Journal for Immunotherapy of Cancer最新文献

{"title":"Single-cell RNA sequencing of baseline PBMCs predicts ICI efficacy and irAE severity in patients with NSCLC.","authors":"Gyeong Dae Kim, So-I Shin, Pureum Sun, Jeong Eun Lee, Chaeuk Chung, Yea Eun Kang, Da Hyun Kang, Jihwan Park","doi":"10.1136/jitc-2025-011636","DOIUrl":"10.1136/jitc-2025-011636","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) have transformed treatment and have provided significant clinical benefits and durable responses for patients with advanced non-small cell lung cancer (NSCLC). However, only a small percentage of patients respond to ICI treatment, and immune-related adverse events (irAEs) leading to treatment discontinuation remain challenging. Despite the recognized need for biomarkers to predict both the efficacy of ICIs and the risk of irAEs, such biomarkers are yet to be clearly identified.</p><p><strong>Methods: </strong>In this study, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from 33 patients with NSCLC before ICIs treatment. To validate our findings, we reanalyzed public scRNA-seq data, conducted a cytometric bead array (CBA), and supported our findings with T-cell receptor sequencing.</p><p><strong>Results: </strong>While the immune response was more pronounced in patients with a favorable prognosis, the hypoxic pathway was more prominent in patients with primary resistance. Lymphocytes such as CD8 T cells, CD4 T cells, and natural killer cells were primarily involved in these pathways, with <i>PRF1</i> and <i>GZMB</i> expression showing strong associations with favorable prognosis. In contrast, irAEs were mainly linked to myeloid cells, such as monocytes and macrophages. As irAE severity increased, inflammation and the TNF-NFKB1 pathway were more prominent. Specifically, increased expression of <i>IL1B</i>, <i>CXCL8</i>, and <i>CXCL2</i> in monocytes and <i>TNF</i> in macrophages was closely associated with severe irAE through involvement in these pathways.Notably, the increase of <i>PRF1</i> and <i>GZMB</i> expression showed a close association with both a favorable prognosis and a reduced severity of irAE, which was validated through CBA analysis. Moreover, the expression of these key markers varied according to prognosis and irAE severity regardless of patient background, such as programmed death-ligand 1 expression levels, tumor histology, or prior treatment regimens.</p><p><strong>Conclusions: </strong>This study identified biological pathways and key biomarkers associated with ICI prognosis and irAE severity using PBMC samples before treatment. These findings provide a foundation for improved therapeutic strategies that enhance clinical outcomes while minimizing ICI treatment-associated risks.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12097017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126202","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":"Blockade of CLEVER-1 restrains immune evasion and enhances anti-PD-1 immunotherapy in gastric cancer.","authors":"Kuan Yu, Yifan Cao, Zihao Zhang, Leihao Wang, Yichao Gu, Tianwei Xu, Xiaolei Zhang, Xinxin Guo, Zhenbin Shen, Jing Qin","doi":"10.1136/jitc-2024-011080","DOIUrl":"10.1136/jitc-2024-011080","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer (GC) remains a major global health burden. Despite the advancements in immunotherapy for patients with GC, the heterogeneity of GC limits response rates, especially in immune \"cold\" subtypes, including genomically stable and epithelial-mesenchymal transition GC. Common lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1), a newly recognized immune checkpoint molecule predominantly expressed on tumor-associated macrophages (TAMs), remains poorly understood in GC. This study aims to explore the clinical significance of CLEVER-1⁺TAM infiltration, elucidate its role in modulating the tumor immune landscape, and investigate the therapeutic potential of CLEVER-1 blockade in enhancing immunotherapy.</p><p><strong>Methods: </strong>This study analyzed two independent GC cohorts and single-cell RNA sequencing data (GSE183904). CLEVER-1 expression in TAMs was assessed via multiplex immunofluorescence, flow cytometry, and RNA sequencing. The clinical relevance of CLEVER-1⁺TAM infiltration was evaluated in relation to tumor, node, metastases staging, molecular subtypes, prognosis, and immunochemotherapy response. Transcriptomic and pathway analyses characterized the immunophenotype of CLEVER-1⁺TAMs. Functional assays examined their suppression on CD8⁺T cells, while interventional experiments assessed the impact of CLEVER-1 blockade alone or with programmed cell death protein-1 (PD-1) inhibition.