Journal for Immunotherapy of Cancer最新文献

{"title":"ANV600 is a novel PD-1 targeted IL-2Rβγ agonist that selectively expands tumor antigen-specific T cells and potentiates PD-1 checkpoint inhibitor therapy.","authors":"Patrizia Murer, Laetitia Petersen, Nicole Egli, Ulisse Salazar, Pia Neubert, Anaïs Zurbach, Alexander Rau, Christian Stocker, Dario Reichenstein, Andreas Katopodis, Christoph Huber","doi":"10.1136/jitc-2025-011905","DOIUrl":"10.1136/jitc-2025-011905","url":null,"abstract":"<p><strong>Background: </strong>Combining interleukin-2 (IL-2) agonism with programmed cell death protein 1 (PD-1) checkpoint inhibition has shown synergistic potential in reinvigorating antitumor T cell responses. However, integrating these two mechanisms within a single molecule has been challenging due to competing requirements for PD-1 engagement and IL-2 receptor signaling. ANV600 is a novel bispecific antibody-cytokine fusion protein that targets a non-blocking epitope on PD-1, enabling <i>cis</i>-targeted IL-2Rβγ agonism while preserving combinability with therapeutic PD-1 inhibitors. This design allows for selective expansion of tumor antigen-specific T cells while avoiding the systemic toxicity and regulatory T cell (Treg) expansion associated with conventional IL-2 therapies.</p><p><strong>Methods: </strong>The PD-1-targeting antibody used in ANV600 was generated by immunization of humanized mice and selected for its ability to bind PD-1 without blocking the binding epitope of PD-1 checkpoint blocking agents. ANV600 was evaluated in multiple syngeneic tumor models using human PD-1 transgenic mice. Tumor-infiltrating lymphocytes were analyzed to assess the selectivity of ANV600 for PD-1+ T cell subsets. Combination studies with pembrolizumab and nivolumab were performed to assess synergy with checkpoint inhibitors.</p><p><strong>Results: </strong>ANV600 significantly inhibited tumor growth as monotherapy across multiple models, including the immune checkpoint-resistant B16F10 melanoma. By targeting PD-1, ANV600 selectively expanded tumor antigen-specific CD8+T cells, particularly progenitor exhausted (Tpex) and cytotoxic exhausted (Tcex) subsets, while sparing Tregs and NK cells. Combination with pembrolizumab and nivolumab resulted in additive effects, consistent with the complementary roles of PD-1 blockade in expanding Tpex cells and IL-2Rβγ signaling in reprogramming Tcex cells. ANV600's efficacy was dependent on CD8+T cells and primarily driven by tumor-resident T cells, as it remained effective despite blocked lymph node trafficking (FTY720) but was abrogated on CD8+ T cell depletion.</p><p><strong>Conclusions: </strong>ANV600 represents a novel approach to delivering IL-2Rβγ agonism specifically to PD-1+ cells while preserving the binding site for PD-1 checkpoint inhibitors. By targeting a non-blocking epitope on PD-1, ANV600 enables the selective expansion of tumor-reactive CD8+ T cells while allowing independent and optimized dosing of both agents. This design ensures combinability with PD-1 inhibitors at clinically relevant doses, including in patients previously treated with checkpoint blockade. These findings support the clinical development of ANV600 as both a monotherapy and a combination therapy in cancer immunotherapy.</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/PMC12265831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642603","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 IL-18 variants with half-life extension and improved stability for cancer immunotherapy.","authors":"Travis W Bainbridge, Lifen Wang, Marina Moskalenko, Robert Herrera, Maciej T Paluch, Dawei Sun, Kazi Tasneem, Harpinder Saini, Manal Sadek, Mandy Kwong, Yoon Min Kim, Jay M Bhatt, Christine Tam, Pamela Pui Fung Chan, Ayse Meric Ovacik, Matthieu Masureel, Yue Zhao, Jonathan T Sockolosky, Yan Qu, Nathaniel R West, Beyza Bulutoglu","doi":"10.1136/jitc-2025-011789","DOIUrl":"10.1136/jitc-2025-011789","url":null,"abstract":"<p><strong>Background: </strong>The pro-inflammatory cytokine, interleukin-18 (IL-18), plays an instrumental role in bolstering anti-tumor immunity. However, the therapeutic application of IL-18 has been limited due to its susceptibility to neutralization by IL-18 binding protein (IL-18BP), short in vivo half-life, and unfavorable physicochemical properties.