Journal for Immunotherapy of Cancer最新文献

{"title":"Bevacizumab, tislelizumab and nab-paclitaxel for previously untreated metastatic triple-negative breast cancer: a phase II trial.","authors":"Meiting Chen, Riqing Huang, Qixiang Rong, Wei Yang, Xiujiao Shen, Qi Sun, Ditian Shu, Kuikui Jiang, Cong Xue, Jing Peng, Xin An, Haifeng Li, Fei Xu, Yanxia Shi","doi":"10.1136/jitc-2024-011314","DOIUrl":"https://doi.org/10.1136/jitc-2024-011314","url":null,"abstract":"<p><strong>Background: </strong>Optimal first-line therapy for metastatic triple-negative breast cancer (mTNBC) varied in different situations. This phase II trial explores the efficacy and safety of combination regimens with <b>be</b>vacizumab, <b>ti</b>slelizumab and <b>na</b>b-paclitaxel (BETINA) in first-line setting for mTNBC.</p><p><strong>Methods: </strong>Patients with previously untreated advanced TNBC received tislelizumab 200 mg and bevacizumab on day 1 and nab-paclitaxel 125 mg/m² on day 1, day 8 in 3-week cycles. Patients were randomized to bevacizumab 7.5 mg/kg or 15 mg/kg. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors V.1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. The trial was registered at the Chinese Clinical Trial Registry (No. ChiCTR2200058567).</p><p><strong>Results: </strong>30 female patients were enrolled from March 11, 2021 to February 5, 2024. Nine patients receiving bevacizumab 15 mg/kg experienced significantly higher hypertension rates versus 7.5 mg/kg (55.5% vs 0%), prompting subsequent enrollment of 12 additional patients at 7.5 mg/kg. By November 30, 2024, the ORR was 73.3% and the disease control rate was 90.0%, while the median PFS was 6.0 months and the median OS was 19.8 months. No new safety signal was reported. Common treatment-related adverse events (AEs) included peripheral sensory neuropathy (83.3%), dyspepsia (70.0%), anemia (70.0%), leukocytopenia (66.7%), and pruritus (53.3%). Hypothyroidism (30.0%) was the most frequent immune-related AE. Biomarker analysis indicated that lower baseline interleukin (IL)-1α was associated with poor survival, while IL-2, vascular endothelial growth factor-A and insulin-like growth factor binding protein-7 levels significantly decreased at progression. RNA sequencing highlighted the enrichment of the fatty acid metabolism pathway in poor responders.</p><p><strong>Conclusions: </strong>BETINA study demonstrated promising efficacy and favorable tolerance in treating patients with mTNBC with bevacizumab with tislelizumab and nab-paclitaxel.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Consensus disease definitions for ophthalmic immune-related adverse events of immune checkpoint inhibitors.","authors":"Eileen L Chang, Renee Liu, Kiandokht Keyhanian, Katie Huynh, Meghan Berkenstock, M Tariq Bhatti, John J Chen, James Chodosh, Fiona Costello, Lauren A Dalvin, Lindsey B DeLott, Marc Dinkin, Robert A Egan, Clare L Fraser, Suzanne K Freitag, Sapna Gangaputra, Lynn K Gordon, Amanda C Guidon, Douglas B Johnson, Ninani Kombo, Michal Kramer, Andrew G Lee, Michael Levy, Anne-Marie Lobo-Chan, Dimosthenis Mantopoulos, George Papaliodis, Misha Pless, Julia Pimkina, Krista M Rubin, H Nida Sen, Afreen Shariff, Prem S Subramanian, Edmund Tsui, Michael K Yoon, Jon McDunn, Johnathan Rine, Kerry L Reynolds, Lucia Sobrin, Bart K Chwalisz","doi":"10.1136/jitc-2024-011049","DOIUrl":"https://doi.org/10.1136/jitc-2024-011049","url":null,"abstract":"<p><p>Ophthalmic immune-related adverse events (Eye-irAEs) from immune checkpoint inhibitors can cause visual morbidity. The absence of standardized definitions for Eye-irAEs not only impedes the development of evidence-based treatments but also progress in translational research. The objective of this study was to develop consensus guidance for an approach to Eye-irAEs.Four ophthalmic physicians (uveitis specialists and neuro-ophthalmologists) drafted Eye-irAE consensus guidance and definitions, which were reviewed by the multidisciplinary Eye-irAE definition panel. The panel was divided into Group A (Neuro-ophthalmology/Orbital Disease) and Group B (Uveitis/Ocular Surface Disease). A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. For each disorder, five diagnostic components were evaluated: symptoms, examination findings, laboratory studies/imaging findings, diagnostic criteria, and treatment. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free-text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND Corporation/ University of California Los Angeles Health Services Utilization Study (RAND/UCLA) Appropriateness Method with prespecified definitions.29 panelists from 25 academic medical centers voted on 114 rating scales (66 neuro-ophthalmic/orbital disease components, 48 uveitis/ocular surface disease components); of these, 86.3% (57/66) in Group A and 89.6% (43/48) in Group B reached first-round consensus. After revisions, all items except 6.1% (4/66) in Group A and 1.6% (1/60) in Group B received second-round consensus. Consensus definitions were achieved for 10/11 neuro-ophthalmic/orbital disorders: optic neuritis, inflammatory optic disc edema, arteritic ischemic optic neuropathy, optic perineuritis, orbital inflammation, thyroid eye disease-like orbital inflammation, cavernous sinus syndrome, oculomotor mononeuritis, trochlear mononeuritis, and abducens mononeuritis. Consensus definitions were achieved for 9/10 uveitis/ocular surface disorders: anterior uveitis, intermediate uveitis, posterior uveitis, panuveitis, Vogt-Koyanagi-Harada-like syndrome, sarcoidosis-like syndrome, acute macular neuroretinopathy, dry eye disease, and scleritis.These disease definitions establish a standardized classification for Eye-irAE, highlighting differences between irAEs and other inflammatory disorders. Importantly, diagnostic certainty does not always align directly with the need to treat as an Eye-irAE. Given the consensus from this representative panel group, it is anticipated the definitions will be used broadly across clinical and research settings.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>JAK3</i> ^A573V and <i>JAK3</i> ^M511I mutations in peripheral T-cell lymphoma mediating resistance to anti-PD-1 therapy through the STAT3/PD-L1 pathway.","authors":"Ning Lou, Mengwei Yang, Zucheng Xie, Ruyun Gao, Lei Zhang, Le Tang, Jiarui Yao, Xiaohong Han, Yuankai Shi","doi":"10.1136/jitc-2024-010783","DOIUrl":"https://doi.org/10.1136/jitc-2024-010783","url":null,"abstract":"<p><strong>Background: </strong>Clinical evidence has established anti-PD-1 antibody as a transformative treatment modality for relapsed/refractory peripheral T-cell lymphoma (r/r PTCL), yet reveals a therapeutic plateau with drug resistance observed in 60% of r/r PTCL. The biological determinants underlying this resistance-particularly the complex interplay between tumor-intrinsic characteristics (including tumor mutation burden and oncogenic mutations) and immune microenvironment features (notably PD-L1 expression)-remain insufficiently illustrated. Therefore, we systematically depicted the comprehensive mutation profile of r/r PTCL patients and correlated them with the efficacy and prognosis of anti-PD-1 therapy.</p><p><strong>Methods: </strong>Here, we enrolled a cohort of 109 patients with r/r PTCL and performed targeted next-generation sequencing of 440 cancer-associated genes. Clinical information was collected and correlated with genetic mutations. We constructed <i>JAK3</i> mutant models using Jurkat and BA/F3 cell lines. We performed single-cell transcriptomics, western blotting, and flow cytometry to elucidate the molecular mechanism. Additionally, we built a <i>JAK3</i>-mutant syngeneic mouse model to demonstrate in vivo antitumor efficacy of Tofacitinib and anti-PD-1 therapy.</p><p><strong>Results: </strong>We identified and validated that PD-L1 was a predictor for the efficacy of anti-PD-1 therapy in PTCL patients. The subset of PTCL patients (13.5%) characterized by enrichment of the APOBEC-related mutation signature had worse overall survival (p=0.031) compared with non-APOBEC-enriched samples. <i>JAK3</i> and <i>EZH2</i> mutations were associated with lower PD-L1 expression (p<0.05), and <i>JAK3</i> mutations were independently correlated with shorter progression-free survival (HR=6.07, p=0.0144). Among all types of <i>JAK3</i> mutations, single-cell transcriptomics, western blotting, and flow cytometry revealed that <i>JAK3</i> p.A573V and p.M511I mutations led to decreased PD-L1 expression in Jurkat and BA/F3 cell lines through inactivation of STAT3. Compared with <i>JAK3</i> wild-type syngeneic mouse models, <i>JAK3</i> p.A573V and p.M511I mutant mice were more sensitive to Tofacitinib but not anti-PD-1 antibody.