Journal for Immunotherapy of Cancer最新文献

{"title":"Napsin A-specific T-cell clonotypes are associated with improved clinical outcomes in patients receiving checkpoint immunotherapy for metastatic non-small cell lung cancer.","authors":"Natalie J Miller, Christina Baik, Joel W Neal, Fangdi Sun, Rafael Santana-Davila, Sylvia Lee, Keith D Eaton, Renato G Martins, Cristina Rodriguez, Heather Wakelee, Sukhmani K Padda, Elena Sotillo, Eric Q Konnick, Alex Camai, Tatyana Pisarenko, Viswam S Nair, Crystal Mackall, A McGarry Houghton, Shin-Heng Chiou, Diane Tseng","doi":"10.1136/jitc-2025-011907","DOIUrl":"10.1136/jitc-2025-011907","url":null,"abstract":"<p><strong>Background: </strong>Napsin A is normally expressed in human lung pneumocytes and is a highly expressed cancer antigen in lung adenocarcinoma. We examined whether T cells specific for Napsin A may play a role in immune checkpoint inhibitor (ICI)-mediated responses. We used bulk T-cell receptor (TCR) repertoire data to assess whether the presence of Napsin A-specific clonotypes in the peripheral blood was associated with improved clinical responses to ICI.</p><p><strong>Methods: </strong>Patients with metastatic non-small cell lung cancer (NSCLC) receiving anti-programmed cell death protein 1 (PD-1) and/or programmed death-ligand 1 (PD-L1) were enrolled at Fred Hutchinson Cancer Center and Stanford University Medical Center (n=62; histology of adenocarcinoma n=48, squamous n=9, NSCLC/other n=5). Peripheral blood mononuclear cells were collected for genomic DNA isolation at one pretreatment and one post-treatment time point (range 3 weeks to 3 months). TCRβ was bulk sequenced via the immunoSEQ platform (Adaptive Biotechnologies). Napsin A-specific TCRβ sequences were identified from publicly available data and their frequencies were quantified in each patient sample. We examined whether overall survival (OS) and progression-free survival (PFS) outcomes differed in patients with or without detectable Napsin A-specific TCRs (herein Napsin TCRs). We used Cox proportional hazards regression to assess the association between detectable Napsin TCRs and PFS or OS in univariable and multivariable analyses.</p><p><strong>Results: </strong>Napsin TCRs were detectable in the blood in a large fraction of our cohort (n=25/62 (40%) pretreatment; n=21/42 (50%) post-treatment). Patients with detectable Napsin TCRs had a significant improvement in OS compared with patients without these TCRs (median OS 45.4 vs 14.8 months, p=0.0043 pretreatment; median OS 55.4 vs 18.9 months, p=0.0066 post-treatment). Among 27 <i>HLA-A*02</i> carriers of 55 human leukocyte antigen-typed patients (49%), patients with detectable pretreatment Napsin TCRs had a significant improvement in OS (median 60.2 vs 16.5 months, p=0.0054) and PFS (median 21.5 vs 7.2 months, p=0.031) compared with patients without these TCRs. In univariate and multivariate analysis, the presence of Napsin TCRs pretreatment was associated with improved OS (p=0.0057, HR 0.40, 95% CI 0.21 to 0.76 univariate; p=0.033, HR 0.45, 95% CI 0.23 to 0.91 multivariate).</p><p><strong>Conclusions: </strong>Napsin TCRs are frequently detected in patients with NSCLC and are associated with improved OS in patients with NSCLC receiving ICI.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642608","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":"Characteristics of cancer mycobiome in patients with acral melanoma.","authors":"Rong Huang, Xinyu Su, Jiayu Wang, Qi Sun, Donglin Kang, Lin Li, Yirong Wu, Lianjun Zhao, Ziyao Xie, Zhengyun Zou","doi":"10.1136/jitc-2024-011097","DOIUrl":"10.1136/jitc-2024-011097","url":null,"abstract":"<p><strong>Background: </strong>Intratumoral fungi have recently been implicated in cancer initiation and progression, with potential as biomarkers for predicting clinical outcomes and treatment response in patients with cancer. However, their role in acral melanoma (AM) has not been previously explored.