Journal for Immunotherapy of Cancer最新文献

{"title":"Expansion of a circulating Ki67-positive effector T-cell population following combined PD-1 and CTLA-4 blockade for melanoma is predictive of treatment response.","authors":"Jack M Edwards, Sashendra Senthi, Robin Smith, Hayley Burridge, Carole Owens, Mark Shackleton, Miles C Andrews, Menno C van Zelm","doi":"10.1136/jitc-2025-012317","DOIUrl":"10.1136/jitc-2025-012317","url":null,"abstract":"<p><strong>Background: </strong>Despite the success of combined cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1) immune checkpoint blockade (cICB), the majority of patients with melanoma fail to respond or experience severe treatment-related toxicity. Currently, there are no reliable biomarkers available to predict these events and guide treatment choices. We here evaluated the peripheral immune compartment to identify features associated with cICB outcome and toxicity.</p><p><strong>Methods: </strong>Blood samples were collected from 51 patients with advanced melanoma prior to commencing and after one cycle of cICB. Patients were classified as responders or non-responders based on radiographic best overall response to treatment, and grouped by the occurrence of severe toxicity. Absolute immune cell counts were obtained and peripheral blood mononuclear cells were cryopreserved prior to spectral flow-cytometric T-cell immunophenotyping.</p><p><strong>Results: </strong>20 patients (39%) failed to respond to treatment, and 29 (57%) experienced severe toxicity. Pre-treatment, patients had fewer T cells than age-matched healthy controls (median 892 vs 1297 cells/µL, p=0.0004), mostly due to reduced naive CD4⁺ (p=0.0038) and CD8⁺ (p=0.0031) T cells. One cycle of cICB restored patient T cells to levels equivalent to healthy controls through expansion and activation of CD4⁺ and CD8⁺ memory and regulatory, but not naive subsets, and skewed the T-cell compartment towards an activated phenotype. This T-cell expansion correlated strongly with pre-treatment PD-1 (r=0.88, p=0.0003) but not CTLA-4 (r=0.32, p=0.34) expression levels, and was accompanied by upregulation of molecules including Ki67, inducible co-stimulator of T cells (ICOS), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT) on effector CD4⁺ and CD8⁺ T cells. Greater upregulation of Ki67 in CD4⁺ central memory cells significantly differentiated responders and non-responders after one cycle of treatment (p=0.0086, area under the curve (AUC)=0.74, 95% CI 0.59 to 0.88), while higher on-treatment TIM-3 frequency within CD8⁺ T cells differentiated patients who experienced severe toxicity (p=0.0086, AUC=0.74, 95% CI 0.59 to 0.88).</p><p><strong>Conclusions: </strong>We here show that response and toxicity to cICB in advanced melanoma are driven by distinct immune features evident after only one cycle of treatment. These could serve as prognostic biomarkers upon validation in larger cohorts.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12516982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258351","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":"Germline determinants of toxicity and efficacy in patients with large B-cell lymphoma treated with CAR T-cell therapy.","authors":"Paolo Strati, Amanda Brandt, Anath C Lionel, Jared Henderson, Jason R Westin, Sherry Adkins, Elizabeth J Shpall, Partow Kebriaei, Jeremy Ramdial, Neeraj Saini, Sairah Ahmed, Christopher Flowers, Sattva S Neelapu, Michelle A T Hildebrandt","doi":"10.1136/jitc-2025-012401","DOIUrl":"10.1136/jitc-2025-012401","url":null,"abstract":"<p><strong>Background: </strong>Recent data have suggested that germline genetic aberrations can affect outcomes in patients with large B-cell lymphoma (LBCL) treated with chimeric antigen receptor T-cell therapy (CART). However, a comprehensive analysis of germline determinants of response and toxicity after CART has not yet been described.</p><p><strong>Methods: </strong>Genome-wide genotyping was performed in 170 patients with LBCL treated with standard of care axicabtagene ciloleucel. Polygenic risk score instruments for blood cell traits and inflammatory markers were obtained from the PGS Catalog and analyzed using PRSice-2. Exploratory gene-based and genome-wide association study analyses were performed. Genetic ancestry of the patients with LBCL was estimated using ADMIXTURE. Analysis was conducted to identify genetic risk of toxicity and efficacy endpoints.