</p><p><strong>Conclusions: </strong>In conclusion, we found that <i>JAK3</i> mutations, especially <i>JAK3</i> p.A573V and <i>JAK3</i> p.M511I mutations, lead to poor prognosis of anti-PD-1 therapy through the STAT3/PD-L1 pathway. Tofacitinib is more suitable than anti-PD-1 antibody for <i>JAK3</i> mutant PTCL patients.</p><p><strong>Trial registration number: </strong>NCT03502629.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD40L stimulates tumor-infiltrating B-cells and improves ex vivo TIL expansion.","authors":"Renata Ariza Marques Rossetti, Leticia Tordesillas, Matthew S Beatty, Junior Cianne, Elena Martinez Planes, Dongliang Du, Sebastian Snedal, Chao Wang, Bradford A Perez, Anders Berglund, Yian Ann Chen, Amod Sarnaik, James J Mulé, Benjamin Creelan, Shari Pilon-Thomas, Daniel Abate-Daga","doi":"10.1136/jitc-2024-011066","DOIUrl":"https://doi.org/10.1136/jitc-2024-011066","url":null,"abstract":"<p><strong>Background: </strong>Adoptive transfer of tumor-infiltrating lymphocytes (TIL) is now a Food and Drug Administration (FDA)-approved treatment for melanoma. While this is a major milestone, there is room for improvement to increase clinical response rates and to further optimize the manufacturing of TIL products. In this study, we characterized the association of tumor-infiltrating B-cells (TIL-B) and tertiary lymphoid structures (TLSs) with clinical response to TIL therapy and tested whether the presence of B-cells in the tumor can be leveraged to optimize TIL manufacture.</p><p><strong>Methods: </strong>Tumor sections from TIL responders (R, n=9) and non-responders (NR, n=11) were analyzed by RNA sequencing, and immune cell content was estimated in silico. To study the association between B-cells and TIL expansion, we quantified B-cell subsets and TIL phenotype by flow cytometry. CD40L-induced effects on melanoma-infiltrating B-cells were analyzed by flow cytometry and scRNA-sequencing.</p><p><strong>Results: </strong>Tumors from TIL clinical responders had greater abundance of class-switched B-cells (p=0.007) and a greater TLS score (p=0.03) than those of NRs. In addition, greater abundance of B-cells (p≤0.05) and switched memory B-cells (CD27⁺ IgD-, p≤0.05) in the tumors were associated with greater TIL expansion. Stimulation of TIL-B through addition of CD40L during TIL ex vivo culture improved their expansion success rate from 33% to 67% (p=0.03). Similarly, the addition of CD40L to non-small cell lung cancer (NSCLC) TIL cultures shortened the manufacturing period by 1 week. Moreover, CD40L-enhanced TIL showed more stem-like T-cells (CD39^- CD69^-, p≤0.05) and an enrichment of neoantigen-reactive T-cell clones in NSCLC TIL. Gene expression analysis showed that CD40L induced gene expression changes in TIL-B after 48 hours in culture (126 differentially expressed genes (DEGs)), with minimal to no changes observed in other immune cell types (including 12 DEG in macrophages, 10 DEG in dendritic cells, and none in monocytes). B-cell DEGs included upregulated co-stimulatory ligands (CD83, CD58), chemokines (CCL22, CCL17), among others. CD40L-induced upregulation of CD58 by melanoma infiltrating B-cells was associated with successful TIL expansion.</p><p><strong>Conclusions: </strong>Our results show that CD40L-stimulated B-cells can be leveraged to enhance the quality and quantity of TIL. Clinical trial NCT05681780 is currently testing this concept applied to NSCLC TIL.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MHC class II-mediated spontaneous rejection of breast carcinomas expressing model neoantigens.","authors":"James William Jenkins, Alvaro Peña, Sarah A Castro, Michael J Hansen, Virginia P Van Keulen, Sean T Foster, Pablo E Rios-Cruz, Joshua Yakubov, Destin T Hinson, Samuel M Olivier, Kevin D Pavelko, Sara J Felts, Aaron J Johnson, Larry R Pease","doi":"10.1136/jitc-2024-010434","DOIUrl":"10.1136/jitc-2024-010434","url":null,"abstract":"<p><strong>Background: </strong>Cancers persist despite expression of immunogenic neoantigens and ongoing antitumor immune responses. While some occult tumors likely are cleared by effective antitumor immune responses, the targeted antigens are not easily identifiable as those tumors spontaneously disappear.