Pub Date : 2024-04-29DOI: 10.1158/2326-6066.cir-23-0692
Matteo Bianchi, Christian Reichen, Amelie Croset, Stefanie Fischer, Aline Eggenschwiler, Yvonne Grübler, Rajlakshmi Marpakwar, Thamar Looser, Patricia Spitzli, Christel Herzog, Denis Villemagne, Dieter Schiegg, Liridon Abduli, Chloé Iss, Alexandra Neculcea, Marco Franchini, Tamara Lekishvili, Simone Ragusa, Christof Zitt, Yvonne Kaufmann, Alienor Auge, Martin Hänggi, Waleed Ali, Teresa M. Frasconi, Stephan Wullschleger, Iris Schlegel, Mirela Matzner, Ursina Lüthi, Bernd Schlereth, Keith M. Dawson, Vladimir Kirkin, Adrian F. Ochsenbein, Sebastian Grimm, Nina Reschke, Carsten Riether, Daniel Steiner, Nicolas Leupin, Anne Goubier
The prognosis of patients with acute myeloid leukemia (AML) is limited, especially for elderly or unfit patients not eligible for hematopoietic stem cell (HSC) transplantation. The disease is driven by leukemic stem cells (LSCs), which are characterized by clonal heterogeneity and resistance to conventional therapy. These cells are therefore believed to be a major cause of progression and relapse. We designed MP0533, a multispecific CD3-engaging DARPin (designed ankyrin repeat protein) that can simultaneously bind to three antigens on AML cells (CD33, CD123, and CD70), aiming to enable avidity-driven T cell–mediated killing of AML cells co-expressing at least two of the antigens. In vitro, MP0533 induced selective T cell–mediated killing of AML cell lines, as well as patient-derived AML blasts and LSCs, expressing two or more target antigens, while sparing healthy HSCs, blood, and endothelial cells. The higher selectivity also resulted in markedly lower levels of cytokine release in normal human blood compared to single antigen–targeting T-cell engagers. In xenograft AML mouse models, MP0533 induced tumor-localized T-cell activation and cytokine release, leading to complete eradication of the tumors while having no systemic adverse effects. These studies show that the multispecific-targeting strategy used with MP0533 holds promise for improved selectivity towards LSCs and efficacy against clonal heterogeneity, potentially bringing a new therapeutic option to this group of patients with high unmet need. MP0533 is currently being evaluated in a dose-escalation phase 1 study in patients with relapsed or refractory AML (NCT05673057).
急性髓性白血病（AML）患者的预后有限，尤其是老年患者或不适合接受造血干细胞（HSC）移植的患者。这种疾病由白血病干细胞（LSC）驱动，其特点是克隆异质性和对传统疗法的抗药性。因此，这些细胞被认为是导致病情恶化和复发的主要原因。我们设计了一种多特异性 CD3 结合 DARPin（设计的碱基重复蛋白）MP0533，它能同时与 AML 细胞上的三种抗原（CD33、CD123 和 CD70）结合，目的是实现由 T 细胞介导的对同时表达至少两种抗原的 AML 细胞的亲和性杀伤。在体外，MP0533 能诱导 T 细胞介导的选择性杀伤表达两种或两种以上靶抗原的急性髓细胞系以及患者来源的急性髓细胞凋亡细胞和 LSCs，而不损伤健康的造血干细胞、血液和内皮细胞。与单抗原靶向 T 细胞吞噬细胞相比，更高的选择性也使正常人血液中细胞因子的释放水平明显降低。在异种移植急性髓细胞性白血病小鼠模型中，MP0533 能诱导肿瘤定位的 T 细胞活化和细胞因子释放，从而彻底消除肿瘤，同时不会产生全身不良反应。这些研究表明，MP0533 采用的多特异性靶向策略有望提高对 LSCs 的选择性和对克隆异质性的疗效，从而有可能为这类需求尚未得到满足的患者带来新的治疗选择。MP0533目前正在复发或难治性急性髓细胞性白血病患者中进行剂量递增1期研究（NCT05673057）。
{"title":"The CD33xCD123xCD70 Multispecific CD3-Engaging DARPin MP0533 Induces Selective T Cell–Mediated Killing of AML Leukemic Stem Cells","authors":"Matteo Bianchi, Christian Reichen, Amelie Croset, Stefanie Fischer, Aline Eggenschwiler, Yvonne Grübler, Rajlakshmi Marpakwar, Thamar Looser, Patricia Spitzli, Christel Herzog, Denis Villemagne, Dieter Schiegg, Liridon Abduli, Chloé Iss, Alexandra Neculcea, Marco Franchini, Tamara Lekishvili, Simone Ragusa, Christof Zitt, Yvonne Kaufmann, Alienor Auge, Martin Hänggi, Waleed Ali, Teresa M. Frasconi, Stephan Wullschleger, Iris Schlegel, Mirela