systematically summarizes recent advances in various TPD strategies-based on both the ubiquitin-proteasome system (UPS) and the lysosomal pathway, such as proteolysis-targeting chimera (PROTAC), molecular glues, lysosome-targeting chimera (LYTAC), and antibody-based PROTAC (AbTAC)-within the context of cancer immunotherapy. We emphasize how TPD molecules can directly degrade key target proteins, including immune checkpoints, to alleviate immunosuppression, as well as clear critical immunomodulatory factors within the TME, thereby synergistically reversing immunosuppression and enhancing antitumor immunity. Furthermore, this article discusses the rational design, preclinical validation, and clinical translation trends of TPD-based immunotherapeutic agents. Despite encouraging progress, challenges such as tissue selectivity, off-target effects, and delivery efficiency remain to be addressed. Finally, we envision future directions for advancing the application of TPD technology in cancer immunotherapy.
{"title":"Recent advances in targeting protein degradation for tumor immunotherapy.","authors":"Shuai Li,Yushan Jin,Huanhuan Wu,Hong Yuan,Jingyuan Zhao","doi":"10.1186/s13045-025-01765-4","DOIUrl":"https://doi.org/10.1186/s13045-025-01765-4","url":null,"abstract":"Immunotherapy has revolutionized the landscape of cancer treatment, yet its efficacy is often limited by drug resistance, the immunosuppressive tumor microenvironment (TME), and the \"undruggable\" nature of key immunoregulatory proteins. Targeted protein degradation (TPD) technology, which harnesses cellular degradation machinery to eliminate disease-associated proteins, is emerging as a transformative strategy in the field of tumor immunotherapy. This review systematically summarizes recent advances in various TPD strategies-based on both the ubiquitin-proteasome system (UPS) and the lysosomal pathway, such as proteolysis-targeting chimera (PROTAC), molecular glues, lysosome-targeting chimera (LYTAC), and antibody-based PROTAC (AbTAC)-within the context of cancer immunotherapy. We emphasize how TPD molecules can directly degrade key target proteins, including immune checkpoints, to alleviate immunosuppression, as well as clear critical immunomodulatory factors within the TME, thereby synergistically reversing immunosuppression and enhancing antitumor immunity. Furthermore, this article discusses the rational design, preclinical validation, and clinical translation trends of TPD-based immunotherapeutic agents. Despite encouraging progress, challenges such as tissue selectivity, off-target effects, and delivery efficiency remain to be addressed. Finally, we envision future directions for advancing the application of TPD technology in cancer immunotherapy.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"95 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145674383","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}
Chimeric antigen receptor (CAR) T-cell therapy has demonstrated substantial efficacy against various hematological malignancies. The remarkable success of CAR-T cell therapy in targeting B-cell malignancies has generated significant interest in its potential application for treating autoimmune diseases (ADs). By engineering T cells to express CARs that specifically recognize B-cell antigens, researchers aim to selectively eliminate or modulate the dysregulated autoimmune responses underlying disease pathology. Early clinical trials targeting the B-cell marker CD19 have shown promising results, including clinical remission in patients with B-cell-mediated ADs. To broaden therapeutic potential and improve the safety profile of CAR-T cell therapy in autoimmunity, innovative strategies are under investigation. These include the development of chimeric autoantibody receptors (CAARs) for the precise depletion of autoantigen-specific B cells, and the engineering of regulatory T cells (Tregs) expressing antigen-specific CARs to achieve targeted immune modulation. Critical considerations for the safe and effective translation of CAR-T therapy to ADs include optimal target cell identification, CAR construct design, toxicity management, and the capacity to induce durable immune tolerance. This review explores strategies to optimize CAR-T cell therapies for ADs, focusing on enhancing efficacy and addressing current limitations. We summarize recent advances in alternative cell sources, CAR structural modifications, genetic and metabolic interventions, clinical translation, and the integration of novel technologies, presenting approaches poised to improve the efficacy and applicability of CAR-T cell therapy in ADs.