</p><p><strong>Methods: </strong>We characterized the mycobiome in AM tumor tissues and adjacent non-tumor tissues. Differences in fungal communities between the two tissues, as well as the prognostic and diagnostic potential of intratumoral fungi, and their associations with the tumor microenvironment and clinicopathologic features, were evaluated through bioinformatics and biostatistical analyses.</p><p><strong>Results: </strong>Although some intratumoral fungi originated from adjacent tissues, AM tumors exhibited a distinct fungal composition characterized by altered species richness, community structure, and an increased Ascomycota-to-Basidiomycota ratio. Several fungal taxa were identified as potential diagnostic and prognostic biomarkers and showed significant correlations with clinical parameters and immune infiltration. Specifically, the CD68-high samples harbored greater fungal diversity and higher relative abundance of <i>Endocarpon</i> compared with CD68-low samples. Furthermore, fungi-bacteria interactions were characterized by significant negative correlations between their diversity, while positive interspecies interactions dominated the network.</p><p><strong>Conclusions: </strong>These findings underscore the potential role of the cancer mycobiome in AM and offer new insights into the tumor microenvironment and its implications for cancer prevention and therapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642604","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":"Unveiling the mechanisms of CEBPD-orchestrated TAM polarization through RGS2/PAR2 pathway and its impact on ICB efficacy in clear cell renal cell carcinoma.","authors":"Xiu-Wu Pan, Hong-Feng Zheng, Mu-Chen Li, Ke-Qin Dong, Yi-Fan Tang, Jia-Xin Chen, Tian-Yue Yang, Jian-Gui Liu, Zi-Chang Liu, Yifan Liu, Wen-Yan Li, Zi-Xuan Gong, Shun Zhang, Wang Zhou, Jun Gu, Xin-Gang Cui","doi":"10.1136/jitc-2024-010898","DOIUrl":"10.1136/jitc-2024-010898","url":null,"abstract":"<p><strong>Background: </strong>The polarization status and function of tumor-associated macrophages (TAMs) influence tumor progression and patients' prognosis. CCAAT/enhancer-binding proteins (CEBPs) family are important transcriptional factors in macrophages differentiation physically and pathologically. This study aims to explore the mechanism of CEBPs in TAMs polarization in clear cell renal cell carcinoma (ccRCC) immune microenvironment and its impact on immune checkpoint blockers (ICBs) therapy.</p><p><strong>Methods: </strong>The expression of CEBPs in ccRCC was analyzed by single-cell transcriptome and western blot. Immunofluorescence and in-vitro polarization assay were used to evaluate the effect of CEBP delta (CEBPD) on TAMs. Chromatin immunoprecipitation sequencing was used to explore targets of CEBPD. Dual-luciferase reporter assay and electrophoretic mobility shift assay were performed to confirm the regulation of CEBPD to RGS2. Specimens of patients received ICB therapy were used to analyze the relationship between CEBPD and immunotherapy.</p><p><strong>Results: </strong>The study identified CEBPD as a key transcriptional factor in ccRCC TAM polarization. Upregulation of CEBPD correlates to decreased M1/M2 ratio of TAMs and poorer clinical outcomes. CEBPD inhibited M1-like polarization in vitro and in vivo via the RGS2/PAR2 axis. Furthermore, CEBPD also affected the therapeutic efficacy of ICB.</p><p><strong>Conclusion: </strong>This study revealed CEBPD regulated TAM polarization via the CEBPD/RGS2/PAR2 axis. Targeting CEBPD may be a potential approach and a complementary strategy to ICB therapies in ccRCC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12258302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637058","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":"JAK-STAT-activated, fratricide-resistant CAR-T cells targeting membrane-bound TNF effectively treat AML and solid tumors.","authors":"Takahiro Nakashima, Tsunenori Ouchida, Yuichi Ishikawa, Yusuke Ito, Taeko Hayakawa, Toshiaki Yoshikawa, Haosong Zhang, Hitomi Kasuya, Yang Li, Tetsuya Matsukawa, Satoshi Inoue, Shinsuke Iida, Hitoshi Kiyoi, Yuki Kagoya","doi":"10.1136/jitc-2024-011067","DOIUrl":"10.1136/jitc-2024-011067","url":null,"abstract":"<p><strong>Background: </strong>While chimeric antigen receptor (CAR)-T cell therapy exhibits a robust therapeutic efficacy against B-cell malignancies and multiple myeloma, its efficacy and safety have not been established for acute myeloid leukemia (AML) and solid tumors due to the paucity of established target antigens. Some AML and solid tumor cells express tumor necrosis factor (TNF), which is initially expressed on the cell surface prior to shedding.