</p><p><strong>Methods: </strong>In order to overcome the poor drug-like properties of IL-18, we installed an artificial disulfide bond, removed the native, unpaired cysteines, and fused the stabilized cytokine to an IgG Fc domain. The stability, potency, pharmacokinetic and pharmacodynamic properties as well as efficacy of disulfide-stabilized IL-18 Fc-fusion (dsIL-18-Fc) were assessed via in vitro and in vivo studies.</p><p><strong>Results: </strong>The stability and mammalian host cell production yields of dsIL-18-Fc were improved, compared to the wild-type (WT) cytokine, while maintaining its biological potency and interactions with IL-18 receptor α (IL-18Rα) and IL-18BP. Recombinant fusion of the cytokine to an IgG Fc domain provided extended half-life. Notably, despite maintaining sensitivity to IL-18BP, dsIL-18-Fc was effective at activating both T and natural killer (NK) cells, and elicited a strong anti-tumor response, either as a single agent, or in conjunction with anti-programmed cell death-ligand 1 (anti-PD-L1) therapy.</p><p><strong>Conclusions: </strong>We engineered IL-18 for reinforced stability, extended half-life, and improved manufacturability. The therapeutic benefit of dsIL-18-Fc, coupled with a more favorable manufacturability profile and enhanced drug-like properties, underscores the potential utility of this engineered cytokine in cancer immunotherapy.</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/PMC12265818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642606","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":"Targeting HK3 in tumor-associated macrophages enhances antitumor immunity through augmenting antigen cross-presentation in cervical cancer.","authors":"Yifan Yang, Xun Tian, Jinglan Chen, Jian Liu, Han Jiang, Liting Liu, Shen Qu, Min Wu, Jingyu Wang, Ying Chen, Shan He, Chaoyang Sun, Yafei Huang, Hui Wang","doi":"10.1136/jitc-2025-011948","DOIUrl":"10.1136/jitc-2025-011948","url":null,"abstract":"<p><strong>Background: </strong>Tumor-associated macrophages (TAMs) are among the most prevalent cells within the tumor microenvironment (TME) of cervical cancer (CC). Although TAMs frequently exhibit an immunosuppressive phenotype, their plasticity enables them as an intriguing reprogrammable target for immunotherapy of CC.</p><p><strong>Methods: </strong>Consensus clustering was employed to delineate immune infiltration patterns in a cohort of 119 patients with CC. Single-cell RNA sequencing, complemented by flow cytometry analysis, was used to characterize hexokinase 3 (HK3)-expressing cell populations. In vivo tumor models were established to assess the functional impact of HK3-expressing cells on the TME, with interventions including <i>Hk3</i> knockout and CD8⁺ T-cell depletion. A comprehensive approach involving bulk RNA sequencing, immunoprecipitation assays, confocal microscopy imaging, and in vitro co-culture systems was implemented to elucidate the mechanisms underlying HK3 inhibition-mediated enhancement of antitumor immunity. Furthermore, the therapeutic efficacy of HK3 inhibition, both as a monotherapy and in combination with immunotherapeutic strategies, was systematically evaluated in preclinical tumor models.</p><p><strong>Results: </strong>We elucidated a cross-regulation between TAMs and CD8⁺ T cells, with HK3 serving as a central regulatory node. Upon HK3 expression was upregulated by CD8⁺ T cells through the IFN-γ-STAT1 signaling axis, TAMs exhibited impaired cross-presentation capacity, which in turn attenuated CD8⁺ T cell-mediated antitumor immunity. Mechanistically, HK3 physically interacted with mechanistic target of rapamycin (mTOR), promoting nuclear translocation of transcription factor EB (TFEB) and resulting in excessive lysosomal activation and antigen degradation. Moreover, targeting HK3 in combination with immune checkpoint blockade yielded a synergistic effect in enhancing antitumor immunity.</p><p><strong>Conclusions: </strong>Targeting HK3 in TAMs represents a promising therapeutic strategy capable of enhancing antitumor immunity and synergizing with immune checkpoint blockade by restoring efficient antigen cross-presentation.