Matzner, Ursina Lüthi, Bernd Schlereth, Keith M. Dawson, Vladimir Kirkin, Adrian F. Ochsenbein, Sebastian Grimm, Nina Reschke, Carsten Riether, Daniel Steiner, Nicolas Leupin, Anne Goubier","doi":"10.1158/2326-6066.cir-23-0692","DOIUrl":"https://doi.org/10.1158/2326-6066.cir-23-0692","url":null,"abstract":"The prognosis of patients with acute myeloid leukemia (AML) is limited, especially for elderly or unfit patients not eligible for hematopoietic stem cell (HSC) transplantation. The disease is driven by leukemic stem cells (LSCs), which are characterized by clonal heterogeneity and resistance to conventional therapy. These cells are therefore believed to be a major cause of progression and relapse. We designed MP0533, a multispecific CD3-engaging DARPin (designed ankyrin repeat protein) that can simultaneously bind to three antigens on AML cells (CD33, CD123, and CD70), aiming to enable avidity-driven T cell–mediated killing of AML cells co-expressing at least two of the antigens. In vitro, MP0533 induced selective T cell–mediated killing of AML cell lines, as well as patient-derived AML blasts and LSCs, expressing two or more target antigens, while sparing healthy HSCs, blood, and endothelial cells. The higher selectivity also resulted in markedly lower levels of cytokine release in normal human blood compared to single antigen–targeting T-cell engagers. In xenograft AML mouse models, MP0533 induced tumor-localized T-cell activation and cytokine release, leading to complete eradication of the tumors while having no systemic adverse effects. These studies show that the multispecific-targeting strategy used with MP0533 holds promise for improved selectivity towards LSCs and efficacy against clonal heterogeneity, potentially bringing a new therapeutic option to this group of patients with high unmet need. MP0533 is currently being evaluated in a dose-escalation phase 1 study in patients with relapsed or refractory AML (NCT05673057).","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":10.1,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140832150","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}
Pub Date : 2024-04-24DOI: 10.1158/2326-6066.CIR-23-0699
Francesco Di Mauro, Giuseppina Arbore
Chemotherapeutics, radiation, targeted therapeutics and immunotherapeutics each demonstrate clinical benefits for a small subset of patients with solid malignancies. Immune cells infiltrating the tumor and the surrounding stroma play a critical role in shaping cancer progression and modulating therapy response. They do this by interacting with the other cellular and molecular components of the tumor microenvironment (TME). Spatial multi-OMICs technologies are rapidly evolving. Currently, such technologies allow high-throughput RNA and protein profiling and retain geographical information about the TME cellular architecture and the functional phenotype of tumor, immune and stromal cells. An in-depth spatial characterization of the heterogenous tumor immune landscape can improve not only the prognosis, but also the prediction of therapy response, directing cancer patients to more tailored and efficacious treatments. This review highlights recent advancements in spatial transcriptomics and proteomics profiling technologies and how these technologies are being applied for the dissection of the immune cell composition in solid malignancies in order to further both basic research in oncology and the implementation of precision treatments in the clinic.
