Cancer immunology research最新文献_第9页

Molecular Pathways and Cellular Subsets Associated with Adverse Clinical Outcomes in Overlapping Immune-Related Myocarditis and Myositis. 与重叠性免疫相关心肌炎和肌炎不良临床结果相关的分子途径和细胞亚群。

IF 8.1 1区医学

Cancer immunology research Pub Date : 2024-08-01 DOI: 10.1158/2326-6066.CIR-24-0011

Bilal A Siddiqui, Nicolas L Palaskas, Sreyashi Basu, Yibo Dai, Zhong He, Shalini S Yadav, James P Allison, Rahul A Sheth, Sudhakar Tummala, Maximilian Buja, Meenakshi B Bhattacharjee, Cezar Iliescu, Anishia Rawther-Karedath, Anita Deswal, Linghua Wang, Padmanee Sharma, Sumit K Subudhi

{"title":"Molecular Pathways and Cellular Subsets Associated with Adverse Clinical Outcomes in Overlapping Immune-Related Myocarditis and Myositis.","authors":"Bilal A Siddiqui, Nicolas L Palaskas, Sreyashi Basu, Yibo Dai, Zhong He, Shalini S Yadav, James P Allison, Rahul A Sheth, Sudhakar Tummala, Maximilian Buja, Meenakshi B Bhattacharjee, Cezar Iliescu, Anishia Rawther-Karedath, Anita Deswal, Linghua Wang, Padmanee Sharma, Sumit K Subudhi","doi":"10.1158/2326-6066.CIR-24-0011","DOIUrl":"10.1158/2326-6066.CIR-24-0011","url":null,"abstract":"Immune checkpoint therapies (ICT) can induce life-threatening immune-related adverse events, including myocarditis and myositis, which are rare but often concurrent. The molecular pathways and immune subsets underlying these toxicities remain poorly understood. To address this need, we performed single-cell RNA sequencing of heart and skeletal muscle biopsies obtained from living patients with cancers treated with ICTs and admitted to the hospital with myocarditis and/or myositis (overlapping myocarditis plus myositis, n = 10; myocarditis-only, n = 1) or ICT-exposed patients ruled out for toxicity utilized as controls (n = 9). All biopsies were obtained within 96 hours of clinical presentation. Analyses of 58,523 cells revealed CD8+ T cells with a cytotoxic phenotype expressing activation/exhaustion markers in both myocarditis and myositis. Furthermore, the analyses identified a population of myeloid cells expressing tissue-resident signatures and FcγRIIIa (CD16a), which is known to bind IgG and regulate complement activation. Immunohistochemistry of affected cardiac and skeletal muscle tissues revealed protein expression of pan-IgG and complement product C4d, which were associated with the presence of high-titer serum autoantibodies against muscle antigens in a subset of patients. We further identified a population of inflammatory IL1B+TNF+ myeloid cells specifically enriched in myocarditis and associated with greater toxicity severity and poorer clinical outcomes. These results provide insight into the myeloid subsets present in human immune-related myocarditis and myositis tissues and nominate new targets for investigation into rational treatments to overcome these high-mortality toxicities. See related Spotlight by Fankhauser et al., p. 954.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"964-987"},"PeriodicalIF":8.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070610","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}

引用次数: 0

Unveiling Cellular Identities and Gene Expression Pathways in Overlapping Myocarditis and Myositis. 揭示重叠性心肌炎和肌炎的细胞特性和基因表达途径

IF 8.1 1区医学

Cancer immunology research Pub Date : 2024-08-01 DOI: 10.1158/2326-6066.CIR-24-0506

Reilly G Fankhauser, Douglas B Johnson, Javid J Moslehi, Justin M Balko

引用次数: 0

Multifunctional Bispecific Nanovesicles Targeting SLAMF7 Trigger Potent Antitumor Immunity. 以 SLAMF7 为靶点的多功能双特异性纳米囊泡可触发强效抗肿瘤免疫。

IF 8.1 1区医学

Cancer immunology research Pub Date : 2024-08-01 DOI: 10.1158/2326-6066.CIR-23-1102

Manman Zhu, Yongjian Wu, Tianchuan Zhu, Jian Chen, Zhenxing Chen, Hanxi Ding, Siyi Tan, Jianzhong He, Qi Zeng, Xi Huang