</p><p><strong>Results: </strong>CLEVER-1 was predominantly expressed on TAMs in GC and was associated with worse clinical outcomes. Transcriptomic and phenotypic analyses revealed that CLEVER-1⁺TAMs display a dynamic immunophenotype and critically suppress T-cell function, fostering an immunosuppressive microenvironment. High CLEVER-1⁺TAM infiltration was linked to poor response or adaptive resistance to PD-1 blockade therapy. CLEVER-1 blockade reprogrammed TAMs toward a pro-inflammatory phenotype, resulting in enhanced CD8⁺T cell cytotoxicity and proliferation. Co-targeting CLEVER-1 and PD-1 synergistically enhanced antitumor responses.</p><p><strong>Conclusions: </strong>High infiltration of CLEVER-1⁺TAMs indicates immune suppression and poor prognosis in GC. The combination of CLEVER-1 and PD-1 blockade emerges as a dual-pronged strategy to boost immune-mediated tumor control and prevent treatment relapse in GC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127636","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":"CAR-NK's balancing act: when scFv affinity is not too tight, not too loose… but just right?","authors":"Yanling Liao, Mitchell S Cairo","doi":"10.1136/jitc-2025-012139","DOIUrl":"10.1136/jitc-2025-012139","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) therapies have revolutionized cancer treatment by enabling immune cells to target tumor cells with high specificity. While extensive research has focused on optimizing single-chain variable fragment (scFv) affinity in CAR-T cells, its impact on CAR-natural killer (NK) cell function remains less understood. A recent study by Rahnama <i>et al</i>, published in the <i>Journal for ImmunoTherapy of Cancer</i>, addresses this gap by investigating how fine-tuning scFv affinity influences CAR-NK efficacy against acute myeloid leukemia. The study demonstrates that lower-affinity 7G3-based CAR-NK cells exhibit superior antigen discrimination, prolonged persistence, and enhanced tumor control compared with their high-affinity counterparts. However, findings with 26292-based CAR-NK cells reveal a more complex, context-dependent relationship between scFv affinity and cytotoxic function. These results highlight the need for individualized optimization of CAR designs, considering factors such as epitope accessibility, ligand-binding kinetics, and cellular context. Future studies incorporating real-time kinetic analyses and tumor microenvironment modeling will be crucial for refining CAR-NK therapies. Striking the right balance between binding affinity, dwell time, and serial killing capacity could enhance CAR-NK therapeutic potential while minimizing toxicity risks.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127639","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":"Onboard, tethered IL-12 boosts potency of the Tmod NOT gate and preserves selectivity.","authors":"Jingli A Zhang, Sara Imboden, Dongwoo Lee, Alexandre Zampieri, Sanam Shafaattalab, Jushen Liang, Richele Bruno, Jon Torres, Alexander Partin, Mark E Daris, Timothy P Riley, Alexander Kamb","doi":"10.1136/jitc-2024-010976","DOIUrl":"10.1136/jitc-2024-010976","url":null,"abstract":"<p><strong>Background: </strong>To reach their full potential in cancer therapy, immune cells engineered with synthetic constructs must achieve the challenging dual objectives of potency and selectivity to overcome the key obstacle: non-specific cytotoxicity. These problems are especially challenging for solid tumor therapy, where antigen tissue specificity, accessibility, and tumor microenvironment are problematic. Cells engineered with receptors that act as synthetic logic gates promise to address the issue of tumor specificity by targeting antigen profiles rather than single antigens. Nevertheless, there are limits to the potency benefit that can be achieved at the level of the antigen-targeting receptors. One approach to enhance potency beyond the acute sensitivity of receptor activation is to co-opt a major source of ancillary stimulation in the normal immune response, cytokine receptors.</p><p><strong>Methods: </strong>Enhancing CAR-T efficacy with engineered onboard cytokines, often referred to as \"armoring\", is one such approach to boost potency. However, such constructs run the risk of overriding tumor selectivity and eroding the therapeutic window. Here we design and test onboard cytokine constructs that enhance potency and preserve selectivity of a synthetic NOT logic gate construct called Tmod, potentially addressing some of the major challenges in oncology in a single synthetic design.