Journal for Immunotherapy of Cancer最新文献

{"title":"Deep learning-based CT model for non-invasive prediction of tertiary lymphoid structures in pancreatic cancer: a multicenter study with prospective validation in an immunochemotherapy cohort.","authors":"Haopeng Yu, Xiaoying Li, Xuan Cheng, Yan Deng, Yuqi Wang, Yu Li, Bingjie Liu, Zixing Huang, Dan Cao","doi":"10.1136/jitc-2026-015705","DOIUrl":"10.1136/jitc-2026-015705","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. Tertiary lymphoid structures (TLS) have emerged as key components of the tumor immune microenvironment, associated with improved survival and enhanced immunotherapy response. However, non-invasive detection of TLS remains a significant clinical challenge.</p><p><strong>Objective: </strong>This multicenter study aimed to develop and validate a deep learning-based CT model to noninvasively predict TLS status and evaluate its prognostic and predictive value across surgical, non-surgical, and prospective immunochemotherapy cohorts.</p><p><strong>Materials and methods: </strong>We enrolled 223 surgically resected patients with PDAC from two centers for model development and 82 non-surgical patients for clinical validation. A ResNet50-based deep learning network (DLN) was trained to predict TLS status from preoperative contrast-enhanced CT. The locked model was evaluated in 44 patients from a prospective immunochemotherapy trial (ChiCTR2000032293), with pathology-anchored verification, outcome assessment, and spatial immune profiling via cyclic multiplex tyramide signal amplification.</p><p><strong>Results: </strong>The DLN achieved area under the curves (AUCs) of 0.987, 0.937, and 0.853 in training, internal, and external validation cohorts. In the non-surgical cohort (n=82), DLN-predicted TLS-positive patients had significantly longer overall survival (OS; median 19 vs 7 months; HR=3.611, p<0.0001). In the prospective cohort, pathology-anchored verification yielded an AUC of 0.929 (specificity=1.000). DLN-high patients demonstrated superior objective response rate (90.0% vs 26.5%, p=0.001), progression-free survival (PFS) (median 13.1 vs 5.3 months, p<0.001), and OS (median 17.6 vs 8.7 months, p<0.001). The DLN score independently predicted OS (HR=0.052, p<0.001) and PFS (HR=0.079, p<0.001) in multivariable analysis. The DLN score was orthogonal to programmed death-ligand 1 (PD-L1) expression (rho=0.011, p=0.946) but correlated with dendritic cell-T helper cell spatial interactions (p=0.037) and T helper-B cell spatial co-localization (rho=0.307, p=0.043)-two hallmarks of functional TLS architecture-and inversely with tumor cell density (rho=-0.399, p=0.007).</p><p><strong>Conclusion: </strong>This DLN-based CT model reliably predicts TLS status in PDAC with prospectively validated prognostic and predictive value in immunochemotherapy, biological grounding in TLS-associated spatial immune architecture, and orthogonal predictive value to PD-L1, supporting a complementary biomarker strategy for immunotherapy patient selection.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13583746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956022","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":"Tumor cell-expressed OX40L enhances the efficacy of PD-1 axis blockade in non-small cell lung cancer.","authors":"Carmen Fernández-Luna, Javier Baena, Antonio Calles, Mónica Antoñanzas-Basa, Yolanda Lage Alfranca, Xabier Mielgo, Maria Sereno, Raquel Cervera, Luis Cabezon-Gutierrez, Ana López, Judit Rubio, Esther Conde, Fernando Lopez-Rios, Luis Alvarez-Vallina, Karmele Valencia, Luis M Montuenga, Gorka Ruiz De Garibay, Magdalena Molero, Vera Adradas, Daniel Curto-Aguilera, Melina Peressini, Esther Carrera-Elvira, Daniel Ballesteros, Adrián Portillo-Fernández, Teresa Lopez-Cárdenas, Cristina Serrano-Gómez, Helena Bote, Javier Torres-Jiménez, Alberto Cruz-Bermúdez, Mariano Provencio, Luis Paz-Ares, Estela Sánchez-Herrero, Jon Zugazagoitia","doi":"10.1136/jitc-2026-016133","DOIUrl":"10.1136/jitc-2026-016133","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors have transformed non-small cell lung cancer (NSCLC) treatment. Understanding the tumor-immune interactions that dictate sensitivity to PD-1 blockade is essential for improving outcomes and optimizing immunotherapy personalization.