</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/PMC12265828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642611","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-galectin-9 therapy synergizes with EGFR inhibition to reprogram the tumor microenvironment and overcome immune evasion.","authors":"Dongli Linghu, Jiaming Song, Liyan Gu, Chengjie Liu, Boning Liu, Riyao Yang, Qihui Chen, Jun Yao, Swathi Priya Manickam, Navaneethan Sundhar, Chih-Yen Tu, Chia-Hung Chen, Zhiguo Liu, Delong Liu, Hsiao-Fan Chen, Shasha Shi, Shunjie Xiong, Mien-Chie Hung, Linlin Sun","doi":"10.1136/jitc-2024-010926","DOIUrl":"10.1136/jitc-2024-010926","url":null,"abstract":"<p><strong>Background: </strong>Despite the remarkable clinical outcomes of epidermal growth factor receptor (EGFR)-targeted therapies in patients with lung cancer, therapeutic resistance eventually develops. This study elucidates the role of galectin-9 (Gal-9), a TIM-3 immune checkpoint ligand, in facilitating tumor immune escape during EGFR tyrosine kinase inhibitor (TKI) therapy, and evaluates the therapeutic potential of combined EGFR-TKI and Gal-9 blockade in preclinical models.</p><p><strong>Methods: </strong>EGFR-TKI-mediated Gal-9 regulation was systematically investigated through multianalysis including RNA-seq transcriptomics, quantitative reverse transcription-PCR, immunoblotting, ELISA, flow cytometry, and immunohistochemical validation across human and murine lung/colorectal cancer cell lines, murine tumor tissues, and paired patient tumor tissues/serum samples. Therapeutic efficacy was evaluated in two syngeneic murine models, with comprehensive immune monitoring of tumor microenvironment (TME), tumor-draining lymph nodes (tdLNs), and splenic compartments. Mechanistic investigations employed CD8⁺ T-cell/macrophage depletion strategies (anti-CD8α monoclonal antibodies (mAbs)/PLX-3397), type I interferon (IFN-I) pathway inhibition (anti-IFNAR1 mAbs), and lymph node retention approaches (FTY720 administration).</p><p><strong>Results: </strong>EGFR-TKI treatment significantly induced Gal-9 expression in both tumor cells and host immune cells, particularly myeloid cells. Clinical validation revealed elevated Gal-9 levels in EGFR-TKI-treated patient with lung cancer tumor tissues and serums, correlating with reduced progression-free survival. Mechanistically, EGFR-TKIs triggered DNA damage-potentiated cytosolic double-stranded DNA accumulation and activated tumor-intrinsic STING-IFN-I innate immune pathway that transcriptionally regulated Gal-9 expression. Notably, Gal-9-neutralizing antibodies synergized with EGFR-TKI to markedly inhibit tumor growth in two syngeneic mouse models, including the poorly immunogenic LLC lung tumor model unresponsive to programmed cell death protein-1/programmed death-ligand 1 blockade. The combination therapy remodeled myeloid landscapes toward antigen-presenting phenotypes, promoted dendritic cell accumulation in the tdLN and enhanced CD8⁺ T response in the TME. Depleting CD8⁺ T cells or macrophages/monocytes abrogated the therapeutic benefits. Blocking the IFN-I pathway attenuated Gal-9 expression and enhanced the antitumor immunity of afatinib in the LLC tumor model.</p><p><strong>Conclusions: </strong>These findings identify Gal-9 upregulation as a key mechanism mediating immune evasion and limiting EGFR-TKI efficacy, providing a promising combinational therapeutic strategy of EGFR-TKI and Gal-9 blockade for the treatment of EGFR-driven cancers.</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/PMC12265805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642602","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 organoids in immunotherapy: from disease modeling to translational research.","authors":"Qi Si, Shuhan Tao, Jizhun Wu, Jing Ma, Zhengxing Li, Xiaohang Feng, Jianping Song, Tiantian Kong, Zhuolong Zhou","doi":"10.1136/jitc-2025-011733","DOIUrl":"10.1136/jitc-2025-011733","url":null,"abstract":"<p><p>Tumor organoids have emerged as transformative tools in cancer research, enabling the study of tumor biology and immunology in a physiologically relevant, three-dimensional in vitro environment. Derived from patient tumor samples, these self-organizing structures recapitulate the histological and genetic heterogeneity of tumors and their microenvironment, offering significant advantages over traditional two-dimensional cell cultures and animal models. This work provides a comprehensive overview of tumor organoid generation, their characteristics, and their use as models to study tumor-immune interactions. We