</p><p><strong>Results: </strong>Increasing PRS for monocyte count was associated with increased risk of cytokine release syndrome of any grade (OR 2.49, 95% CI 1.18 to 5.25, p=0.016). Similarly, genetically predicted interleukin (IL)-1Rα and (IL)-27 levels were decreased (p=0.002) and increased (p=0.012) in patients with G3-4 day 30 cytopenia, respectively. The latter was also associated with variation in the hemophagocytic lymphohistiocytosis-related gene <i>RAB27A</i> (p=0.041). Genome-wide significant (p<5×10^-8) variants were identified in association with progression-free and overall survival, including <i>SPOCK1, SLC28A2-AS1 and DUOX1</i>. No significant differences in outcomes were observed based on ancestry, except for a decrease in risk for D30 G3-4 cytopenia for patients of European ancestry (p=0.026).</p><p><strong>Conclusion: </strong>Germline genetic aberrations relevant to myeloid cell biology can predict toxicity and efficacy of CART in patients with LBCL. Elucidating such intrinsic determinants may help improve patient selection and develop strategies to enhance the therapeutic index of CART.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12516986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258302","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":"Novel tetrameric bispecific KK-LC-1×CD16A-armed memory-like NK cells enhance antitumor efficacy in gastric cancer.","authors":"Mengzhu Li, Tianran Chen, Siwen Wu, Yuxiang Li, Qin Liu, Ying Wang, Jingyi Guo, Lanqi Cen, Lu Zou, Manman Tian, Wenxiu Chen, Rutian Li, Jie Shen, Baorui Liu, Jie Shao","doi":"10.1136/jitc-2025-012504","DOIUrl":"10.1136/jitc-2025-012504","url":null,"abstract":"<p><strong>Background: </strong>Cytokine-induced memory-like natural killer (CIML NK) cells demonstrate potent antitumor efficacy against hematological malignancies. Nevertheless, the therapeutic potential of adoptive NK cell transfer remains constrained in solid tumors due to insufficient tumor infiltration efficiency. Developing a novel tetravalent bispecific killer engager (BiKE) to modify CIML NK cells would be a promising strategy to enhance therapeutic efficacy.</p><p><strong>Methods: </strong>We employed SpyTag-SpyCatcher technology to engineer tetravalent BiKEs, specifically KK-LC-1×CD16A, and to equip CIML NK cells with this protein. Flow cytometry and a luciferase reporter gene system were used to evaluate the activation and cytotoxicity of CIML NK cells. Histological analysis and in vivo real-time fluorescence imaging were employed in the xenograft tumor model to confirm the tumor-infiltrating effectiveness of KK-LC-1×CD16A-armed CIML NK cells. The in vivo antitumor efficacy of armed CIML NK cells was evaluated in subcutaneous gastric cancer xenograft models.</p><p><strong>Results: </strong>We successfully developed a tetravalent NK cell engager, KK-LC-1×CD16A, which exhibits excellent binding affinity to its targets. CIML NK cells armed with this protein exhibit enhanced activation and augmented cytotoxicity against tumor cells. In xenograft tumor models, the accumulation of KK-LC-1×CD16A-armed CIML NK cells at the tumor site was significantly increased, resulting in marked suppression of tumor growth and prolonged survival in mice.</p><p><strong>Conclusion: </strong>KK-LC-1×CD16A-armed CIML NK cells demonstrate significant clinical potential as a multifunctional therapeutic platform, effectively overcoming both tumor infiltration limitations and functional suppression in conventional NK cell therapies. This approach provides valuable insights for optimizing the therapeutic efficacy of CIML NK cell therapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12516970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251178","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":"Multiomics elucidation of surrounding AT2 cells impeding tertiary lymphoid structures function in neoadjuvant chemoimmunotherapy response of multiple primary lung cancers.","authors":"Wenxiang Wang, Sida Cheng, Hongchengcheng Chen, Fanjie Meng, Yaxing Zhao, Chao Zhang, Wen-Zhao Zhong, Xiang Yan, Yun Li, Jian Zhou, Jianpeng Sheng, Kezhong Chen, Hao