</p><p><strong>Methods: </strong>In this study, we obtained monoclonal antibodies against the N-terminal fragment of TNF (TNF-NTF) that remains on the cell surface after shedding. We then generated CAR-T cells to target TNF-NTF using the antibody sequence. To enhance the therapeutic efficacy of TNF-NTF CAR-T cells, we further engineered the previously developed chimeric cytokine receptor consisting of GP130, IL6R, and constitutively active IL7R with the M452L mutation (G6/7R).</p><p><strong>Results: </strong>TNF-NTF CAR-T cells efficiently lysed TNF-expressing leukemia cells <i>in vitro</i>, while showing limited antitumor efficacy <i>in vivo</i> due to poor expansion and persistence. Activated T cells upregulate TNF, which was recognized by TNF-NTF CAR-T cells and led to fratricide. Genetic knockout (KO) of <i>TNF</i> significantly enhanced the viability and proliferation of TNF-NTF CAR-T cells, while slightly reducing their cytotoxic activity. In addition, ectopic expression of G6/7R improved the effector function of TNF-NTF CAR-T cells through constitutive activation of janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling. The G6/7R-expressing <i>TNF</i>-KO TNF-NTF CAR-T cells exhibited superior persistence and durable antileukemic efficacy <i>in vivo</i> compared with parental CAR-T cells. We also confirmed that TNF-NTF CAR-T cells can target primary AML cells, including a leukemia-initiating population with colony-forming capacity. Unlike CD33, targeting TNF-NTF did not show cytotoxicity against normal hematopoietic stem/progenitor cells. Finally, we demonstrated the curative efficacy of G6/7R <i>TNF</i>-KO TNF-NTF CAR-T cells against TNF-expressing ovarian tumor cells <i>in vivo</i>.</p><p><strong>Conclusions: </strong>Our studies highlight TNF-NTF as a promising cell surface target for CAR-T cell therapy that can be applied to AML as well as solid tumors.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12258316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637056","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":"T cell-specific non-viral DNA delivery and in vivo CAR-T generation using targeted lipid nanoparticles.","authors":"Jaime Fernández Bimbo, Eline van Diest, Daniel E Murphy, Ator Ashoti, Martijn J W Evers, Suneel A Narayanavari, Diana Pereira Vaz, Hanneke Rijssemus, Christina Zotou, Nadine Saber, Zhiyong Lei, Peter Mayrhofer, Maurits Geerlings, Raymond Schiffelers, Jacek Lubelski","doi":"10.1136/jitc-2025-011759","DOIUrl":"10.1136/jitc-2025-011759","url":null,"abstract":"<p><strong>Background: </strong>Ex vivo chimeric antigen receptor (CAR)-T therapies have revolutionized cancer treatment. However, treatment accessibility is hindered by high costs, long manufacturing times, and the need for specialized centers and inpatient care. Strategies to generate CAR-T cells in vivo have emerged as a promising alternative that could bypass CAR-T manufacturing bottlenecks. Most current in vivo CAR-T approaches, while demonstrating encouraging preclinical efficacy, rely on transient messenger RNA (mRNA) delivery or viral vectors which both have limitations in terms of efficiency, durability, and scalability. To address these challenges, we developed a novel DNA-based targeted lipid nanoparticle (LNP) which we termed NCtx.</p><p><strong>Methods: </strong>Minicircle DNA (mcDNA) encoding a CAR construct and SB100x transposase mRNA were encapsulated within a novel lipid formulation which was functionalized with T cell-specific anti-CD7 and anti-CD3 binders. In vitro, we evaluated T cell specificity, mcDNA and mRNA transfection efficiency, transposon-mediated CAR integration and functionality of the resulting CAR-T cells. In vivo efficacy was assessed in peripheral blood mononuclear cell and CD34⁺ stem cell humanized murine xenograft models of B cell leukemia.