discuss how tumor organoids faithfully recapitulate tumor heterogeneity, support immune cell infiltration, and simulate immunosuppressive environments, making them ideal platforms for investigating immunotherapy strategies. Emerging technologies, including advanced imaging and single-cell analysis, as well as gene editing tools, further enhance the utility of tumor organoids in dissecting immune-tumor interactions at unprecedented resolution. We also highlight the translational potential of tumor organoids in preclinical immunotherapy research. Organoids offer a promising approach for predicting patient response to immunotherapy and developing personalized treatment strategies. As tumor organoid technology continues to evolve, its application in clinical settings holds great promise for advancing cancer immunotherapy, improving patient outcomes, and overcoming the challenges of drug resistance. Finally, the future direction of tumor organoid development is speculated according to current challenges.</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/PMC12265810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642612","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":"Randomized phase II study of consolidation immunotherapy with nivolumab and ipilimumab or nivolumab alone following concurrent chemoradiotherapy for unresectable stage IIIA/IIIB non-small-cell lung cancer (NSCLC): Big Ten Cancer Research Consortium LUN16-081.","authors":"Greg Durm, Hirva Mamdani, Sandra Althouse, Susan Perkins, Salma K Jabbour, Apar Kishor Ganti, Shadia Jalal, Jason Chesney, Jarushka Naidoo, Borys Hrinczenko, Mary Jo Fidler, Ticiana A Leal, Lawrence Feldman, Naomi Fujioka, Nasser H Hanna","doi":"10.1136/jitc-2024-010316","DOIUrl":"10.1136/jitc-2024-010316","url":null,"abstract":"<p><strong>Background: </strong>For unresectable stage III non-small-cell lung cancer (NSCLC), the optimal duration and regimen of consolidation immunotherapy following chemoradiation is unknown. Despite improved outcomes with 12 months of durvalumab, which has become the standard of care, new strategies to improve survival are needed. This study evaluates dual immunotherapy in the consolidation setting following concurrent chemoradiation as well as a shorter (6 months) treatment duration.</p><p><strong>Methods: </strong>Following concurrent chemoradiation, subjects were randomized 1:1 to nivolumab alone (480 mg intravenously every 4 weeks) or combination nivolumab (240 mg intravenously every 2 weeks) and ipilimumab (1 mg/kg every 6 weeks) for up to 6 months. Primary endpoint was 18-month progression-free survival (PFS), and each arm was compared with appropriate historical controls. Secondary endpoints included overall survival (OS), time to metastatic disease, and toxicity.</p><p><strong>Results: </strong>105 patients enrolled (54 nivolumab alone; 51 nivolumab/ipilimumab). Median follow-up was 29.1 months for nivolumab and 30 months for nivolumab/ipilimumab. For nivolumab alone, 18-month PFS was 65.5% (95% CI, 49.8% to 77.3%), a statistically significant improvement over the historical control of chemoradiation alone (p<0.1). Median PFS was 29.7 months (95% CI, 16.5 to Not Reached), and median OS was 32 months (95% CI, 32 to NR). For nivolumab/ipilimumab, 18-month PFS was 66.3% (95% CI, 56.3% to 74.5%), a statistically significant improvement over the historical control of chemoradiation followed by durvalumab (p<0.1). Median PFS was 26.3 months (95% CI, 18.6 to NR), and median OS was not reached (95% CI, 30.9 to NR). Rate of any-grade treatment-related adverse events was 72.2% (grade ≥3=18.5%) for nivolumab and 80.4% (grade ≥3=29.4%) for nivolumab/ipilimumab. Most common adverse events (grade 3/4) for nivolumab were fatigue 31.5% (0%), pneumonitis 20.4% (7.4%), rash 16.7% (3.7%), dyspnea 14.8% (0%), and hypothyroidism 14.8% (0%). For nivolumab/ipilimumab, they were fatigue 31.4% (3.9%), pneumonitis 23.5% (11.7%), diarrhea 19.6% (2%), dyspnea 19.6% (0%), pruritus 17.7% (0%), hypothyroidism 15.7% (0%), rash 15.7% (2%), arthralgias 11.8% (0%), and nausea 11.8% (0%). Grade 2 or higher pneumonitis was similar for nivolumab (20.4%) and nivolumab/ipilimumab (19.6%), but grade 3 or higher pneumonitis was more common in the nivolumab/ipilimumab arm (11.8% vs 7.4%).