</p><p><strong>Methods: </strong>We used mouse models with a defined antigenic protein mimicking tumor-specific neoantigens to address the nature of these spontaneous anti-tumor immune responses.</p><p><strong>Results: </strong>BALB/c (<i>H-2^d</i> ) mice challenged with BALB/c breast tumors expressing the rat-erbB2 oncoprotein succumb to their tumors despite ongoing immune responses targeting tumor-specific model antigens. Meanwhile, congenic BALB.B (<i>H-2^b</i> ) and <i>H-2^d/H-2^b</i> F1 hybrid mice spontaneously eliminate genetically matched tumors in a major histocompatibility complex (MHC)-II dependent manner. Adoptive transfer and immune cell depletion strategies revealed CD4+ T cells and CD20+ B cells are crucial mediators of the protective response in <i>H-2^b</i> mice. Furthermore, passive transfer of immune serum from mice rejecting their tumors confers resistance in tumor antigen-tolerant animals with an inversely proportional relationship between tumor outgrowth and the amount of rat-erbB2 specific antibody present in tumor-bearing mice. Introduction of the rat-erb2 ectodomain into other <i>H-2^b</i> tumor models also promotes their spontaneous tumor rejection. Notably, the tumor microenvironments differ in rat-erbB2+ tumor-bearing BALB.B and BALB/c mice at the time of fate decision in the models reflecting the differences between effective and ineffective tumor immune responses.</p><p><strong>Conclusions: </strong>We find that the effective antitumor immunity targeting neoantigens in these breast cancer models is determined by MHC-II-restricted presentation of optimal cancer-associated antigens. These responses are dependent on CD4+ T cells, B cells, and antigen-specific antibodies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973762/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788382","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":"β-blocker suppresses both tumoral sympathetic neurons and perivascular macrophages during oncolytic herpes virotherapy.","authors":"Konstantina Kyritsi, Rafal Pacholczyk, Eugene Douglass, Miao Yu, Hui Fang, Gang Zhou, Balveen Kaur, Qin Wang, David H Munn, Bangxing Hong","doi":"10.1136/jitc-2024-011322","DOIUrl":"10.1136/jitc-2024-011322","url":null,"abstract":"<p><strong>Background: </strong>The autonomic nervous system (ANS) plays a key role in regulating tumor development and therapy resistance in various solid tumors. Within the ANS, the sympathetic nervous system (SNS) is typically associated with protumor effects. However, whether the SNS influences the antitumor efficacy of intratumoral injections of oncolytic herpes simplex virus (oHSV) in solid tumors remains unknown.</p><p><strong>Methods: </strong>In this study, we examined SNS innervation and its interaction with immune cell infiltration in both human and murine triple-negative breast cancer models during intratumoral oHSV injections and SNS blockade on oHSV's antitumor activity.</p><p><strong>Results: </strong>Intratumor oHSV injection promotes SNS innervation accompanied by CD45+cell infiltration in both the human MDA-MB-468 orthotopic model and the murine 4T1 mammary tumor model. Mechanistically, tumor-secreted factors vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and transforming growth factor beta (TGF-β) and transcription factors (CREB, AP-1, MeCP2, and REST), which promote SNS innervation, were found to be upregulated in oHSV-treated tumors. Combining the SNS antagonist, a β-blocker, with oHSV significantly increased immune cell infiltration, particularly CD8+T cells in oHSV-treated 4T1 tumors. Single-cell messenger RNA sequencing revealed that oHSV injection upregulated a specific population of perivascular macrophages (pvMacs) expressing high levels of VEGFA, CD206, CCL3, and CCL4, which suppress T-cell activation. The use of a β-blocker reduced the infiltration of oHSV-induced pvMacs, transition to inflammatory macrophages expressing Hexb, enhancing the diversity of T-cell receptor clonotypes. Further analysis suggested that TGF-β signaling within the tumor partially mediates SNS activation in the 4T1 model.</p><p><strong>Conclusion: </strong>Our findings demonstrate that combining a β-blocker with oHSV significantly enhances the antitumor efficacy of oHSV in breast cancer by targeting TGF-β-mediated SNS innervation and immunosuppression.