</p><p><strong>Results: </strong>In vitro, NCtx displayed high specificity and transfection efficiency with both mcDNA and mRNA in primary T cells. Transposase mRNA facilitated genomic integration of the CAR gene, leading to the generation of stable CAR-T cells that exhibited antigen-specific cytotoxicity and cytokine release. In vivo, a single intravenous dose of NCtx induced robust CAR-T cell generation resulting in effective tumor control and significantly improved survival in two distinct xenograft models.</p><p><strong>Conclusions: </strong>Our findings demonstrate for the first time that targeted LNPs can be employed for efficient DNA delivery to T cells in vitro and in vivo. We show that when combined with transposase technology, this LNP-based system can efficiently generate stable CAR-T cells directly in vivo, inducing potent and durable antitumor responses. NCtx represents a novel non-viral gene therapy vector for in vivo CAR-T therapy, offering a scalable and potentially more accessible alternative to traditional approaches in CAR-T cell generation.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12258353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637057","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":"Pretreatment and on-treatment ctDNA and tissue biomarkers predict recurrence in patients with stage IIIB-D/IV melanoma treated with adjuvant immunotherapy: CheckMate 915.","authors":"Georgina V Long, Hao Tang, Keyur Desai, Sheen Wang, Michele Del Vecchio, James Larkin, Corey Ritchings, Shu-Pang Huang, Jonathan Baden, David Balli, Han Chang, Gina Fusaro, Daniel Tenney, Sonia Dolfi, Jeffrey Weber","doi":"10.1136/jitc-2025-012034","DOIUrl":"10.1136/jitc-2025-012034","url":null,"abstract":"<p><strong>Purpose: </strong>CheckMate 915 (NCT03068455) compared adjuvant nivolumab monotherapy versus combination nivolumab+ipilimumab in patients with resected stage III/IV melanoma. This exploratory analysis was performed to identify biomarkers that correlate with benefit from adjuvant immunotherapy.</p><p><strong>Patients and methods: </strong>1,844 patients received nivolumab 480 mg every 4 weeks or nivolumab 240 mg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks. Tumor and peripheral biomarkers were evaluated, including tumor-informed circulating tumor DNA (ctDNA) at postresection baseline and on-treatment, for their association with recurrence-free survival and distant metastases-free survival.</p><p><strong>Results: </strong>Biomarker analyses were conducted in 60-96% of the intention-to-treat population. ctDNA positivity at baseline (seen in 16.2% of patients) and on-treatment was associated with higher risk of recurrence than ctDNA negativity (HR, 1.97; 95% CI, 1.57 to 2.46), with a high specificity (87%) and modest sensitivity (39%). ctDNA status, tumor mutational burden (TMB) status (TMB < or ≥350 mutations/tumor) and interferon gamma-RNA signature score (< or ≥median) evaluated together, as well as ctDNA status with tumor CD8 or cell programmed death ligand 1 expression, were more predictive of survival than ctDNA alone. Tumor bulk RNA-seq expression patterns identified gene expression at baseline associated with recurrence.</p><p><strong>Conclusions: </strong>This study represents the largest assessment of ctDNA and other baseline tumor and peripheral biomarkers for predicting recurrence-free survival in patients with resected melanoma receiving adjuvant immunotherapy. ctDNA alone and in combination with more established biomarkers predicted recurrence-free and distant metastasis-free survival and has potential utility for assessing and monitoring the risk of recurrence in patients with resected melanoma treated with immunotherapy in the adjuvant setting.</p><p><strong>Trial registration number: </strong>NCT03068455.