{"title":"Challenges and strategies in clinical applications of CAR-T therapy for autoimmune diseases.","authors":"Xiaomei Chen,Kaifan Liu,Bowen Liu,Shiyin Li,Yulian Wang,Xin Du,Jianyu Weng,Bing Song,Kongming Wu,Peilong Lai","doi":"10.1186/s13045-025-01769-0","DOIUrl":"https://doi.org/10.1186/s13045-025-01769-0","url":null,"abstract":"Chimeric antigen receptor (CAR) T-cell therapy has demonstrated substantial efficacy against various hematological malignancies. The remarkable success of CAR-T cell therapy in targeting B-cell malignancies has generated significant interest in its potential application for treating autoimmune diseases (ADs). By engineering T cells to express CARs that specifically recognize B-cell antigens, researchers aim to selectively eliminate or modulate the dysregulated autoimmune responses underlying disease pathology. Early clinical trials targeting the B-cell marker CD19 have shown promising results, including clinical remission in patients with B-cell-mediated ADs. To broaden therapeutic potential and improve the safety profile of CAR-T cell therapy in autoimmunity, innovative strategies are under investigation. These include the development of chimeric autoantibody receptors (CAARs) for the precise depletion of autoantigen-specific B cells, and the engineering of regulatory T cells (Tregs) expressing antigen-specific CARs to achieve targeted immune modulation. Critical considerations for the safe and effective translation of CAR-T therapy to ADs include optimal target cell identification, CAR construct design, toxicity management, and the capacity to induce durable immune tolerance. This review explores strategies to optimize CAR-T cell therapies for ADs, focusing on enhancing efficacy and addressing current limitations. We summarize recent advances in alternative cell sources, CAR structural modifications, genetic and metabolic interventions, clinical translation, and the integration of novel technologies, presenting approaches poised to improve the efficacy and applicability of CAR-T cell therapy in ADs.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"25 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145613386","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}
Pub Date : 2025-11-27DOI: 10.1186/s13045-025-01757-4
Jayastu Senapati,Marina Konopleva,Ghayas C Issa,Elias Jabbour,Tapan Kadia,Courtney DiNardo,Gautam Borthakur,Naveen Pemmaraju,Nicholas J Short,Musa Yilmaz,Indraneel Deshmukh,Joie Alvarez,Sanam Loghavi,Guilin Tang,Hussein A Abbas,Michael Andreeff,Kapil Bhalla,Narasimha M Midde,Nabil Said,Amy Noyalis,Derek E Mires,Jing Ning,Lianchun Xiao,Farhad Ravandi,Guillermo Garcia-Manero,Hagop M Kantarjian,Naval G Daver
Several menin inhibitors are in development targeting menin dependent leukemias, however available preclinical results show variable level of activity. We report the phase 1 portion (to establish a recommended phase 2 dose [RP2D]) and pharmacokinetic analysis of a phase 1/2 first-in-human clinical trial of DS-1594b menin inhibitor. Eligible patients included adults (≥ 18 years of age) with relapsed/refractory (R/R) acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) including but not restricted to those with KMT2A-rearrangement (r) or NPM1 mutation. Seventeen patients at a median of age 56 years (range, 19-82 years) were treated, 15 (88%) had R/R AML, and 2 (12%) had R/R B-ALL; 9 (53%) had a KMT2A-r but none had an NPM1 mutation. The median prior lines of therapy was 3 (range 1-8) and 5 patients (29%) had received prior menin inhibitors. Five dose escalation cohorts were evaluated; no RP2D was established, and the trial was stopped at phase 1 due to a decision by supporting company due to lack of efficacy at studied dose levels and portfolio realignment. Differentiation syndrome (DS) was seen in 5 patients (29%); 2 in cohort 1 (70 mg twice daily, n = 4) 1 each had grade 1 and grade 4 DS, 3 patients in cohort 2 (50 mg twice daily/100 mg daily, n = 4) of whom 2 had grade 2 and 1 patient had grade 3 DS (considered as dose limiting toxicity). No DS was noted at cohort 3 (20 mg/day), and in subsequent dose-escalation cohorts (cohorts 4 and 5) a lead-in ramp-up dosing starting at 20 mg/day was instituted to improve tolerability. Other relevant treatment emergent adverse events of grade ≥ 3 included infections; pneumonia and febrile neutropenia in 7 patients each (41%), and sepsis in 6 patients (35%). No study drug related deaths were noted. No patient achieved a response, however 4 patients (23%) had > 25% bone marrow blast reduction. Pharmacokinetic analysis showed DS-1594b reached maximum concentration approximately in 2 h with total exposure increasing with escalating doses and reached stead-state by Cycle 1 Day 8. DS-1594b showed limited efficacy at the doses tested but appeared safe with a lead-in dosing approach.