{"title":"Spatial dissection of the immune landscape of solid tumors to advance precision medicine.","authors":"Francesco Di Mauro, Giuseppina Arbore","doi":"10.1158/2326-6066.CIR-23-0699","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-23-0699","url":null,"abstract":"Chemotherapeutics, radiation, targeted therapeutics and immunotherapeutics each demonstrate clinical benefits for a small subset of patients with solid malignancies. Immune cells infiltrating the tumor and the surrounding stroma play a critical role in shaping cancer progression and modulating therapy response. They do this by interacting with the other cellular and molecular components of the tumor microenvironment (TME). Spatial multi-OMICs technologies are rapidly evolving. Currently, such technologies allow high-throughput RNA and protein profiling and retain geographical information about the TME cellular architecture and the functional phenotype of tumor, immune and stromal cells. An in-depth spatial characterization of the heterogenous tumor immune landscape can improve not only the prognosis, but also the prediction of therapy response, directing cancer patients to more tailored and efficacious treatments. This review highlights recent advancements in spatial transcriptomics and proteomics profiling technologies and how these technologies are being applied for the dissection of the immune cell composition in solid malignancies in order to further both basic research in oncology and the implementation of precision treatments in the clinic.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":10.1,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140661329","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}
Pub Date : 2024-04-19DOI: 10.1158/2326-6066.cir-23-0339
Meng Meng, Zhaoyang Zhong, Liang Song, Zhaohui Zhang, Xiaofeng Yin, Xiqiang Xie, Lei Tian, Wei Wu, Yao Yang, Yafei Deng, Hongyan Peng, Shuting Wu, Guanghe Ran, Yuqing Lin, Qiangqiang Lai, Qinghua Bi, Fulin Yan, Yan Ji, Yang Wang, Xiaohui Li, Ping Yi, Jianhua Yu, Youcai Deng
Natural killer (NK) cells can be rapidly activated in response to cytokines during host defense against malignant cells or viral infection. However, it remains unclear what mechanisms precisely and rapidly regulate the expression of the numerous genes involved in activating NK cells. In this study, we discovered that NK-cell N6-methyladenosine (m6A) methylation levels were rapidly upregulated upon short-term NK-cell activation and were repressed in the tumor microenvironment. Deficiency of methyltransferase-like 3 (METTL3) or METTL14 moderately influenced NK-cell homeostasis, while double knockout of METTL3/14 significantly impacted NK-cell homeostasis, maturation, and antitumor immunity. This suggests a cooperative role of METTL3 and METTL14 in regulating NK-cell development and effector functions. Using methylated RNA immunoprecipitation sequencing (MeRIP-seq), we demonstrated that genes involved in NK-cell effector functions, such as Prf1 and Gzmb, were directly modified by m6A methylation. Furthermore, inhibiting mTOR complex 1 (mTORC1) activation prevented m6A methylation levels from increasing when NK cells were activated, and this could be restored by S-adenosylmethionine (SAM) supplementation. Collectively, we have unraveled crucial roles for rapid m6A mRNA methylation downstream of the mTORC1–SAM signal axis in regulating NK-cell activation and effector functions.