</p><p><strong>Methods: </strong>We performed compartment-specific (tumor/immune) spatial proteomic profiling (GeoMx) on a discovery cohort of 104 patients with advanced, PD-L1-high (tumor proportion score ≥50%) NSCLC treated with first-line pembrolizumab. Identified markers were further assessed using orthogonal methods in two independent early-stage NSCLC cohorts treated with neoadjuvant/perioperative chemo-immunotherapy: (a) NADIM trial (n=36) with bulk RNA-seq and (b) NeoITX_H12O cohort (N=41) with quantitative immunohistochemistry. Potential baseline prognostic value without immunotherapy was evaluated in the TCGA dataset (N=940). Functional validation was assessed using in vitro and in vivo (nude and syngeneic) models.</p><p><strong>Results: </strong>We identified tumor-cell OX40L, but not immune-cell OX40L, as the single marker significantly associated with prolonged progression-free survival (PFS) and overall survival under single-agent pembrolizumab in patients with PD-L1-high tumors. Spatially resolved analysis linked tumor-intrinsic OX40L to an active immune microenvironment with increased antigen presentation. In both neoadjuvant/perioperative cohorts, high OX40L levels in residual tumors from patients with non-pathological complete response were associated with superior PFS. Conversely, no significant association with survival was observed in the immunotherapy-naïve TCGA cohort. Functional studies confirmed that OX40L-expressing NSCLC cells directly co-stimulate T cells in vitro and significantly enhance anti-PD-1 efficacy in vivo (p=0.0005), without affecting intrinsic tumor growth.</p><p><strong>Conclusions: </strong>OX40L expressed by tumor cells contributes to an enhanced efficacy of PD-1 blockade in patients with NSCLC. These findings may open new therapeutic avenues and potentially contribute to improving immunotherapy personalization in this disease.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13583861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955691","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":"PLP1-triggered NOT gate to address neurotoxicity risk of PSMA-targeted prostate cancer therapy.","authors":"Sanam Shafaattalab, Alexander Partin, Aaron Winters, Richele Bruno, Vasantika Suryawanshi, Jushen Liang, Ryan Elshimali, Nicolas G Pedroncelli, Chawita Netirojjanakul, Timothy P Riley, Jingli A Zhang, Alexander Kamb","doi":"10.1136/jitc-2026-015068","DOIUrl":"10.1136/jitc-2026-015068","url":null,"abstract":"<p><strong>Background: </strong>On-target, off-tumor toxicity is a recurring challenge for solid tumor therapeutics targeted to antigens preferentially expressed on malignant cells. Prostate-specific membrane antigen (PSMA) is a tumor-associated antigen that is expressed on the healthy prostate and is generally upregulated in prostate cancer. It is also detected via RNA-Seq in the central and peripheral nervous system (CNS and PNS) at levels that can exceed those in the prostate itself. The CNS/PNS expression of PSMA has been largely ignored in the oncology field, and it is possible that therapeutics targeting PSMA have limited access to antigens in the nervous system. However, many PSMA-targeted therapeutics that are active in the clinic induce substantial neurotoxicity, in some cases, even treatment-associated fatalities.</p><p><strong>Methods: </strong>To protect PSMA-expressing neural tissues from on-target, off-tumor toxicity, we applied a synthetic cellular NOT gate that uses a LIR-1-based inhibitory receptor. We selected the NOT gate target antigen by searching genomic databases for a surface protein co-expressed with PSMA in the brain.</p><p><strong>Results: </strong>Here, we demonstrate that proteolipid protein 1 (PLP1), a protein expressed on the surface of oligodendrocytes and Schwann cells, is co-expressed with PSMA in the CNS and PNS. A NOT gate construct (PSMA | PLP1 Tmod) protects human oligodendrocytes in vitro from the cytotoxicity of a PSMA CAR. Though PSMA is not expressed in mouse brains at high levels, we show that PLP1 CARs induce toxicity in mice, consistent with the possibility that CNS/PNS expression of the target of an immunotherapeutic poses a serious risk. This toxicity is mitigated by a Tmod construct (PLP1 | PLP1), in which a PLP1 CAR substitutes for a PSMA CAR, a proof of principle that circumvents the problematic expression pattern of PSMA in the mouse.