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12248205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144618101","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":"Commentary on differential impact of TIM-3 ligands on NK cell function.","authors":"Rieneke van de Ven","doi":"10.1136/jitc-2025-012125","DOIUrl":"10.1136/jitc-2025-012125","url":null,"abstract":"<p><p>T-cell immunoglobin and mucin-domain containing molecule 3 (TIM-3) is an immune checkpoint receptor and a target for immune checkpoint blockers (ICBs). Unfortunately in human patients the success rate of anti-TIM-3 ICB remains rather limited. Multiple immune cells express TIM-3 and their functioning is affected by receptor-ligand interactions. Four ligands of TIM-3 have been identified: high-mobility group protein B1, galectin-9, phosphatidylserine and carcinoembryonic antigen cell adhesions molecule 1. Wang <i>et al</i> investigated which of these ligands interact with TIM-3 on natural killer (NK) cells, impairing NK cytotoxicity and proliferation. They demonstrated that galectin-9 was able to inhibit NK cell cytotoxicity in a TIM-3-dependent manner, and to block NK cell proliferation through interaction with CD44 on NK cells. They also showed that in head and neck squamous cell carcinoma (HNSCC), a high TIM-3+NK cell transcriptional signature was linked to poor survival probability, specifically in HNSCC caused by human papillomavirus infection. This study enhances our understanding of why anti-TIM-3 ICB may not be so effective as monotherapy and provides leads toward rational design of combination strategies and patient selection.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12248188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144618100","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":"Shared epitopes create safety and efficacy concerns in several cancer vaccines.","authors":"Guillaume Kellermann, Baharia Mograbi, Paul Hofman, Patrick Brest","doi":"10.1136/jitc-2025-012217","DOIUrl":"10.1136/jitc-2025-012217","url":null,"abstract":"<p><p>Tumor-associated antigens (TAAs) are the targets of several therapeutic cancer vaccines. However, many TAAs contain epitopes identical to unintended targets, creating shared epitopes with other human proteins in normal tissues. Moreover, for some TAAs like ASCL2, KLK2, TPTE, CLDN6, and PSMA, the off-targeted proteins are often expressed at a higher level in healthy tissues than the target in cancer, potentially impacting both the safety and the efficacy of T cell immunity. Altogether, our analysis indicates a suboptimal design of several cancer vaccines currently in clinical development: ATP128, BNT111, BNT112, BNT116, INO-5401. We recommend that next-generation cancer vaccines should integrate rigorous epitope filtering strategies to eliminate shared sequences in TAAs.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12248204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144618102","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":"Enhancing outcomes in medically inoperable early-stage NSCLC with gut-targeted antibiotics and stereotactic body radiotherapy: results from a randomized pilot study.","authors":"Steven Joel Feigenberg, Francesca Costabile, Ceylan Tanes, Kyle Bittinger, Roderick O'Connor, Divyansh Agarwal, Giorgos Skoufos, Silavano Salaris, Artemis Hatzigeorgiou, Nektarios Kostopoulos, Shane Lloyd, Cole Friedes, Lisha Chen, Nikhil Yegya-Raman, Keith Cengel, William Levin, Bakir Valentić, Tyler Quarton, Alexander A Shestov, Abigail Berman, Jeffrey Bradley, Amit Maity, Costantinos Koumenis, Edgar Ben-Josef, Andrea Facciabene","doi":"10.1136/jitc-2024-011356","DOIUrl":"10.1136/jitc-2024-011356","url":null,"abstract":"<p><strong>Background: </strong>Gut microbiota modulation is an emerging strategy to improve cancer therapy outcomes. This study evaluated the safety and therapeutic potential of combining oral vancomycin-a non-absorbed, gut-restricted antibiotic with primary activity against gram-positive bacteria-with stereotactic body radiotherapy (SBRT) in early-stage non-small cell lung cancer (NSCLC). The underlying hypothesis was that vancomycin-induced changes in gut microbiota could enhance the antitumor effects of SBRT.