在宿主抵御恶性细胞或病毒感染的过程中，自然杀伤（NK）细胞可在细胞因子的作用下被迅速激活。然而，目前仍不清楚是什么机制精确而快速地调控了参与激活 NK 细胞的众多基因的表达。在这项研究中，我们发现 NK 细胞 N6-甲基腺苷（m6A）甲基化水平在 NK 细胞短期激活后迅速上调，并在肿瘤微环境中被抑制。甲基转移酶样3（METTL3）或METTL14的缺失会适度影响NK细胞的稳态，而METTL3/14的双基因敲除则会显著影响NK细胞的稳态、成熟和抗肿瘤免疫。这表明METTL3和METTL14在调控NK细胞发育和效应功能方面发挥着协同作用。利用甲基化 RNA 免疫沉淀测序（MeRIP-seq），我们证明了参与 NK 细胞效应功能的基因，如 Prf1 和 Gzmb，直接被 m6A 甲基化修饰。此外，抑制 mTOR 复合物 1（mTORC1）的活化可阻止 NK 细胞活化时 m6A 甲基化水平的升高，而补充 S-腺苷蛋氨酸（SAM）可恢复这种情况。总之，我们揭示了 mTORC1-SAM 信号轴下游的快速 m6A mRNA 甲基化在调节 NK 细胞活化和效应功能中的关键作用。
{"title":"mTOR signaling promotes rapid m6A mRNA methylation to regulate NK-cell activation and effector functions","authors":"Meng Meng, Zhaoyang Zhong, Liang Song, Zhaohui Zhang, Xiaofeng Yin, Xiqiang Xie, Lei Tian, Wei Wu, Yao Yang, Yafei Deng, Hongyan Peng, Shuting Wu, Guanghe Ran, Yuqing Lin, Qiangqiang Lai, Qinghua Bi, Fulin Yan, Yan Ji, Yang Wang, Xiaohui Li, Ping Yi, Jianhua Yu, Youcai Deng","doi":"10.1158/2326-6066.cir-23-0339","DOIUrl":"https://doi.org/10.1158/2326-6066.cir-23-0339","url":null,"abstract":"Natural killer (NK) cells can be rapidly activated in response to cytokines during host defense against malignant cells or viral infection. However, it remains unclear what mechanisms precisely and rapidly regulate the expression of the numerous genes involved in activating NK cells. In this study, we discovered that NK-cell N6-methyladenosine (m6A) methylation levels were rapidly upregulated upon short-term NK-cell activation and were repressed in the tumor microenvironment. Deficiency of methyltransferase-like 3 (METTL3) or METTL14 moderately influenced NK-cell homeostasis, while double knockout of METTL3/14 significantly impacted NK-cell homeostasis, maturation, and antitumor immunity. This suggests a cooperative role of METTL3 and METTL14 in regulating NK-cell development and effector functions. Using methylated RNA immunoprecipitation sequencing (MeRIP-seq), we demonstrated that genes involved in NK-cell effector functions, such as Prf1 and Gzmb, were directly modified by m6A methylation. Furthermore, inhibiting mTOR complex 1 (mTORC1) activation prevented m6A methylation levels from increasing when NK cells were activated, and this could be restored by S-adenosylmethionine (SAM) supplementation. Collectively, we have unraveled crucial roles for rapid m6A mRNA methylation downstream of the mTORC1–SAM signal axis in regulating NK-cell activation and effector functions.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":10.1,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140624140","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}
Pub Date : 2024-04-17DOI: 10.1158/2326-6066.cir-23-0786
Yueru Hou, Yejin Cao, Ying He, Lin Dong, Longhao Zhao, Yingjie Dong, Ruiying Niu, Yujing Bi, Guangwei Liu
Follicular helper T (TFH) cells are essential for inducing germinal center (GC) reactions to mediate humoral adaptive immunity in tumors, but the mechanisms underlying TFH cell differentiation remain unclear. Here, we found that the metabolism sensor sirtuin 3 (SIRT3) is critical for TFH cell differentiation and GC formation during tumor and viral infection. SIRT3 deficiency in CD4+ T cells intrinsically enhanced TFH cell differentiation and GC reactions during tumor and virus infection. Mechanistically, damaged oxidative phosphorylation (OXPHOS) compensatively triggered the NAD+-glycolysis pathway to provide a cellular energy supply, which was necessary for SIRT3 deficiency-induced TFH cell differentiation. Blocking NAD+ synthesis–glycolysis signaling or recovering OXPHOS activities reversed the TFH cell differentiation induced by SIRT3 deficiency. Moreover, the mTOR and HIF1α signaling axis was found to be responsible for TFH cell differentiation induced by SIRT3 deficiency. HIF1α directly interacted with and regulated the activity of the transcription factor Bcl-6. Thus, our findings identify a cellular energy compensatory mechanism, regulated by the mitochondrial sensor SIRT3, that triggers NAD+-dependent glycolysis during mitochondrial OXPHOS injuries and a mTOR–HIF1α–Bcl-6 pathway to reprogram TFH cell differentiation. These data have implications for future cancer immunotherapy research targeting SIRT3 in T cells.