{"title":"Multifunctional Bispecific Nanovesicles Targeting SLAMF7 Trigger Potent Antitumor Immunity.","authors":"Manman Zhu, Yongjian Wu, Tianchuan Zhu, Jian Chen, Zhenxing Chen, Hanxi Ding, Siyi Tan, Jianzhong He, Qi Zeng, Xi Huang","doi":"10.1158/2326-6066.CIR-23-1102","DOIUrl":"10.1158/2326-6066.CIR-23-1102","url":null,"abstract":"The effectiveness of immune checkpoint inhibitor (ICI) therapy is hindered by the ineffective infiltration and functioning of cytotoxic T cells and the immunosuppressive tumor microenvironment (TME). Signaling lymphocytic activation molecule family member 7 (SLAMF7) is a pivotal co-stimulatory receptor thought to simultaneously trigger NK-cell, T-cell, and macrophage antitumor cytotoxicity. However, the potential of this collaborative immune stimulation in antitumor immunity for solid tumors is underexplored due to the exclusive expression of SLAMF7 by hematopoietic cells. Here, we report the development and characterization of multifunctional bispecific nanovesicles (NVs) targeting SLAMF7 and glypican-3-a hepatocellular carcinoma (HCC)-specific tumor antigen. We found that by effectively \"decorating\" the surfaces of solid tumors with SLAMF7, these NVs directly induced potent and specific antitumor immunity and remodeled the immunosuppressive TME, sensitizing the tumors to programmed cell death protein 1 (PD1) blockade. Our findings highlight the potential of SLAMF7-targeted multifunctional bispecific NVs as an anticancer strategy with implications for designing next-generation targeted cancer therapies.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1007-1021"},"PeriodicalIF":8.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141178296","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}

引用次数: 0

Impact of scFv on Functionality and Safety of Third-Generation CD123 CAR T Cells. scFv 对第三代 CD123 CAR T 细胞功能性和安全性的影响。

IF 8.1 1区医学

Cancer immunology research Pub Date : 2024-08-01 DOI: 10.1158/2326-6066.CIR-23-0548

Maxime Fredon, Margaux Poussard, Sabeha Biichlé, Francis Bonnefoy, Charles-Frédéric Mantion, Evan Seffar, Florian Renosi, Elodie Bôle-Richard, Romain Boidot, Sandrine Chevrier, François Anna, Maria Loustau, Julien Caumartin, Mathieu Gonçalves-Venturelli, Eric Robinet, Philippe Saas, Eric Deconinck, Etienne Daguidau, Xavier Roussel, Yann Godet, Olivier Adotévi, Fanny Angelot-Delettre, Jeanne Galaine, Francine Garnache-Ottou

{"title":"Impact of scFv on Functionality and Safety of Third-Generation CD123 CAR T Cells.","authors":"Maxime Fredon, Margaux Poussard, Sabeha Biichlé, Francis Bonnefoy, Charles-Frédéric Mantion, Evan Seffar, Florian Renosi, Elodie Bôle-Richard, Romain Boidot, Sandrine Chevrier, François Anna, Maria Loustau, Julien Caumartin, Mathieu Gonçalves-Venturelli, Eric Robinet, Philippe Saas, Eric Deconinck, Etienne Daguidau, Xavier Roussel, Yann Godet, Olivier Adotévi, Fanny Angelot-Delettre, Jeanne Galaine, Francine Garnache-Ottou","doi":"10.1158/2326-6066.CIR-23-0548","DOIUrl":"10.1158/2326-6066.CIR-23-0548","url":null,"abstract":"Chimeric antigen receptor (CAR) T cells express an extracellular domain consisting of a single-chain fragment variable (scFv) targeting a surface tumor-associated antigen. scFv selection should involve safety profiling with evaluation of the efficacy/toxicity balance, especially when the target antigen also is expressed on healthy cells. Here, to assess differences in terms of efficacy and on-target/off-tumor effects, we generated five different CARs targeting CD123 by substituting only the scFv. In in vitro models, T cells engineered to express three of these five CD123 CARs were effectively cytotoxic on leukemic cells without increasing lysis of monocytes or endothelial cells. Using the IncuCyte system, we confirmed the low cytotoxicity of CD123 CAR T cells on endothelial cells. Hematotoxicity evaluation using progenitor culture and CD34 cell lysis showed that two of the five CD123 CAR T cells were less cytotoxic on hematopoietic stem cells. Using a humanized mouse model, we confirmed that CD123- cells were not eliminated by the CD123 CAR T cells. Two CD123 CAR T cells reduced tumor infiltration and increased the overall survival of mice in three in vivo models of blastic plasmacytoid dendritic cell neoplasm. In an aggressive version of this model, bulk RNA sequencing analysis showed that these CD123 CAR T cells upregulated genes associated with cytotoxicity and activation/exhaustion a few days after the injection. Together, these results emphasize the importance of screening different scFvs for the development of CAR constructs to support selection of cells with the optimal risk-benefit ratio for clinical development.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1090-1107"},"PeriodicalIF":8.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141178316","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}