</p><p><strong>Methods: </strong>We conducted a randomized, open-label pilot study in patients with early-stage NSCLC. Patients received oral vancomycin (125 mg, four times daily for 5 weeks, starting 1 week prior to SBRT). Safety, progression-free survival (PFS), overall survival (OS), gut microbiota composition, gut metabolome, and immune responses were evaluated.</p><p><strong>Results: </strong>The combination of vancomycin and SBRT was well tolerated, with no grade 3 or 4 adverse events reported. Vancomycin treatment selectively depleted certain bacterial strains while enriching others, leading to significant restructuring of the gut microbiota and alterations in the gut metabolome, including reductions in short-chain fatty acids and shifts in other important immunomodulatory metabolites. These changes were associated with dendritic cell and T cell activation, suggesting enhanced systemic immune engagement. Patients receiving vancomycin showed improved outcomes, with a PFS HR of 0.42 (95% CI 0.18 to 0.96; p=0.049) and OS HR of 0.38 (95% CI 0.14 to 0.99; p=0.033), compared with controls.</p><p><strong>Conclusions: </strong>This pilot study demonstrates that gut microbiome modulation using a gram-positive-targeting, gut-restricted antibiotic in combination with SBRT is safe and may improve clinical outcomes in early-stage NSCLC. These findings support further investigation of targeted microbiome modulation strategies as adjuvants to immunogenic therapies like radiation.</p><p><strong>Trial registration number: </strong>NCT03546829.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12258320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608402","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":"Oncolytic adenovirus serotype 35 mediated tumor growth suppression <i>via</i> efficient activation of antitumor immunity.","authors":"Ryosuke Ono, Sora Tokuoka, Masashi Tachibana, Ken J Ishii, Fuminori Sakurai, Hiroyuki Mizuguchi","doi":"10.1136/jitc-2022-006558","DOIUrl":"10.1136/jitc-2022-006558","url":null,"abstract":"<p><strong>Background: </strong>Oncolytic adenoviruses (OAds) mediate superior antitumor effects both by inducing direct oncolysis and activating antitumor immunity. Previously, we developed a novel OAd fully composed of human adenovirus serotype 35 (OAd35). OAd35 efficiently killed a variety of human tumor cells; however, OAd35-mediated activation of antitumor immunity remains to be evaluated. In this study, we examined whether OAd35-induced activation of immune cells contributes to the antitumor effects of OAd35.</p><p><strong>Methods: </strong>Tumor infiltration and activation of immune cells following intratumoral administration of OAd35 in tumor-bearing immune-competent and nude mice were analyzed. The involvement of immune cells in the tumor growth-suppression effects of OAd35 was evaluated in asialo GM1 (aGM1)⁺ cell-depleted mice. The key signals for the OAd35-mediated tumor infiltration of NK cells were examined in interferon (IFN) alpha and beta receptor subunit 1 (IFNAR1) knockout and toll-like receptor 9 knockout mice.</p><p><strong>Results: </strong>OAd35 efficiently induced tumor infiltration of activated natural killer (NK) cells and T cells after intratumoral administration in B16 tumor-bearing mice. Depletion of aGM1⁺ cells, including NK cells and a portion of CD8⁺ T cells, significantly hindered the OAd35-mediated tumor growth suppression in C57BL/6J wild-type mice and BALB/c nude mice. In IFNAR1 knockout mice, OAd35-induced tumor infiltration of activated NK cells and OAd35-mediated tumor growth suppression were significantly attenuated.</p><p><strong>Conclusions: </strong>These data described above suggested that immune cells, including aGM1⁺ cells, contributed to the antitumor effects of OAd35. OAd35 significantly promoted activation and tumor infiltration of NK cells. The type-I IFN signal was crucial for the OAd35-mediated tumor infiltration, activation of NK cells, and tumor growth suppression. These findings suggest that OAd35 is a promising cancer immunotherapy agent via its enhancement of the antitumor activities of immune cells.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12258317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608404","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}