</p><p><strong>Results: </strong>We focused especially on a module encoding membrane-tethered interleukin (IL)-12, a construct that significantly enhances Tmod antigen-dependent long-term proliferation and potency both in vitro and in vivo, without compromising the NOT gate selectivity. Notably, three substantially different in vivo models, including one that employs mouse surrogate antigens, were used to assess preclinical dose-dependent efficacy and safety. Together, these studies make a strong case for the robustness of the design.</p><p><strong>Conclusions: </strong>We conclude that the mem-IL-12 module can be combined with multiple Tmod constructs to boost efficacy and persistence while preserving the on-tumor selectivity.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127717","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":"INBRX-106: a hexavalent OX40 agonist that drives superior antitumor responses via optimized receptor clustering.","authors":"Nisha Holay, Rashi Yadav, Sae Jeong Ahn, Melissa J Kasiewicz, Anya Polovina, Annah S Rolig, Thi Staebler, Bryan Becklund, Noah D Simons, Yoshinobu Koguchi, Brendan P Eckelman, Yaiza Diaz de Durana, William L Redmond","doi":"10.1136/jitc-2025-011524","DOIUrl":"10.1136/jitc-2025-011524","url":null,"abstract":"<p><strong>Background: </strong>Immunotherapies targeting immune checkpoint inhibitors have revolutionized cancer treatment but are limited by incomplete patient responses. Costimulatory agonists like OX40 (CD134), a tumor necrosis factor receptor family member critical for T-cell survival and differentiation, have shown preclinical promise but limited clinical success due to suboptimal receptor activation. Conventional bivalent OX40 agonists fail to induce the trimeric engagement required for optimal downstream signaling. To address this, we developed INBRX-106, a hexavalent OX40 agonist designed to enhance receptor clustering independently of Fc-mediated crosslinking and boost antitumor T-cell responses.</p><p><strong>Methods: </strong>We assessed INBRX-106's effects on receptor clustering, signal transduction, and T-cell activation using NF-kß reporter assays, confocal microscopy, flow cytometry, and single-cell RNA sequencing. Therapeutic efficacy was evaluated in murine tumor models and <i>ex vivo</i> human samples. Clinical samples from a phase I/II trial (NCT04198766) were also analyzed for immune activation.</p><p><strong>Results: </strong>INBRX-106 demonstrated superior receptor clustering and downstream signaling compared with bivalent agonists, leading to robust T-cell activation and proliferation. In murine models, hexavalent OX40 agonism resulted in significant tumor regression, enhanced survival, and increased CD8⁺ T-cell effector function. Clinical pharmacodynamic analysis in blood samples from patients treated with INBRX-106 showed heightened T-cell activation and proliferation, particularly in central and effector memory subsets, validating our preclinical findings.</p><p><strong>Conclusions: </strong>Our data establish hexavalent INBRX-106 as a differentiated and more potent OX40 agonist, showcasing its ability to overcome the limitations of conventional bivalent therapies by inducing superior receptor clustering and multimeric engagement. This unique clustering mechanism amplifies OX40 signaling, driving robust T-cell activation, proliferation, and effector function in preclinical and clinical settings. These findings highlight the therapeutic potential of INBRX-106 and its capacity to redefine OX40-targeted immunotherapy, providing a compelling rationale for its further clinical development in combination with checkpoint inhibitors.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12097044/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127675","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":"Engineered <i>Mycobacterium smegmatis</i> expressing anti-PD-L1/IL-15 immunocytokine induces and activates specific antitumor immunity.","authors":"Yi Mei, Junmeng Zhu, Jie Shao, Lin Li, Fangcen Liu, Xiaoxuan Sha, Yang Yang, Jie Shen, Rutian Li, Baorui Liu","doi":"10.1136/jitc-2024-010118","DOIUrl":"10.1136/jitc-2024-010118","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors and cytokines have revolutionized tumor treatment but are still limited by dose-dependent toxicity and efficacy. In situ vaccine platforms based on intelligent microbes are promising therapeutic strategies that sustainably deliver drugs locally without causing severe systemic risks.