引用次数: 0

Overexpression of an Engineered SERPINB9 Enhances Allogeneic T-cell Persistence and Efficacy. 过表达工程化 SerpinB9 可增强异体 T 细胞的存活率和疗效

IF 8.1 1区医学

Cancer immunology research Pub Date : 2024-08-01 DOI: 10.1158/2326-6066.CIR-23-1001

Pei Y Teo, Youngrock Jung, David H Quach, Joanna Koh, Richard W Ong, Angeline Goh, Alrina Tan, Chee H Ng, Cheah C Seh, Kar W Tan, Ivan D Horak, Lionel Low

{"title":"Overexpression of an Engineered SERPINB9 Enhances Allogeneic T-cell Persistence and Efficacy.","authors":"Pei Y Teo, Youngrock Jung, David H Quach, Joanna Koh, Richard W Ong, Angeline Goh, Alrina Tan, Chee H Ng, Cheah C Seh, Kar W Tan, Ivan D Horak, Lionel Low","doi":"10.1158/2326-6066.CIR-23-1001","DOIUrl":"10.1158/2326-6066.CIR-23-1001","url":null,"abstract":"Allogeneic chimeric antigen receptor (CAR)-expressing T cells offer many advantages over autologous therapies, but their benefits are curtailed by graft-versus-host disease and elimination by recipient immune cells. Moreover, just as with autologous therapies, allogeneic CAR T cells are susceptible to activation-induced cell death (AICD) caused by chronic antigen exposure (CAE). Granzyme B- and Fas/Fas ligand-initiated caspase-mediated apoptoses are key mechanisms of T-cell death caused by T/NK cell-mediated allorejection or CAE. We explored a protective strategy of engineering CAR T cells to overexpress variants of the Granzyme B-specific serine protease inhibitor SERPINB9 (SB9) to improve allogeneic T-cell persistence and antitumor efficacy. We showed that the overexpression of an SB9 variant with broadened caspase specificity, SB9(CAS), not only significantly reduced rejection of allogeneic CAR T cells but also increased their resistance to AICD and enabled them to thrive better under CAE, thus improving allogeneic T-cell persistence and antitumor activity in vitro and in vivo. In addition, although SB9(CAS) overexpression improved the efficacy of allogeneic CAR T-cell therapy by conferring protection to cell death, we did not observe any autonomous growth, and the engineered CAR T cells were still susceptible to an inducible suicide switch. Hence, SB9(CAS) overexpression is a promising strategy that can strengthen current development of cell therapies, broadening their applications to address unmet medical needs.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1108-1122"},"PeriodicalIF":8.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141236953","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}

引用次数: 0

A Sampling of Highlights from the Literature. 文献精华选集》。

IF 8.1 1区医学

Cancer immunology research Pub Date : 2024-07-02 DOI: 10.1158/2326-6066.CIR-12-7-WWR

引用次数: 0

IL3-Driven T Cell-Basophil Crosstalk Enhances Antitumor Immunity. IL-3 驱动的 T 细胞-嗜碱性粒细胞串联增强了抗肿瘤免疫力。

IF 8.1 1区医学

Cancer immunology research Pub Date : 2024-07-02 DOI: 10.1158/2326-6066.CIR-23-0851

Jian Wei, Colleen L Mayberry, Xiaoting Lv, Fangyan Hu, Taushif Khan, Natalie A Logan, John J Wilson, John D Sears, Damien Chaussabel, Chih-Hao Chang