</p><p><strong>Conclusions: </strong>Together, these findings not only highlight some of the potential risks and benefits of immunotherapy for solid tumors regarding antigens expressed in the brain, but also suggest a specific solution for PSMA CAR-Ts.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13583702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955680","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":"Neoadjuvant chemoimmunotherapy with afatinib for locally advanced head and neck squamous cell carcinoma (neoCHANCE-2): an open-label, single-arm, phase 2 study.","authors":"Zhigong Wei, Huijiao Chen, Dejuan Wang, Leyu Li, Yiyan Pei, Huaju Yang, Feng Wang, Jing Jin, Yiqiao Luo, Fei Chen, Jun Liu, Xingchen Peng","doi":"10.1136/jitc-2025-014100","DOIUrl":"10.1136/jitc-2025-014100","url":null,"abstract":"<p><strong>Background: </strong>While immune checkpoint inhibitor-based neoadjuvant therapy shows promise in locally advanced head and neck squamous cell carcinoma (LA-HNSCC), the optimal regimen has yet to be established. We report, for the first time, a neoadjuvant treatment that combines chemotherapy with dual blockade of the programmed cell death protein 1 and epidermal growth factor receptor pathways in LA-HNSCC.</p><p><strong>Methods: </strong>In this single-arm phase 2 trial (NCT05516589) conducted at a single academic center, patients with LA-HNSCC were enrolled and received two cycles of tislelizumab and TP chemotherapy (nab-paclitaxel and cisplatin), administered on day 1 of each 3-week cycle, along with afatinib during the interval between chemoimmunotherapy cycles, followed by surgical resection. The primary endpoint was the complete pathologic response (pCR) rate. Secondary endpoints included the major pathologic response (MPR) rate, objective response rate (ORR), event-free survival, overall survival (OS), and safety.</p><p><strong>Results: </strong>A total of 40 patients were enrolled and received neoadjuvant treatment, 32 of whom proceeded to surgical resection; among these patients, the pCR rate was 40.6% (95% CI 23.7% to 59.4%). The ORR was 82.5% (95% CI 67.2% to 92.7%). The 1-year OS rate was 97.3% (95% CI 92.2% to 100%). The most common treatment-related adverse event (TRAE) of grade 3-4 was lymphopenia (5/40, 12.5%). No grade 5 TRAEs leading to death occurred, and no treatment-related surgical delays were observed. In the prespecified exploratory biomarker analysis, increased cytotoxic T lymphocytes and B cells in the tumor immune microenvironment may be associated with pCR/MPR. Neoadjuvant treatment induced a significant increase in the proportion of peripheral CD8+T cells, along with a reduction in B cells.</p><p><strong>Conclusions: </strong>We report, for the first time, the promising efficacy and acceptable safety profile of neoadjuvant chemoimmunotherapy combined with afatinib in patients with LA-HNSCC. Neoadjuvant treatment potentially induced an immune-enhanced tumor microenvironment. Further evaluation in large-scale clinical trials with longer follow-up periods is needed.</p><p><strong>Trial registration number: </strong>NCT05516589.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13583779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955339","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":"PRKX-mediated stabilization of PD-L1 characterizes an immunosuppressive gastric cancer subtype.","authors":"Qiyue Wang, Yinqi Chen, Dongdong Huang, Hui Wu, Tongshuo Wu, Yuejun Han, Chengzhi Cai, Jingjie Li, Yifei Shao, Jian Ruan, Haiping Jiang","doi":"10.1136/jitc-2026-015452","DOIUrl":"10.1136/jitc-2026-015452","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer (GC) derives limited benefit from immunotherapy, with clinical responses observed in only a minority of patients. Increasing evidence suggests that heterogeneity within the tumor immune microenvironment (TME) is a critical determinant of immunotherapeutic efficacy, highlighting the need for precise immune stratification and the identification of molecular biomarkers that shape the TME.