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788380","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: Tissue-specific properties of type 1 dendritic cells in lung cancer: implications for immunotherapy.","authors":"","doi":"10.1136/jitc-2024-010547corr1","DOIUrl":"10.1136/jitc-2024-010547corr1","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788363","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":"Potency-optimized CD28-activating bispecific antibody for the targeted treatment of Nectin-4 positive cancers.","authors":"Manpreet Kaur, Katja Rüger, Elaine C Chen, Udaya S Rangaswamy, Laura M Davison, Sebastian Moreno Arteaga, Imani Smith, Ruth Chu, Soumili Chattopadhyay, Mathias Rickert, Shelley Force Aldred, Katherine E Harris, Nathan D Trinklein, Starlynn C Clarke","doi":"10.1136/jitc-2024-011323","DOIUrl":"10.1136/jitc-2024-011323","url":null,"abstract":"<p><strong>Background: </strong>T-cell costimulation is crucial for an effective and sustained antitumor immune response, and inadequate expression of costimulatory ligands within tumors can impair T-cell function. Bispecific antibodies (bsAbs) targeting a tumor-associated antigen and the T-cell costimulatory receptor CD28 represent a novel class of immune-stimulatory therapeutics designed to enhance antitumor immune responses by selectively delivering T-cell costimulation directly to the tumor microenvironment. This approach holds the potential to improve the survival, proliferation, and cytotoxic function of antitumor T cells while minimizing the risk of systemic immune activation. Urothelial cancer (UC) is associated with significant morbidity and mortality worldwide, particularly in advanced disease settings. Nectin-4, a membrane protein highly expressed in UC with limited expression in healthy tissues, presents a compelling target for therapeutic intervention.</p><p><strong>Methods: </strong>Using our proprietary high-throughput antibody discovery pipeline, we identified a panel of novel antibodies with a range of affinities for CD28 and Nectin-4 and successfully engineered them as bsAbs. We tested the T-cell costimulatory function of these molecules <i>in vitro</i> using primary human T cells and human cancer cell lines. Based on these results, we selected a clinical candidate which we assessed in a syngeneic mouse tumor model system and investigated tolerability and pharmacokinetics (PK) in non-human primates (NHP).</p><p><strong>Results: </strong>Our <i>in vitro</i> studies demonstrated that these bsAbs effectively enhance T-cell activation and cytotoxicity against Nectin-4 positive tumor cells in the presence of T-cell receptor engagement. The bsAb panel exhibited a range of potencies, enabling the selection of a clinical candidate, termed RNDO-564, that maximized antitumor efficacy as well as the likelihood of a broad therapeutic window. Tumor-bearing syngeneic mouse models confirmed the <i>in vivo</i> efficacy of RNDO-564, demonstrating significant tumor regression both as a single agent and in combination with an immune checkpoint inhibitor. We observed favorable PK and tolerability profiles in NHP assessments.</p><p><strong>Conclusions: </strong>Our study reports the first CD28 bsAb targeting Nectin-4 and highlights the potential of CD28 × Nectin-4 bsAbs as a new immunotherapeutic modality. The findings support the clinical development of RNDO-564 in patients with locally advanced and metastatic UC and other Nectin-4 positive malignancies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788388","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":"PRMT5 deficiency in myeloid cells reprograms macrophages to enhance antitumor immunity and synergizes with anti-PD-L1 therapy.","authors":"Shiyu Chen, Zheyi Chen, Bingqian Zhou, Yongyu Chen, Yiren Huang, Jian Cao, Lisong Shen, Yingxia Zheng","doi":"10.1136/jitc-2024-011299","DOIUrl":"10.1136/jitc-2024-011299","url":null,"abstract":"<p><strong>Background: </strong>Arginine methyltransferase protein arginine methyltransferase 5 (PRMT5) plays a significant role in immune regulation, particularly within the tumor microenvironment (TME). Macrophages are crucial modulators of both innate and adaptive immune responses, and their differentiation into tumor-associated macrophages is critical in shaping the TME. Despite ongoing clinical trials of small molecule inhibitors of PRMT5 for cancer therapy, their effects on macrophages, a key component of the immune system, remain poorly understood.