Li","doi":"10.1136/jitc-2025-011882","DOIUrl":"10.1136/jitc-2025-011882","url":null,"abstract":"<p><p>The inconsistent immunotherapy response among lesions in patients with multiple primary lung cancer (MPLC) remains poorly understood, presenting a significant challenge for effective treatment. In this study, we conducted a comprehensive multiomics analysis of all lesions from a patient with MPLC who exhibited varied responses to neoadjuvant chemoimmunotherapy. Further verification was conducted through external single-cell data and multiplex immunohistochemistry of three cases of MPLC.Notably, tertiary lymphoid structures (TLSs) were observed across all nodules, regardless of response, suggesting possible TLS impairment in non-responsive nodules. Cell neighborhood (CN) analysis revealed that type II alveolar epithelial cell (AT2) cell-positive CNs were prevalent in non-responsive nodules, while AT2-negative CNs appeared in responsive nodules, strongly associating AT2 cell presence with a reduced therapeutic response. Spatial colocalization analysis further showed that AT2 cells surrounding TLSs upregulated immunosuppressive markers on B cells within TLSs. The mechanism of this suppressive effect was further unveiled that macrophage migration inhibitory factor (MIF), secreted by AT2 cells, binds to sialic acid acetylesterase (SIAE) receptors on B cells by single-cell RNA sequencing analysis, which were validated in four additional non-responsive nodules from three other patients with MPLC. Multiomics analysis revealed AT2 cells exert immunosuppressive effects by inhibiting B cells within TLS through MIF-SIAE signaling axis in patients with MPLC. These findings offered new perspectives for tailored immunotherapy for patients with MPLC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12516992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251152","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":"Neural stem cell-delivered oncolytic virus via intracerebroventricular administration enhances glioblastoma therapy and immune modulation.","authors":"Huihui Chai, Houshi Xu, Shan Jiang, Tingting Zhang, Jiawen Chen, Ruize Zhu, Yue Wang, Maoyuan Sun, Beining Liu, Xiaoming Wang, Xicai Sun, Kangjian Zhang, Liangfu Zhou, Zhi-Feng Shi","doi":"10.1136/jitc-2025-012934","DOIUrl":"10.1136/jitc-2025-012934","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis and limited treatment options. Oncolytic virus (OV) therapy holds promise but is hindered by immune neutralization and poor tumor infiltration. Neural stem cells (NSCs) can enhance OV delivery, and intracerebroventricular (ICV) administration offers broader tumor access. This study evaluates NSC-OV therapy via ICV injection for improved tumor targeting and immune modulation in GBM.</p><p><strong>Methods: </strong>NSCs were infected with OV and assessed for viral uptake and replication. In vitro assays examined NSC-OV effects on glioma proliferation and migration. In vivo xenograft and orthotopic models evaluated tumor targeting, therapeutic efficacy, and immune modulation. Humanized immune system mouse models enabled single-cell RNA sequencing and flow cytometry analysis of immune responses.</p><p><strong>Results: </strong>NSCs retained their stemness after OV infection. NSCs-OV significantly inhibited glioma cell migration, proliferation, and colony formation in vitro. In orthotopic GBM models, NSCs-OV exhibited enhanced tumor homing, prolonged viral persistence, and reduced tumor burden while minimizing inflammation and systemic toxicity. NSCs protected OV from neutralizing antibodies, leading to sustained efficacy. Single-cell RNA sequencing indicated that NSCs-OV therapy reduced tumor-promoting inflammation by downregulating S100A8/A9, markers of myeloid-derived suppressor cells (MDSCs) and chemotactic factors that recruited MDSCs into tumors. Combining NSCs-OV with Paquinimod further suppressed tumor growth by reducing MDSCs and increasing activated T cells.</p><p><strong>Conclusions: </strong>NSCs serve as efficient OV carriers, enhancing tumor targeting, suppressing GBM progression, and modulating the immune landscape. The combination with Paquinimod amplifies therapeutic benefits, offering a promising strategy for improving GBM treatment outcomes.