</p><p><strong>Conclusion: </strong>Despite only 6 months of consolidation immunotherapy, nivolumab alone and combination nivolumab/ipilimumab both demonstrated improved 18-month PFS over appropriate historical controls. Overall toxicity, including grade 3 pneumonitis, was higher in the combination arm.</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/PMC12265819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642609","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":"Review: radiotherapy-mediated B cells within the TLS influence the tumor microenvironment.","authors":"Haihua Yang, Kuifei Chen, Yinan Meng, Ziran Chen, Yixiu Xu, Dandan Zhou, Suna Zhou, Xiaozhi Zhang","doi":"10.1136/jitc-2025-011617","DOIUrl":"10.1136/jitc-2025-011617","url":null,"abstract":"<p><p>The tumor microenvironment (TME) is a diverse and intricate structure consisting of tumor cells, stromal cells, endothelial cells, and immune cells. It is characterized by the communication between tumor cells and both innate and adaptive immune cells. Tertiary lymphoid structures (TLS) are temporary abnormal collections of lymphoid tissues in which specialized immune responses against tumors can occur. B cells are crucial for the prognostic prediction of various cancers, particularly in response to immunotherapy. There are many types of B cells within the TME, including naive, terminally differentiated plasma, and memory B cells. Our focus was to understand the various types of B cells and how radiation therapy influences B cells in TLS. In this review, we discuss the notion that radiotherapy may alter the creation and function of B cells in TLS, which could result in a powerful and advanced form of cancer immunity.</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/PMC12265816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642610","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":"Allogeneic cetuximab-armed gamma delta T cells using antibody-cell conjugation technology for the treatment of EGFR-expressing solid tumors.","authors":"Hao-Kang Li, Tai-Sheng Wu, Ying Ru, Yi-Chiu Kuo, Chia-Yun Lee, Pei-Ju Leng, Yi-Chun Hsieh, Yun-Jung Chiang, Zih-Fei Cheng, Yan-Liang Lin, Shih-Chia Hsiao, Sai-Wen Tang","doi":"10.1136/jitc-2024-010500","DOIUrl":"10.1136/jitc-2024-010500","url":null,"abstract":"<p><strong>Background: </strong>Targeting epidermal growth factor receptor (EGFR) has become a strategic approach in cancer therapy, using various modalities including chimeric antigen receptor (CAR)-αβT cell therapies. Despite significant advancements in autologous CAR-αβT cell therapies in B-cell lymphoma, current cell therapies face challenges such as potential risks associated with genetic engineering, waiting time and high costs of autologous CAR-αβT cell therapies. Innovations in click chemistry and bioorthogonal chemistry have enabled the development of antibody-cell conjugation (ACC) technology, which links cancer-targeting antibodies to immune cells without genetic modifications, potentially providing a safer profile.</p><p><strong>Methods: </strong>In this study, we introduce ACE2016, an innovative allogeneic cell therapy targeting EGFR. ACE2016 is generated by ACC technology to conjugate donor-derived γδ2 T cells with the EGFR-specific antibody cetuximab.</p><p><strong>Results: </strong>Our preclinical studies demonstrate that ACE2016 exhibits superior cytotoxicity against various EGFR-expressing cancer cell lines and minimal cytotoxic effects on normal cells. Mechanistic studies revealed that ACE2016 enhances cytotoxicity through increased capacity towards EGFR-expressing cancer cells, enhanced levels of cytotoxic cytokines and recruitment of peripheral cytotoxic cells, reflecting significant tumor suppression and prolonged survival in ACE2016-treated groups without causing treatment-related toxicity in vivo.</p><p><strong>Conclusions: </strong>These findings support the clinical potential of ACE2016 as an off-the-shelf γδ2 T-cell therapy for EGFR-expressing cancers, offering a combination of specificity, scalability, and safety in the development of solid tumor 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/PMC12265807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642601","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":"Disruption of cell-intrinsic PCSK9 enhances the antitumor efficacy of CD8⁺ T cells.","authors":"Bing Liu, Letong Cai, Yiwen Yan, Chengzhou Mao, Xiaohui Zhang, Yudan He, Si Chen, Lizhong Liu, Zhe Xu, Long Xu, FuSheng Wang, Li Yu, A H Jan Danser, Xifeng Lu, Shaojun Xing","doi":"10.1136/jitc-2025-011657","DOIUrl":"10.1136/jitc-2025-011657","url":null,"abstract":"<p><strong>Background: </strong>Tumor-derived proprotein convertase subtilisin/kexin type 9 (PCSK9) facilitates tumor progression, but the role of immune cell-intrinsic PCSK9 in tumor control remains unclear.