</p><p><strong>Methods: </strong>We integrated single-cell transcriptomic data from our cohort and public datasets to characterize immune microenvironment heterogeneity in GC. Functional experiments were performed using in vitro assays and in vivo mouse models to investigate the molecular mechanisms regulating immune exhaustion. Clinical relevance was evaluated using tumor specimens from patients with GC receiving anti-programmed cell death protein 1 (PD-1) therapy. Survival analyses and biomarker evaluation were conducted to assess the prognostic and predictive value of candidate markers.</p><p><strong>Results: </strong>We identified two distinct GC immune microenvironment subtypes: the immunosuppressive (GC1) and the immune-activated (GC2). PRKX was identified as a key regulator associated with immune heterogeneity and exhaustion. Clinically, a high density of PanCK⁺ PRKX⁺ PD-L1⁺ tumor cells was significantly associated with poor prognosis and served as a robust biomarker predicting 5-year survival in patients treated with anti-PD-1 therapy. Mechanistically, PRKX phosphorylates programmed death-ligand 1 (PD-L1) at T285, promoting YWHAE recruitment and preventing UBE2M-mediated ubiquitination and degradation, thereby stabilizing PD-L1 protein. Through this phosphorylation-dependent regulation of PD-L1 stability, PRKX suppresses CD8⁺ T-cell cytotoxicity, promotes immune exhaustion, and limits the efficacy of anti-PD-1 therapy in vivo. Therapeutically, lipid nanoparticle-mediated delivery of PRKX-targeting siRNA effectively suppressed PRKX expression and synergized with anti-PD-1 therapy to enhance antitumor efficacy.</p><p><strong>Conclusion: </strong>PRKX drives immune exhaustion in the GC1 subtype by stabilizing PD-L1 through phosphorylation-dependent inhibition of ubiquitination, thereby promoting immune evasion. Targeting PRKX represents a potential strategy to overcome resistance to anti-PD-1 therapy, and PRKX expression may serve as a prognostic biomarker to guide immunotherapy in GC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13561019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148919780","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":"HIF1A⁺CSF3R⁺ neutrophils-dominated hypoxic niche induced metabolic reprogramming for neoadjuvant therapy resistance in NSCLC.","authors":"Yaoyao Zhou, Ziyun Liu, Parhat Kaysar, Yuxi Han, Yijian Ma, Xiaozhou Yu, Bo Ni, Zuoyu Chen, Yongjie Xie, Haoling Zhang, Yueguo Li","doi":"10.1136/jitc-2026-014772","DOIUrl":"10.1136/jitc-2026-014772","url":null,"abstract":"<p><strong>Background: </strong>Non-small cell lung cancer (NSCLC) is one of the frequently occurring cancers characterized by molecular heterogeneity and multiple immune cell infiltration patterns, which are associated with treatment sensitivity and resistance. However, the specific microenvironmental cells and their mechanisms that lead to treatment resistance in patients need to be explored in greater depth.</p><p><strong>Methods: </strong>On the basis of patients receiving neoadjuvant therapy in our center, a multicenter, multicohort NSCLC spatial transcriptome, single-cell transcriptome, T-cell receptor repertoire sequencing, bulk RNA transcriptome, phosphorylated proteome, genome mutation, and clinical data were included for a comprehensive assessment of the therapeutic and prognostic impact of HIF1A⁺ CSF3R⁺ neutrophils in NSCLC. In vitro experiments validated the functional phenotype of HIF1A⁺ CSF3R⁺ neutrophils and co-localization interactions with other cellular subpopulations. Gradient boosting machine (GBM) constructed region of interest (ROI) models for evaluation. Computer-aided drug design (CADD) was used to predict targeted small molecule drugs, and in vivo mouse models were constructed to assess the effectiveness of the combination treatment regimen.</p><p><strong>Results: </strong>Centered on HIF1A⁺ CSF3R⁺ neutrophils, recruited exhausted T cells and stromal cells form a hypoxic niche within the tumor region, which was enriched in non-response patients. ROI composed of these specific cellular subpopulations, associated with senescence and glycolysis, accurately predicting NSCLC progression, prognosis, and microenvironment composition. CADD analysis identified that platycodin-D2 specifically targeted CSF3R, reducing HIF1A expression and inhibiting neutrophil activity. Combining navitoclax, platycodin-D2 with anti-programmed cell death protein 1 (PD-1) significantly suppressed tumor proliferation and improved the immunosuppressive microenvironment.