{"title":"SIRT3 negatively regulates TFH cell differentiation in cancer","authors":"Yueru Hou, Yejin Cao, Ying He, Lin Dong, Longhao Zhao, Yingjie Dong, Ruiying Niu, Yujing Bi, Guangwei Liu","doi":"10.1158/2326-6066.cir-23-0786","DOIUrl":"https://doi.org/10.1158/2326-6066.cir-23-0786","url":null,"abstract":"Follicular helper T (TFH) cells are essential for inducing germinal center (GC) reactions to mediate humoral adaptive immunity in tumors, but the mechanisms underlying TFH cell differentiation remain unclear. Here, we found that the metabolism sensor sirtuin 3 (SIRT3) is critical for TFH cell differentiation and GC formation during tumor and viral infection. SIRT3 deficiency in CD4+ T cells intrinsically enhanced TFH cell differentiation and GC reactions during tumor and virus infection. Mechanistically, damaged oxidative phosphorylation (OXPHOS) compensatively triggered the NAD+-glycolysis pathway to provide a cellular energy supply, which was necessary for SIRT3 deficiency-induced TFH cell differentiation. Blocking NAD+ synthesis–glycolysis signaling or recovering OXPHOS activities reversed the TFH cell differentiation induced by SIRT3 deficiency. Moreover, the mTOR and HIF1α signaling axis was found to be responsible for TFH cell differentiation induced by SIRT3 deficiency. HIF1α directly interacted with and regulated the activity of the transcription factor Bcl-6. Thus, our findings identify a cellular energy compensatory mechanism, regulated by the mitochondrial sensor SIRT3, that triggers NAD+-dependent glycolysis during mitochondrial OXPHOS injuries and a mTOR–HIF1α–Bcl-6 pathway to reprogram TFH cell differentiation. These data have implications for future cancer immunotherapy research targeting SIRT3 in T cells.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":10.1,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140610787","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}
Pub Date : 2024-04-17DOI: 10.1158/2326-6066.cir-23-0926
Haifeng Pan, Siyuan Yu, Haoyun Zhuang, Han Yang, Jinlu Jiang, Haihui Yang, Shuling Ren, Guoxing Luo, Xuan Yu, Shuping Chen, Yanhua Lin, Roufang Sheng, Shiyin Zhang, Quan Yuan, Chenghao Huang, Tianying Zhang, Tingdong Li, Shengxiang Ge, Jun Zhang, Ningshao Xia
The intrinsic pharmacokinetic limitations of traditional peptide-based cancer vaccines hamper effective cross-presentation and codelivery of antigens and adjuvants, which are crucial for inducing robust antitumor CD8+ T-cell responses. Here, we report the development of a versatile strategy that simultaneously addresses the different pharmacokinetic challenges of soluble subunit vaccines composed of antigens and CpG to modulate vaccine efficacy via translating an engineered chimeric peptide, eTAT, as an intramolecular adjuvant. Linking antigens to eTAT enhanced cytosolic delivery of the antigens. This, in turn, led to improved activation and lymph node–trafficking of antigen-presenting cells and antigen cross-presentation, thus promoting antigen-specific T-cell immune responses. Simple mixing of eTAT-linked antigens and CpG significantly enhanced codelivery of antigens and CpG to the antigen-presenting cells, and this substantially augmented the adjuvant effect of CpG, maximized vaccine immunogenicity and elicited robust and durable CD8+ T-cell responses. Vaccination with this formulation altered the tumor microenvironment and exhibited potent antitumor effects, with generally further enhanced therapeutic efficacy when used in combination with anti-PD1. Altogether, the engineered chimeric peptide–based orchestrated codelivery of antigen and adjuvant may serve as a promising but simple strategy to improve the efficacy of peptide-based cancer vaccines.