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12516981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251172","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":"Fungal microbiota signatures anticipate neoadjuvant immunochemotherapy outcomes in esophageal cancer.","authors":"Liping Liang, Shijie Mai, Gautam Sethi, Yingjie Luo, Zeheng Ma, Lele Wu, Di Lu, Jimin Han, Ruijun Cai, Yongjian Zhou, Xinying Wang, Le Liu","doi":"10.1136/jitc-2025-011508","DOIUrl":"https://doi.org/10.1136/jitc-2025-011508","url":null,"abstract":"<p><strong>Background: </strong>Predicting neoadjuvant immunochemotherapy (NICT) response remains a critical challenge in esophageal squamous cell carcinoma (ESCC) management. While the gut bacteriome's role in immunotherapy has been established, the mycobiome's predictive potential remains largely unexplored. This study investigated whether gut fungal signatures could serve as reliable biomarkers for NICT response prediction in patients with ESCC.</p><p><strong>Methods: </strong>We performed internal transcribed spacer 2 sequencing on 155 fecal samples from 68 patients with ESCC (pre-NICT and post-NICT) and 19 healthy controls. Patients were stratified by tumor regression grade scores. We analyzed mycobiome-immune marker correlations and developed multilayer perceptron (MLP) models using Boruta feature selection. Performance was validated in 37 independent pretreatment patients. Functional causality was confirmed using <i>Candida_boidinii</i> in syngeneic mouse experiments with anti-programmed cell death protein-1 (PD-1) therapy.</p><p><strong>Results: </strong>Patients with ESCC exhibited significant mycobiome dysbiosis compared with healthy controls, characterized by reduced alpha diversity and enrichment of pathogenic fungi including <i>s_Rhodotorula_minuta</i>, <i>s_Actinomucor_elegans</i>, and <i>s_Candida_zeylanoides</i>. Baseline mycobiome profiles distinguished treatment responders from non-responders before therapy initiation. Responders demonstrated higher fungal diversity, more stable co-occurrence networks, and enrichment of beneficial taxa (<i>s_Candida_boidinii</i>, <i>g_Meyerozyma</i>, <i>s_Meyerozyma_guilliermondii</i>, <i>s_Trichosporon_dermatis</i>) that correlated with Th1-polarized immunity and elevated cytotoxic markers (interferon-γ, interleukin (IL)-12p70, IL-2). Non-responders harbored immunosuppressive fungi (<i>s_Candida_albicans</i>, <i>s_Candida_parapsilosis</i>, <i>s_Candida_glabrata</i>, <i>g_Saccharomyces</i>) associated with Th2 skewing and regulatory cytokines (IL-4, IL-10, IL-13). Functional analysis revealed responders exhibited enhanced catabolic pathways and phospholipase activities, while non-responders showed upregulated nucleotide biosynthesis. The MLP model achieved robust discriminative performance (genus-level: training area under the receiver operating characteristic curve (AUC) 98.0%, test AUC 82.9%; species-level: training AUC 87.1%, test AUC 87.4%). <i>Candida_boidinii</i> administration enhanced anti-PD-1 efficacy in mice, validating predicted metabolomic and immune changes.</p><p><strong>Conclusions: </strong>Baseline gut mycobiome signatures predict NICT response in ESCC with high accuracy. Experimental validation confirms functional causality, enabling precision medicine approaches for patient stratification and identifying therapeutic targets.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251110","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":"Longitudinal tissue analysis reveals microenvironmental changes correlate with combined immunotherapy and targeted therapy response in metastatic breast cancer.","authors":"Jian-You Liao, Jien Wang, Hengyu Li, Zhijun Liu, Zhenluan Tian, Xinying Lv, Jianjian Peng, Chuangui Song, Jieqiong Liu","doi":"10.1136/jitc-2025-012629","DOIUrl":"10.1136/jitc-2025-012629","url":null,"abstract":"<p><p>The ability to interrogate changes within the tumor microenvironment (TME) before, during and following therapeutic intervention could yield important understanding of treatment response and causes for disease progression. Yet, the role of investigational tissue analysis faces key challenges in the clinical setting and the value of integrating longitudinal biopsies with emerging multimodal molecular analyses (\"Multi-omics\") remains to be defined. In this study, we conducted a multicenter phase 2 clinical trial