</p><p><strong>Methods: </strong>Orthotopic models of pancreatic cancer and melanoma in <i>Pcsk9</i>-deficient mice were established and tumor-infiltrating immune cells were analyzed using single-cell RNA sequencing and flow cytometry. The effect of genetic disruptions of PCSK9 on murine CD8⁺ T cells and human chimeric antigen receptor (CAR)-T cells was evaluated both in vitro and in vivo.</p><p><strong>Results: </strong>Ablation of host Pcsk9 remarkably suppressed tumor growth and prolonged the survival of tumor-bearing mice, while tumor cells still express PCSK9. The enhanced tumor suppression in <i>Pcsk9</i>-deficient mice depended on CD8⁺ T cells. Notably, PCSK9 expression was induced in CD8⁺ tumor-infiltrating lymphocytes (TILs). Consequently, Pcsk9 ablation potentiated the antitumor capacity of CD8⁺ T cells, showing increased intratumoral infiltration and improved cytotoxic function, along with higher proportions of both effector-memory precursor exhausted (T_PEX) and terminally exhausted (T_TEX) CD8⁺ TILs. Additionally, disruption of PCSK9 in both murine CD8⁺ T cells and human CAR-T cells, synergistic with PD-1 blockade, promoted tumor suppression.</p><p><strong>Conclusion: </strong>These findings indicate that PCSK9 inhibits the antitumor function of CD8⁺ T cells, suggesting it may be a promising target for enhancing T-cell-based cancer immunotherapy.</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/PMC12265815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642605","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 red blood cell extracellular vesicles for delivery of Dox and siIDO1 enhance targeted chemo-immunotherapy of acute myeloid leukemia.","authors":"Yongcan Liu, Jiayuan Hu, Yan Shu, Genyou Li, Fangfang Jin, Jun Ren, Jing Yang, Can Lin, Lisha Tang, Xingyu Wei, Minghui Sun, Xinyi Chen, Nan Wu, Zesong Yang, Ziwei Li, Ling Zhang","doi":"10.1136/jitc-2024-011148","DOIUrl":"10.1136/jitc-2024-011148","url":null,"abstract":"<p><strong>Background: </strong>As a malignancy of hematopoietic origin, the standard-of-care cytoreductive chemotherapy can not provide satisfactory treatment effect for patients with acute myeloid leukemia (AML). Immunotherapy has received increasing attention in leukemia treatment. However, the immunosuppressive microenvironment and low cancer immunogenicity of AML blasts create major obstacles to effectively inducing immune responses.</p><p><strong>Methods: </strong>We developed an extracellular vesicle-based dual-delivery biosystem, which enhanced anti-AML immune responses by activating the immunogenicity of leukemia cells and relieving immunosuppression in AML allografted mice. Red blood cell-derived extracellular vesicles (REVs) were selected as delivery carriers due to the excellent biocompatibility. REVs were ligated with leukemia-targeting peptide P9 and subsequently loaded with immunogenic cell death (ICD) inducer (Doxorubicin, Dox) and indoleamine 2,3-dioxygenase-1 siRNA (siIDO1) to construct a chemoimmunological cascade biosystem (REVs-Dox/siIDO1-P9).</p><p><strong>Results: </strong>The biosystem can specifically deliver the loaded Dox and siIDO1 into target leukemia cells and was validated capable of inducing efficient ICD. ICD-mediated release of damage-associated molecular patterns synergistically functions with siIDO1-mediated IDO1 silence to effectually recruit CD8⁺ T cells and enhance CD8⁺ T cell's functions. In the AML mouse model, REVs-Dox/siIDO1-P9 can evoke a strong antileukemia response and prolong leukemia-bearing mice survival compared with REVs-Dox/siNC-P9 and REVs-siIDO1-P9.</p><p><strong>Conclusion: </strong>Our findings indicate that the extracellular vesicle-based chemoimmunological cascade biosystem provides a novel strategy for AML treatment.</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/PMC12265820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642607","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}