</p><p><strong>Conclusion: </strong>Our study emphasized the role of HIF1A⁺ CSF3R⁺ neutrophils in immunotherapeutic resistance of NSCLC, constructed a microenvironmental immune dysregulation network in a hypoxic ecological niche with HIF1A⁺ CSF3R⁺ neutrophils as the center. Platycodin-D2 specifically targeted HIF1A⁺ CSF3R⁺ neutrophils, enhancing the efficacy of anti-PD-1 therapy in NSCLC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13561000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912182","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":"Camrelizumab plus nimotuzumab as second-line therapy for advanced esophageal squamous cell carcinoma: a multicenter phase II study.","authors":"Jin Xia, Xiangrui Meng, Guozhong Jiang, Yonggui Hong, Yinghua Ji, Cailing Wang, Xiuli Yang, Yu Meng, Weijie Zhang, Zhiquan Luo, Donghai Cui, Junsheng Wang, Zhengzheng Shan, Lulu Guan, Yao Lu, Xu Yang, Chao Ren, Xiangli Meng, Hongli Wang, Ling Shen, Yaosheng Zhang, Zongqiang Kou, Taiying Lu, Qingxia Fan, Michael Quante, Tongjin Zhao, Shenglei Li, Feng Wang","doi":"10.1136/jitc-2026-015887","DOIUrl":"10.1136/jitc-2026-015887","url":null,"abstract":"<p><strong>Background: </strong>Therapeutic options for advanced esophageal squamous cell carcinoma (ESCC) after first-line failure remain limited, particularly in patients previously exposed to immune checkpoint inhibitors (ICIs). We evaluated the efficacy, safety, and exploratory biomarker correlates of camrelizumab, an ICI, combined with nimotuzumab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, as second-line therapy for ESCC.</p><p><strong>Methods: </strong>In this multicenter, single-arm, phase II study, patients with advanced ESCC who progressed after first-line therapy received camrelizumab (200 mg every 2 weeks) plus nimotuzumab (400 mg weekly). The primary endpoint was the objective response rate (ORR).</p><p><strong>Results: </strong>Between November 2021 and December 2024, 46 patients were enrolled. The confirmed ORR was 32.6% (15/46; 95% CI 19.5 to 48.0) and the disease control rate was 82.6% (38/46; 95% CI 68.6 to 92.2). Median progression-free survival (PFS) was 9.13 months (95% CI 5.95 to 9.76), and median overall survival (OS) was 12.62 months (95% CI 9.40 to 15.01). Clinical activity was observed across subgroups, including immunotherapy-naïve and previously treated patients (ORR 32.0% vs 33.3%). Patients with EGFR amplification demonstrated a higher ORR (47.1% vs 24.0%) and longer median OS (13.17 vs 9.99 months). Among patients with M1 disease (n=39), the ORR was 30.8% (95% CI 17.0 to 47.6), the median PFS was 8.48 months (95% CI 5.95 to 9.59), and the median OS was 12.55 months (95% CI 7.95 to 14.88). Treatment-related adverse events occurred in 80.4% of patients, with grade ≥3 events in 8.7%. Exploratory analyses suggested that <i>MUC16</i> mutations were associated with lower ORR (8.3% vs 46.4%, p=0.030), <i>NOTCH3</i> mutations with prolonged survival (median PFS not reached vs 8.21 months, HR 0.20, p=0.015; median OS not reached vs 10.58 months, HR 0.22, p=0.026), and <i>MTAP</i> deletions with shorter PFS (3.71 vs 9.49 months, HR 3.18, p=0.005).</p><p><strong>Conclusions: </strong>Camrelizumab combined with nimotuzumab demonstrated encouraging antitumor activity and a manageable safety profile as second-line therapy for advanced ESCC.</p><p><strong>Trial registration number: </strong>NCT03766178.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13561002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912111","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":"Anti-CMV IgG titer determines organ-specific protection toward immune checkpoint blockade-induced toxicities.","authors":"Gusztav Milotay, Martin Little, Sophie MacKay, Dylan Patrick Browne Muldoon, An-Nhi Huynh, Andrea Farkas, Shawn Sun, Guangyi Niu, Orion Tong, Chelsea A Taylor, Robert Watson, Harry Potts, Mark R Middleton, Paul Klenerman, Benjamin Fairfax","doi":"10.1136/jitc-2026-016050","DOIUrl":"10.1136/jitc-2026-016050","url":null,"abstract":"<p><strong>Background: </strong>Immune-related adverse events (irAEs) post-immune checkpoint blockade (ICB) are a leading cause of patient morbidity. Robust peripheral biomarkers of irAEs are required to improve patient stratification to existing treatment regimens, and these are currently lacking. Seropositivity for human cytomegalovirus (CMV) is associated with protection against severe (grade 3+) irAEs post-ICB; however, the impact of infection on systemic immunity is highly variable. Here, in a prospectively recruited pan-cancer ICB-treated cohort (n=472 patients), we investigate a novel relationship between the relative baseline titer of anti-CMV IgG antibody and organ-specific protection against irAEs.</p><p><strong>Methods: </strong>Peripheral blood samples were collected from 472 patients prior to and following one cycle of ICB. CMV serotyping was performed on plasma, while flow cytometry and single-cell RNA/V(D)J sequencing were performed on peripheral blood mononuclear cells. Bulk RNA-sequencing was performed on sorted CD8⁺ T cells. Serological and phenotyping data were integrated with long-term clinical follow-up of response and irAEs.</p><p><strong>Results: </strong>In CMV seropositive patients, whereas anti-CMV IgG antibody level demonstrates stability over years, high pretreatment titer is independently associated with reduced all-organ grade 3+ irAEs. This pan-organ association subdivides into organ-specific effects; protection against non-colitis irAEs being observed only in those with an above median titer of anti-CMV IgG antibody (P_{High titer vs CMV}-=2.1×10^-4), whereas CMV-related protection against colitis is unrelated to titer (P_{Low titer}=0.0012, P_{High titer}=0.0031). We demonstrate that anti-CMV IgG antibody titer is robustly coupled to peripheral immune subset composition, with higher anti-CMV IgG titer associated with elevated CD4⁺ and CD8⁺ T cell cytotoxicity and effector cell expansion. Conversely, CMV seropositivity is associated with generally reduced circulating T_regs cells irrespective of titer. Furthermore, we find exacerbated T cell receptor repertoire skewing toward the largest clones in High Titer individuals, with reduced survival of these clones following ICB treatment.</p><p><strong>Conclusions: </strong>This work reinforces the importance of CMV in modulating ICB-induced irAEs, revealing a complex relationship between the degree of humoral anti-CMV immunity and organ-specific protection, while further highlighting the clinical utility of CMV serology in predicting ICB-induced irAEs.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13560976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906078","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":"Anti-CTLA-4 antibody potentiates the antitumor effect of armed oncolytic virus OVM18 via enhancing intratumoral IL-18R1⁺CD8⁺ T cells.","authors":"Xueying Lin, Jifu Zhang, Zhen Fan, Jingyu Yang, Shiming Yi, Hanrui Wang, Huizhen Zou, Linyi Hu, Wenbo Zhu, Yuan Lin, Jun Hu, Jing Cai, Guangmei Yan, Jiankai Liang","doi":"10.1136/jitc-2025-014273","DOIUrl":"10.1136/jitc-2025-014273","url":null,"abstract":"<p><strong>Background: </strong>Oncolytic virus M1 encoding a mutant IL-18 decoy (OVM18) represents a novel virotherapy that integrates selective oncolysis with localized activation of the IL-18 pathway. However, the heterogeneity of therapeutic responses suggests that host immune determinants influence its efficacy.</p><p><strong>Methods: </strong>To elucidate these determinants, we performed integrated immune profiling using bulk and single-cell transcriptomics, flow cytometry, and T cell receptor (TCR) repertoire analyses. The functional contribution of specific immune subsets was validated using Batf3⁻/⁻ mice and FTY720-mediated lymphocyte trafficking blockade. Potential synergistic immunotherapies were identified through transcriptomic database screening and confirmed in tumor-bearing mice receiving combined OVM18 and immune checkpoint blockade.