examining the effect of a novel cytotoxic T-lymphocyte-associated protein 4/programmed death-ligand 1 bispecific antibody in combination with a dual-epitope blocking anti-human epidermal growth factor receptor 2 antibody in treatment-resistant metastatic breast cancer. We performed longitudinal sampling of patient tumor tissues before and following treatment. Single-cell RNA and T cell receptor sequencing from 334,183 cells from site-matched tumors reveals significant temporal shift of various immune cell populations and phenotypes within the TME associated with treatment responses. Conversely, regulatory T cells were activated while effector T cells, natural killer cells, and dendritic cells were significantly depleted in non-responding tumors. Taken together, these results support that longitudinal analysis of TME to generate multiomics data that can lead to rich insight into disease process and to provide clinical value in evaluating treatment responses. <b>Trial registration number</b> NCT04521179.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238639","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":"Causal AI-based clinical and radiomic analysis for optimizing patient selection in combined immunotherapy and SABR in early-stage NSCLC: a secondary analysis of the phase II I-SABR trial.","authors":"Maliazurina B Saad, Eman Showkatian, Vivek Verma, Qasem Al-Tashi, Muhammad Aminu, Xinyan Xu, Muhamed Qayati Mohamed, Morteza Salehjahromi, Sheeba J Sujit, Yuliya Kitsel, Steven H Lin, Zhongxing Liao, Saumil Gandhi, David Qian, David Jaffray, Caroline Chung, Natalie I Vokes, Jianjun Zhang, J Jack Lee, John V Heymach, Jia Wu, Joe Y Chang","doi":"10.1136/jitc-2025-013074","DOIUrl":"10.1136/jitc-2025-013074","url":null,"abstract":"<p><strong>Background: </strong>The recent phase II randomized stereotactic ablative radiotherapy with and without immunotherapy (I-SABR) trial has shown improved event-free survival (EFS) when adding immunotherapy to stereotactic ablative radiotherapy (SABR) for early-stage inoperable non-small cell lung cancer (NSCLC). However, optimizing patient selection thereof is critical, because not every patient benefits from immunotherapy. Leveraging the powerful use of artificial intelligence, this secondary analysis of the I-SABR trial developed a modeling system (named \"I-SABR-SELECT\") based on clinical and radiomic factors to address which patients should receive additional immunotherapy.</p><p><strong>Methods: </strong>The discovery/validation cohorts were from the I-SABR trial, with external validation from the single-arm STARS trial. Individual treatment effect scores, estimating the benefit of adding immunotherapy, were derived from radiomic and clinical predictors using counterfactual reasoning. Dimensionality reduction was applied to mitigate overfitting and enhance model robustness. We also evaluated the average treatment effect between subgroups of patients who were treated following versus against the model's recommendation.</p><p><strong>Results: </strong>The model recommended that 49% (69/141) patients enrolled in the I-SABR trial switch treatments (65% (49/75) in the SABR arm and 30% (20/66) in the I-SABR arm). Patients treated by the model's recommendation had higher EFS, with HRs of 0.06 (in the I-SABR arm, p<0.001) and 0.26 (in the SABR alone arm, p=0.0042) from the I-SABR trial population, and 0.38 (p=0.031) for the STARS trial. Following model stratification, among patients recommended for SABR+immunotherapy, the restricted mean survival time for EFS is prolonged by 1.43 years compared to those who received SABR alone. The absolute risk reduction of the added immunotherapy effect was over twofold greater than that observed in the I-SABR trial without selection.</p><p><strong>Conclusions: </strong>Combining clinical and radiomic parameters, I-SABR-SELECT uses causal reasoning to individualize treatment selection for patients with early-stage inoperable NSCLC. If validated, it could serve as a foundation for a treatment-focused digital twin by integrating real-time adaptive decision-making. <b>Code:</b> https://github.com/WuLabMDA/ISABR-SELECT.