{"title":"IL3-Driven T Cell-Basophil Crosstalk Enhances Antitumor Immunity.","authors":"Jian Wei, Colleen L Mayberry, Xiaoting Lv, Fangyan Hu, Taushif Khan, Natalie A Logan, John J Wilson, John D Sears, Damien Chaussabel, Chih-Hao Chang","doi":"10.1158/2326-6066.CIR-23-0851","DOIUrl":"10.1158/2326-6066.CIR-23-0851","url":null,"abstract":"Cytotoxic T lymphocytes (CTL) are pivotal in combating cancer, yet their efficacy is often hindered by the immunosuppressive tumor microenvironment, resulting in CTL exhaustion. This study investigates the role of interleukin-3 (IL3) in orchestrating antitumor immunity through CTL modulation. We found that intratumoral CTLs exhibited a progressive decline in IL3 production, which was correlated with impaired cytotoxic function. Augmenting IL3 supplementation, through intraperitoneal administration of recombinant IL3, IL3-expressing tumor cells, or IL3-engineered CD8+ T cells, conferred protection against tumor progression, concomitant with increased CTL activity. CTLs were critical for this therapeutic efficacy as IL3 demonstrated no impact on tumor growth in Rag1 knockout mice or following CD8+ T-cell depletion. Rather than acting directly, CTL-derived IL3 exerted its influence on basophils, concomitantly amplifying antitumor immunity within CTLs. Introducing IL3-activated basophils retarded tumor progression, whereas basophil depletion diminished the effectiveness of IL3 supplementation. Furthermore, IL3 prompted basophils to produce IL4, which subsequently elevated CTL IFNγ production and viability. Further, the importance of basophil-derived IL4 was evident from the absence of benefits of IL3 supplementation in IL4 knockout tumor-bearing mice. Overall, this research has unveiled a role for IL3-mediated CTL-basophil cross-talk in regulating antitumor immunity and suggests harnessing IL3 sustenance as a promising approach for optimizing and enhancing cancer immunotherapy. See related Spotlight, p. 798.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"822-839"},"PeriodicalIF":8.1,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11219266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140911428","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}

引用次数: 0

Do Not Forget the Granulocytic Compartment's Role in T cell-Mediated Antitumor Immunity. 不要忘记粒细胞区在 T 细胞介导的抗肿瘤免疫中的作用。

IF 8.1 1区医学

Cancer immunology research Pub Date : 2024-07-02 DOI: 10.1158/2326-6066.CIR-24-0395

Udo S Gaipl

引用次数: 0

PVRIG is Expressed on Stem-Like T Cells in Dendritic Cell-Rich Niches in Tumors and Its Blockade May Induce Immune Infiltration in Non-Inflamed Tumors. PVRIG 在肿瘤中树突状细胞丰富的龛位中的干样 T 细胞上表达，阻断 PVRIG 可诱导非炎症肿瘤中的免疫浸润。

IF 8.1 1区医学

Cancer immunology research Pub Date : 2024-07-02 DOI: 10.1158/2326-6066.CIR-23-0752

Zoya Alteber, Gady Cojocaru, Roy Z Granit, Inbal Barbiro, Assaf Wool, Masha Frenkel, Amit Novik, Adi Shuchami, Yu Liang, Vered D Carmi, Niv Sabath, Rob Foreman, Natalia Petrenko, Jiang He, Yossef Kliger, Adva Levy-Barda, Ram Eitan, Oded Raban, Eran Sadot, Omri Sulimani, Abraham Avi Nathan, Henry Adewoye, Pierre Ferre, Zurit Levine, Eran Ophir

{"title":"PVRIG is Expressed on Stem-Like T Cells in Dendritic Cell-Rich Niches in Tumors and Its Blockade May Induce Immune Infiltration in Non-Inflamed Tumors.","authors":"Zoya Alteber, Gady Cojocaru, Roy Z Granit, Inbal Barbiro, Assaf Wool, Masha Frenkel, Amit Novik, Adi Shuchami, Yu Liang, Vered D Carmi, Niv Sabath, Rob Foreman, Natalia Petrenko, Jiang He, Yossef Kliger, Adva Levy-Barda, Ram Eitan, Oded Raban, Eran Sadot, Omri Sulimani, Abraham Avi Nathan, Henry Adewoye, Pierre Ferre, Zurit Levine, Eran Ophir","doi":"10.1158/2326-6066.CIR-23-0752","DOIUrl":"10.1158/2326-6066.CIR-23-0752","url":null,"abstract":"Cancers that are poorly immune infiltrated pose a substantial challenge, with current immunotherapies yielding limited clinical success. Stem-like memory T cells (TSCM) have been identified as a subgroup of T cells that possess strong proliferative capacity and that can expand and differentiate following interactions with dendritic cells (DCs). In this study, we explored the pattern of expression of a recently discovered inhibitory receptor poliovirus receptor-related immunoglobulin domain protein (PVRIG) and its ligand, poliovirus receptor-related ligand 2 (PVRL2), in the human tumor microenvironment. Using spatial and single-cell RNA transcriptomics data across diverse cancer indications, we found that among the T-cell checkpoints, PVRIG is uniquely expressed on TSCM and PVRL2 is expressed on DCs in immune aggregate niches in tumors. PVRIG blockade could therefore enhance TSCM-DC interactions and efficiently drive T-cell infiltration to tumors. Consistent with these data, following PVRIG blockade in patients with poorly infiltrated tumors, we observed immune modulation including increased tumor T-cell infiltration, T-cell receptor (TCR) clonality, and intratumoral T-cell expansion, all of which were associated with clinical benefit. These data suggest PVRIG blockade as a promising strategy to induce potent antitumor T-cell responses, providing a novel approach to overcome resistance to immunotherapy in immune-excluded tumors.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"876-890"},"PeriodicalIF":8.1,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140944097","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}