{"title":"A phase 1/2 study of DS-1594 menin inhibitor in relapsed/refractory acute leukemias.","authors":"Jayastu Senapati,Marina Konopleva,Ghayas C Issa,Elias Jabbour,Tapan Kadia,Courtney DiNardo,Gautam Borthakur,Naveen Pemmaraju,Nicholas J Short,Musa Yilmaz,Indraneel Deshmukh,Joie Alvarez,Sanam Loghavi,Guilin Tang,Hussein A Abbas,Michael Andreeff,Kapil Bhalla,Narasimha M Midde,Nabil Said,Amy Noyalis,Derek E Mires,Jing Ning,Lianchun Xiao,Farhad Ravandi,Guillermo Garcia-Manero,Hagop M Kantarjian,Naval G Daver","doi":"10.1186/s13045-025-01757-4","DOIUrl":"https://doi.org/10.1186/s13045-025-01757-4","url":null,"abstract":"Several menin inhibitors are in development targeting menin dependent leukemias, however available preclinical results show variable level of activity. We report the phase 1 portion (to establish a recommended phase 2 dose [RP2D]) and pharmacokinetic analysis of a phase 1/2 first-in-human clinical trial of DS-1594b menin inhibitor. Eligible patients included adults (≥ 18 years of age) with relapsed/refractory (R/R) acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) including but not restricted to those with KMT2A-rearrangement (r) or NPM1 mutation. Seventeen patients at a median of age 56 years (range, 19-82 years) were treated, 15 (88%) had R/R AML, and 2 (12%) had R/R B-ALL; 9 (53%) had a KMT2A-r but none had an NPM1 mutation. The median prior lines of therapy was 3 (range 1-8) and 5 patients (29%) had received prior menin inhibitors. Five dose escalation cohorts were evaluated; no RP2D was established, and the trial was stopped at phase 1 due to a decision by supporting company due to lack of efficacy at studied dose levels and portfolio realignment. Differentiation syndrome (DS) was seen in 5 patients (29%); 2 in cohort 1 (70 mg twice daily, n = 4) 1 each had grade 1 and grade 4 DS, 3 patients in cohort 2 (50 mg twice daily/100 mg daily, n = 4) of whom 2 had grade 2 and 1 patient had grade 3 DS (considered as dose limiting toxicity). No DS was noted at cohort 3 (20 mg/day), and in subsequent dose-escalation cohorts (cohorts 4 and 5) a lead-in ramp-up dosing starting at 20 mg/day was instituted to improve tolerability. Other relevant treatment emergent adverse events of grade ≥ 3 included infections; pneumonia and febrile neutropenia in 7 patients each (41%), and sepsis in 6 patients (35%). No study drug related deaths were noted. No patient achieved a response, however 4 patients (23%) had > 25% bone marrow blast reduction. Pharmacokinetic analysis showed DS-1594b reached maximum concentration approximately in 2 h with total exposure increasing with escalating doses and reached stead-state by Cycle 1 Day 8. DS-1594b showed limited efficacy at the doses tested but appeared safe with a lead-in dosing approach.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"200 1","pages":"108"},"PeriodicalIF":28.5,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145613257","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}
Pub Date : 2025-11-27DOI: 10.1186/s13045-025-01767-2
Deepika Kanojia, Manoj Garg, Jacqueline Martinez, Anand M T, Samuel B Luty, Ngan B Doan, Jonathan W Said, Charles Forscher, Jeffrey W Tyner, H Phillip Koeffler
{"title":"Retraction Note: Kinase profiling of liposarcomas using RNAi and drug screening assays identified druggable targets.","authors":"Deepika Kanojia, Manoj Garg, Jacqueline Martinez, Anand M T, Samuel B Luty, Ngan B Doan, Jonathan W Said, Charles Forscher, Jeffrey W Tyner, H Phillip Koeffler","doi":"10.1186/s13045-025-01767-2","DOIUrl":"10.1186/s13045-025-01767-2","url":null,"abstract":"","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"18 1","pages":"106"},"PeriodicalIF":40.4,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12659540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145634414","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}
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