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238719","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":"Positive and negative roles of myeloid cells in cancer immunotherapy.","authors":"Jaroslav Zak, Judith A Varner","doi":"10.1136/jitc-2025-012743","DOIUrl":"10.1136/jitc-2025-012743","url":null,"abstract":"<p><p>Myeloid cells are a diverse group of immune cell types with systemic and organ-specific functions. Myeloid cells are frequently found in the tumor microenvironment and their infiltration correlates with survival and response to treatment. High myeloid infiltration is typically a poor prognostic factor, and the immune suppressive and prometastatic roles of myeloid cells are well established. However, there is an increasing appreciation of the antitumor functions performed by myeloid cells, which include direct tumor cell killing, phagocytosis, antigen presentation and T and natural killer cell recruitment. Moreover, advances in immune phenotyping have uncovered myeloid subsets with positive prognostic significance, including subsets correlating with higher response rates to immunotherapy. This review summarizes recent progress in mapping and dissecting the opposing effects of myeloid cells on cancer progression and immunotherapy response. The overall impact of myeloid cells is context-dependent, and combination therapies are needed to leverage the antitumor potential of these cells.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238671","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":"Pharmacokinetics and safety of subcutaneous nivolumab: results from the phase I/II CheckMate 8KX study.","authors":"Sara Lonardi, Iwona Ługowska, Anne O'Donnell, Christopher Jackson, Loes Maria Latten-Jansen, Richard North, Rastislav Bahleda, Marcelo Garrido, Armando Santoro, Matías Rodrigo Chacon, Linghui Li, Devanand Joseph, Heather E Vezina, Urvi Aras, Bryan Bennett, Deepak Perumal, Balmeet Gurm, Wee-Teck Ng, R Donald Harvey, José Trigo, Aitana Calvo","doi":"10.1136/jitc-2025-011918","DOIUrl":"10.1136/jitc-2025-011918","url":null,"abstract":"<p><strong>Background: </strong>CheckMate 8KX was a phase I/II study investigating the pharmacokinetics and safety of subcutaneous (SC) nivolumab±recombinant human hyaluronidase PH20 (rHuPH20).</p><p><strong>Methods: </strong>Patients with advanced solid tumors who were immune-checkpoint inhibitor-naïve were included. In parts A and B, patients received one single dose of nivolumab SC 720 mg or 960 mg±rHuPH20 2000 U/mL followed by nivolumab intravenous (IV) 480 mg every 4 weeks (Q4W). Patients receiving nivolumab IV could switch to nivolumab SC 1200 mg+rHuPH20 2000 U/mL Q4W in part C. Patients in part D received nivolumab SC 1200 mg+rHuPH20 Q4W. The primary objective was to describe the pharmacokinetics of nivolumab SC±rHuPH20. Secondary objectives included assessing safety and immunogenicity of nivolumab SC. Exploratory objectives included evaluating patient experience and preference and characterizing biomarker measures of immune function (pretreatment and on-treatment peripheral blood and tumor biopsies).</p><p><strong>Results: </strong>A total of 103 patients with various solid tumor types were treated between December 4, 2018 and September 7, 2022. Mean duration of injection was <5 min for nivolumab SC±rHuPH20. Nivolumab exposures over the first dosing interval increased with increasing dose; geometric-mean time to maximum concentration across doses was 117-167 hours (5-7 days). Nivolumab SC+rHuPH20 was well tolerated; grade 3/4 treatment-related adverse events occurred in 0%-11.1% of patients; antidrug antibodies were reported in some patients but were not associated with altered safety; no neutralizing antibodies were detected. Overall, patients preferred SC delivery over IV or had no preference. Increased tumor and peripheral pharmacodynamic biomarkers were observed postnivolumab SC, consistent with historical data for nivolumab IV.</p><p><strong>Conclusion: </strong>The pharmacokinetics of nivolumab SC have been well characterized and enabled dose selection for further study. Nivolumab SC has an acceptable safety profile, allows for rapid administration, and is preferred by more patients than nivolumab IV. These results encourage large-scale investigation of nivolumab SC.</p><p><strong>Trial registration number: </strong>NCT03656718.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238631","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}