引用次数: 0

Engineering CD3/CD137 Dual Specificity into a DLL3-Targeted T-Cell Engager Enhances T-Cell Infiltration and Efficacy against Small-Cell Lung Cancer. 将 CD3/CD137 双特异性植入 DLL3 靶向 T 细胞吸引器，可增强 T 细胞浸润和对小细胞肺癌的疗效。

IF 8.1 1区医学

Cancer immunology research Pub Date : 2024-06-04 DOI: 10.1158/2326-6066.CIR-23-0638

Hirofumi Mikami, Shu Feng, Yutaka Matsuda, Shinya Ishii, Sotaro Naoi, Yumiko Azuma, Hiroaki Nagano, Kentaro Asanuma, Yoko Kayukawa, Toshiaki Tsunenari, Shogo Kamikawaji, Ryutaro Iwabuchi, Junko Shinozuka, Masaki Yamazaki, Haruka Kuroi, Samantha Shu Wen Ho, Siok Wan Gan, Priyanka Chichili, Chai Ling Pang, Chiew Ying Yeo, Shun Shimizu, Naoka Hironiwa, Yasuko Kinoshita, Yuichiro Shimizu, Akihisa Sakamoto, Masaru Muraoka, Noriyuki Takahashi, Tatsuya Kawa, Hirotake Shiraiwa, Futa Mimoto, Kenji Kashima, Mika Kamata-Sakurai, Shumpei Ishikawa, Hiroyuki Aburatani, Takehisa Kitazawa, Tomoyuki Igawa

{"title":"Engineering CD3/CD137 Dual Specificity into a DLL3-Targeted T-Cell Engager Enhances T-Cell Infiltration and Efficacy against Small-Cell Lung Cancer.","authors":"Hirofumi Mikami, Shu Feng, Yutaka Matsuda, Shinya Ishii, Sotaro Naoi, Yumiko Azuma, Hiroaki Nagano, Kentaro Asanuma, Yoko Kayukawa, Toshiaki Tsunenari, Shogo Kamikawaji, Ryutaro Iwabuchi, Junko Shinozuka, Masaki Yamazaki, Haruka Kuroi, Samantha Shu Wen Ho, Siok Wan Gan, Priyanka Chichili, Chai Ling Pang, Chiew Ying Yeo, Shun Shimizu, Naoka Hironiwa, Yasuko Kinoshita, Yuichiro Shimizu, Akihisa Sakamoto, Masaru Muraoka, Noriyuki Takahashi, Tatsuya Kawa, Hirotake Shiraiwa, Futa Mimoto, Kenji Kashima, Mika Kamata-Sakurai, Shumpei Ishikawa, Hiroyuki Aburatani, Takehisa Kitazawa, Tomoyuki Igawa","doi":"10.1158/2326-6066.CIR-23-0638","DOIUrl":"10.1158/2326-6066.CIR-23-0638","url":null,"abstract":"Small-cell lung cancer (SCLC) is an aggressive cancer for which immune checkpoint inhibitors (ICI) have had only limited success. Bispecific T-cell engagers are promising therapeutic alternatives for ICI-resistant tumors, but not all patients with SCLC are responsive. Herein, to integrate CD137 costimulatory function into a T-cell engager format and thereby augment therapeutic efficacy, we generated a CD3/CD137 dual-specific Fab and engineered a DLL3-targeted trispecific antibody (DLL3 trispecific). The CD3/CD137 dual-specific Fab was generated to competitively bind to CD3 and CD137 to prevent DLL3-independent cross-linking of CD3 and CD137, which could lead to systemic T-cell activation. We demonstrated that DLL3 trispecific induced better tumor growth control and a marked increase in the number of intratumoral T cells compared with a conventional DLL3-targeted bispecific T-cell engager. These findings suggest that DLL3 trispecific can exert potent efficacy by inducing concurrent CD137 costimulation and provide a promising therapeutic option for SCLC.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"719-730"},"PeriodicalIF":8.1,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140334853","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}

引用次数: 0