</p><p><strong>Methods: </strong>In this study, we have innovatively engineered a non-pathogenic, adjuvant-acting <i>Mycobacterium smegmatis</i> (<i>M. smegmatis</i>) that co-expresses a programmed cell death-ligand 1 (PD-L1) inhibitor and an interleukin-15 (IL-15) cytokine complex containing the interleukin-15 receptor alpha (IL-15Rα) sushi domain (Ms-PDL1scfv-IL15).</p><p><strong>Results: </strong>We demonstrate that the fusion protein of PD-L1 inhibitor and IL-15 cytokine systemically binds mouse or human PD-L1 and maintains IL-15 stimulatory activity. The bifunctional Ms-PDL1scfv-IL15 overcomes resistance to PD-L1 blockade, recruits numerous immune cells in situ, induces dendritic cells (DCs) maturation, initiates the M1 antitumor polarization of macrophages, increases the proliferation and activation of natural killer cells and tumor-infiltrating CD8⁺ T cells, inhibits regulatory T cells, elicits abscopal effects, stimulates rapid tumor regression, prevents metastasis, and leads to long-term survival in several syngeneic tumor mouse models. We also found that the combination of Ms-PDL1scfv-IL15 with granulocyte-macrophage colony-stimulating factor (GM-CSF) synergistically stunted the tumor progress and stasis. Moreover, intratumoral administration of Ms-PDL1scfv-IL15 can capture tumor antigen fragments, and boost DCs presentation of antigens, which remarkably initiates tumor antigen-specific immune response, leading to durable tumor regression and specific antitumor immunity.</p><p><strong>Conclusion: </strong>In summary, the engineered <i>M. smegmatis</i> can recruit and activate innate and adaptive antitumor immune responses, offering a potent cancer immunotherapy strategy to treat patients with cold tumors or resistance to checkpoint blockade.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12097051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: SPI1+CD68+ macrophages as a biomarker for gastric cancer metastasis: a rationale for combined antiangiogenic and immunotherapy strategies.","authors":"","doi":"10.1136/jitc-2024-009983corr1","DOIUrl":"10.1136/jitc-2024-009983corr1","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127642","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":"Development and validation of a serum proteomic test for predicting patient outcomes in advanced non-small cell lung cancer treated with atezolizumab or docetaxel.","authors":"Minu K Srivastava, Wei Zou, Mark McCleland, Joanna Roder, Senait Asmellash, Patrick Norman, Lelia Net, Laura Maguire, Heinrich Roder, Robert Georgantas, David S Shames","doi":"10.1136/jitc-2024-010578","DOIUrl":"10.1136/jitc-2024-010578","url":null,"abstract":"<p><strong>Background: </strong>Programmed cell death-ligand 1 (PD-L1) expression is used in treatment decision-making for patients with advanced non-small cell lung cancer, determining if immune checkpoint inhibitors (ICI) are recommended. Patient selection for ICI treatment can be improved by incorporating the host response. We developed and carried out multiple independent validations of a blood-based test designed to stratify outcomes for patients treated with atezolizumab.</p><p><strong>Methods: </strong>A mass spectrometry-based test was developed from a cohort of patients treated with atezolizumab and validated in two clinical trials (n=269, 823) comparing atezolizumab with docetaxel. The test classifies patients as Good or Poor indicating better or worse outcomes, respectively. The prognostic and predictive power of the test was assessed and evaluated within PD-L1 subgroups. Protein enrichment methods were used to investigate the association of test classification with biological processes.</p><p><strong>Results: </strong>Approximately 50% of patients were assigned to each classification in all three cohorts. When treated with atezolizumab, the Good subgroup had superior outcomes in all cohorts. Overall survival (OS) HR (95% CI) for Good patients in each cohort was: 0.23 (0.12 to 0.44), 0.32 (0.21 to 0.51), and 0.52 (0.41 to 0.66) and persisted in all PD-L1 subgroups. The test was predictive of differential OS and progression-free survival in one cohort, but not in the other. Enrichment techniques indicated the test was associated with acute inflammatory response, acute phase response, and complement activation.</p><p><strong>Conclusions: </strong>Aspects of host immune response to disease can be assessed from the circulating proteome and provide outcome stratification for patients treated with atezolizumab. Combining this information with PD-L1 measurements improves prediction of outcomes.