</p><p><strong>Results: </strong>We identified intratumoral IL-18R1⁺CD8⁺ T cells as an important effector population, whose IL-18R1 expression and intratumoral abundance positively correlate with OVM18 efficacy. Integrated single-cell RNA-sequencing and cytometry analyses revealed that IL-18R1⁺CD8⁺ T cells are clonally expanded, tumor antigen-enriched, polyfunctional cytotoxic T cells. Their generation requires conventional type 1 dendritic cells (cDC1)-dependent priming within tumor-draining lymph nodes, followed by trafficking into tumors to mediate antitumor responses. Notably, CTLA-4 blockade enhances cDC1-derived IL-12 and promotes IL-18R1⁺CD8⁺ T-cell expansion, thereby overcoming resistance to OVM18 therapy. Combination treatment with OVM18 and anti-CTLA-4 enhances intratumoral IL-18R1⁺CD8⁺ T cell infiltration, delays tumor progression, and prolongs survival in poor-responsive models.</p><p><strong>Conclusions: </strong>Our findings establish IL-18R1⁺CD8⁺ T cells as an important effector population in OVM18 therapy, thereby providing a strong rationale for combining OVM18 with CTLA-4 blockade to overcome therapeutic resistance and achieve durable antitumor responses.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13561005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906088","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":"Phase 1/1b open-label, first-in-human study of HER2×CD3×CD28 trispecific T-cell engager (SAR443216) in participants with R/R HER2-expressing solid tumors.","authors":"Ecaterina E Dumbrava, Do-Youn Oh, Min-Hee Ryu, Emiliano Calvo, Elena Garralda, Wei-Pang Chung, Li-Yuan Bai, Katerin Rojas, Ozlem Yildirim, Serena Masciari, Gu Mi, Lei Wang, Federico Rotolo, Sarah Gailhac, Elham Attieh, Pinar Kanlikilicer, Barbara Buday, Raymond Perez, Faiza Rharbaoui, Giovanni Abbadessa, Victor Moreno","doi":"10.1136/jitc-2025-014309","DOIUrl":"10.1136/jitc-2025-014309","url":null,"abstract":"<p><strong>Background: </strong>SAR443216 is an engineered human trispecific antibody that targets human epidermal growth factor receptor 2 (HER2)-positive (HER2+) cancer cells and activates T cells via co-engagement of cluster of differentiation (CD)3 and CD28. This first-in-human, dose-escalation study evaluated the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics of SAR443216 in participants with relapsed/refractory (R/R) HER2-expressing solid tumors.</p><p><strong>Methods: </strong>In this multicenter, open-label, non-randomized Phase 1 study (NCT05013554), SAR443216 was administered intravenously at dose levels (DLs) of 18-900 µg. Dose escalation occurred within participants using intraparticipant lead-in dosing (2-week and 3-week lead-in cohorts). The primary objective was to determine the maximum tolerated dose (MTD); secondary objectives included PK, immunogenicity, and preliminary clinical activity.</p><p><strong>Results: </strong>40 participants (n≥3 at each DL) were treated with SAR443216. The median treatment duration was ~8 weeks in both 2-week and 3-week lead-in cohorts. Nearly all participants (97.5%) had at least one treatment-emergent adverse event (TEAE), of which 45% were grade ≥3. Most frequent TEAEs were cytokine release syndrome (CRS, 50%), fever (35%), alanine aminotransferase elevation (32.5%), aspartate aminotransferase elevation (27.5%), and infusion-related reactions (IRRs, 27.5%). No severe CRS, IRRs, fever, or pulmonary and cardiac toxicities were observed. Disease control rates were 34.5% in the 2-week and 36.4% in the 3-week lead-in cohorts. Average duration of disease stabilization was 10.48 weeks. Median follow-up time was 3.43 weeks. No objective responses were observed. The MTD was not reached. Dose-dependent PK showed overall consistent PK profiles across DLs. SAR443216 induced serum proinflammatory cytokines and increased multiple T-cell activation markers in peripheral blood mononuclear cells, indicating T-cell activation and target engagement. However, no clear trend in T-cell abundance or activation was observed among tumor-infiltrating T cells or other immune cells.</p><p><strong>Conclusion: </strong>These findings indicate that SAR443216 treatment is feasible and well tolerated in participants with R/R HER2+solid tumors. Further evaluation is warranted to fully characterize the efficacy and safety of SAR443216.</p><p><strong>Trial registration number: </strong>NCT05013554.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13561007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906195","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}