</p><p><strong>Methods: </strong>A pan-cancer single-cell transcriptional analysis was initially conducted to investigate the expression of PRMT5 in tumor-infiltrating myeloid cells. Myeloid-specific deletion of Prmt5 in mice, as well as the use of a PRMT5-specific inhibitor, was performed to evaluate the impact of PRMT5 on macrophage polarization and tumor progression. Bulk and single-cell transcriptomics were employed to explore the mechanistic roles of PRMT5 in regulating lipid metabolism and macrophage polarization. Additionally, the therapeutic potential of combining Prmt5 deletion with anti-programmed death-ligand 1 (PD-L1) therapy was assessed to study its effects on antitumor immunity in vivo.</p><p><strong>Results: </strong>The pan-cancer single-cell transcriptional analysis revealed that PRMT5 is highly expressed in the PPARG-macrophage subset, which correlates with poor patient survival. Myeloid-specific deletion of Prmt5 reprogrammed macrophages towards an antitumor phenotype, effectively inhibiting tumor progression. Mechanistically, PRMT5 was found to regulate lipid metabolism and drive macrophage polarization toward an anti-inflammatory state via the STAT6-PPARγ pathway, fostering an immunosuppressive TME conducive to tumor growth. Notably, Prmt5 deletion induced PD-L1 expression on myeloid cells. Combining Prmt5 deletion with anti-PD-L1 therapy significantly enhanced antitumor efficacy, demonstrating a synergistic therapeutic effect.</p><p><strong>Conclusions: </strong>These findings uncover a crucial role for PRMT5 in macrophage biology and suggest that targeting PRMT5 in myeloid cells offers a promising new approach for cancer immunotherapy. The combination of PRMT5 inhibition with anti-PD-L1 therapy may provide a potent strategy to reprogram the TME and enhance antitumor immune responses.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788356","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":"Flagellin engineering enhances CAR-T cell function by reshaping tumor microenvironment in solid tumors.","authors":"Xiangyun Niu, Pengchao Zhang, Liujiang Dai, Xixia Peng, Zhongming Liu, Yexiao Tang, Guizhong Zhang, Xiaochun Wan","doi":"10.1136/jitc-2024-010237","DOIUrl":"10.1136/jitc-2024-010237","url":null,"abstract":"<p><strong>Background: </strong>Adoptive cell therapy using genetically engineered chimeric antigen receptor (CAR)-T cells is a new type of immunotherapy that directs T cells to target cancer specifically. Although CAR-T therapy has achieved significant clinical efficacy in treating hematologic malignancies, its therapeutic benefit in solid tumors is impeded by the immunosuppressive tumor microenvironment (TME). Therefore, we sought to remodel the TME by activating tumor-infiltrating immune cells to enhance the antitumor function of CAR-T cells.</p><p><strong>Methods: </strong>We engineered CAR-T cells expressing <i>Salmonella</i> flagellin (Fla), a ligand for toll-like receptor 5, to activate immune cells and reshape the TME in solid tumors. Functional validation of the novel Fla-engineered CAR-T cells was performed in co-cultures and mouse tumor models.</p><p><strong>Results: </strong>Fla could activate tumor-associated macrophages and dendritic cells, reshaping the TME to establish an \"immune-hot\" milieu. Notably, this \"cold\" to \"hot\" evolution not only improved CAR-T cell function for better control of target-positive tumors, but also encouraged the production of endogenous cytotoxic CD8⁺T cells, which targeted more tumor-associated antigens and were thus more effective against tumors with antigenic heterogeneity.</p><p><strong>Conclusion: </strong>Our study reveals the potential and cellular mechanisms for Fla to rewire antitumor immunity. It also implies that modifying CAR-T cells to express Fla is a viable strategy to improve the efficacy of CAR-T cell treatment against solid tumors.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788366","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}