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127647","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":"Interplay between sarcopenia, GDF-15, and the efficacy of nivolumab plus ipilimumab in patients with mismatch repair deficient metastatic colorectal cancer: final survival analysis of the phase II GERCOR NIPICOL study.","authors":"Leonard Depotte, Paula Nay, Christophe Borg, Aurélia Meurisse, Julie Henriques, Jaafar Bennouna, Christelle De La Fouchardière, David Tougeron, Thibault Mazard, Benoist Chibaudel, Christophe Tournigand, Dewi Vernerey, Frédéric Pigneur, Thierry Andre, Romain Cohen","doi":"10.1136/jitc-2024-011220","DOIUrl":"10.1136/jitc-2024-011220","url":null,"abstract":"<p><strong>Background: </strong>Sarcopenia and growth differentiation factor 15 (GDF-15) are linked to poor cancer survival. In this exploratory analysis, we evaluated their interaction with nivolumab-ipilimumab efficacy in chemoresistant metastatic colorectal cancer (mCRC) harboring microsatellite instability and/or mismatch-repair deficiency (MSI/dMMR), based on the final survival analysis of the NIPICOL phase II trial.</p><p><strong>Patients and methods: </strong>57 patients with MSI/dMMR chemoresistant mCRC received nivolumab-ipilimumab for 3 months (3M), then, nivolumab alone for 9M. Skeletal muscle mass index (SMI) was evaluated by CT scan at baseline and 12M to assess sarcopenia. GDF-15 levels were assessed at baseline and 3M. Main endpoints were overall survival (OS) and immune Response Evaluation Criteria In Solid Tumors progression-free survival (iPFS).</p><p><strong>Results: </strong>After excluding three patients not confirmed as MSI/dMMR by central review, the overall median follow-up was 60.4 months. The 3-year and 5 year iPFS rates were 72.0% and 65.3%, with OS rates of 77.5% and 73.3%, respectively. Among 49 patients with evaluable GDF-15, high-baseline GDF-15 was associated with poorer survival: 3-year iPFS rate of 56.3% for GDF-15≥2500 versus 81.7% for GDF-15<2500 (PFS HR=2.45, 95% CI 0.91 to 6.55), 3-year OS rates of 61.4% versus 84.5% (OS HR=2.08, 95% CI 0.70 to 6.22). Of the 48 evaluable patients for SMI, 31 (65.0%) displayed sarcopenia at baseline. 11 out of 20 (55%) patients with baseline sarcopenia and assessed for SMI at 12M, reversed sarcopenia by 12M. They had higher baseline GDF-15 levels and greater GDF-15 decrease by 3M (delta mean change: -69.8% vs -40.3%) compared with patients who remained sarcopenic.</p><p><strong>Conclusion: </strong>1-year nivolumab-ipilimumab demonstrates consistent efficacy after 5-year follow-up in an MSI/dMMR chemoresistant mCRC population. GDF-15 confirms to be a promising biomarker for sarcopenia and survival.</p><p><strong>Trial registration number: </strong>NCT03350126.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12090849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101813","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":"Paclitaxel, interferons and functional reprogramming of tumor-associated macrophages in optimized chemo-immunotherapy.","authors":"Pawel Kalinski, Kathleen M Kokolus, Shipra Gandhi","doi":"10.1136/jitc-2024-010960","DOIUrl":"10.1136/jitc-2024-010960","url":null,"abstract":"<p><p>Immune checkpoint inhibition (ICI) targeting programmed cell death protein-1 (PD1) prevents the elimination of activated cytotoxic T lymphocytes (CTLs) by programmed death-ligand 1/2-expressing cancer and myeloid cells in the tumor microenvironment (TME). ICI has shown its effectiveness in many solid tumors, but it lacks activity against \"cold\" tumors which lack CTL infiltration, including most of the colon, prostate, lung and breast cancers. Metastatic triple-negative breast cancer (TNBC) responds to PD-1 blockade only in 5-20% cases. Chemotherapy has been shown to have a PD1-sensitizing effect in a fraction of patients with TNBC but the underlying mechanism and the reasoning behind its limitation to only a subset of patients are unknown. Recent data demonstrate the key roles played by paclitaxel-driven Toll-like receptor 4 (TLR4) signaling and the resulting activation of type-1 and type-2 interferon pathways in tumor-associated macrophages, resulting in local M2 to M1 transition and enhanced tumor antigen cross-presentation, in the paclitaxel-driven sensitization of \"cold\" tumors to ICI. These data and the known ability of the TLR4-activated MyD88-NFκB pathway to mobilize both antitumor and tumor-promoting events in the TME provide new tools to enhance the efficacy of chemo-immunotherapy for metastatic, and potentially early, TNBC and other taxane-sensitive cancers.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12090863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101838","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}