传统多肽类癌症疫苗固有的药代动力学局限性阻碍了抗原和佐剂的有效交叉呈递和联合递送，而这对于诱导强大的抗肿瘤 CD8+ T 细胞应答至关重要。在此，我们报告了一种多功能策略的开发情况，该策略通过将工程嵌合肽 eTAT 转化为分子内佐剂，同时解决了由抗原和 CpG 组成的可溶性亚单位疫苗所面临的不同药代动力学挑战，以调节疫苗功效。将抗原与 eTAT 连接起来可增强抗原的胞浆传递。这反过来又改善了抗原递呈细胞的活化和淋巴结迁移以及抗原交叉递呈，从而促进了抗原特异性 T 细胞免疫反应。eTAT 链接抗原与 CpG 的简单混合大大增强了抗原和 CpG 对抗原呈递细胞的编码传递，这大大增强了 CpG 的佐剂效应，最大限度地提高了疫苗的免疫原性，并激发了强健持久的 CD8+ T 细胞应答。接种这种制剂的疫苗可改变肿瘤微环境，并显示出强大的抗肿瘤效果，与抗-PD1联合使用时，疗效会进一步提高。总之，基于嵌合肽的工程化抗原和佐剂协调联合递送可作为一种前景广阔而又简单的策略来提高基于肽的癌症疫苗的疗效。
{"title":"Orchestrated codelivery of peptide antigen and adjuvant to antigen-presenting cells by using an engineered chimeric peptide enhances antitumor T-cell immunity","authors":"Haifeng Pan, Siyuan Yu, Haoyun Zhuang, Han Yang, Jinlu Jiang, Haihui Yang, Shuling Ren, Guoxing Luo, Xuan Yu, Shuping Chen, Yanhua Lin, Roufang Sheng, Shiyin Zhang, Quan Yuan, Chenghao Huang, Tianying Zhang, Tingdong Li, Shengxiang Ge, Jun Zhang, Ningshao Xia","doi":"10.1158/2326-6066.cir-23-0926","DOIUrl":"https://doi.org/10.1158/2326-6066.cir-23-0926","url":null,"abstract":"The intrinsic pharmacokinetic limitations of traditional peptide-based cancer vaccines hamper effective cross-presentation and codelivery of antigens and adjuvants, which are crucial for inducing robust antitumor CD8+ T-cell responses. Here, we report the development of a versatile strategy that simultaneously addresses the different pharmacokinetic challenges of soluble subunit vaccines composed of antigens and CpG to modulate vaccine efficacy via translating an engineered chimeric peptide, eTAT, as an intramolecular adjuvant. Linking antigens to eTAT enhanced cytosolic delivery of the antigens. This, in turn, led to improved activation and lymph node–trafficking of antigen-presenting cells and antigen cross-presentation, thus promoting antigen-specific T-cell immune responses. Simple mixing of eTAT-linked antigens and CpG significantly enhanced codelivery of antigens and CpG to the antigen-presenting cells, and this substantially augmented the adjuvant effect of CpG, maximized vaccine immunogenicity and elicited robust and durable CD8+ T-cell responses. Vaccination with this formulation altered the tumor microenvironment and exhibited potent antitumor effects, with generally further enhanced therapeutic efficacy when used in combination with anti-PD1. Altogether, the engineered chimeric peptide–based orchestrated codelivery of antigen and adjuvant may serve as a promising but simple strategy to improve the efficacy of peptide-based cancer vaccines.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":10.1,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140611084","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}
Pub Date : 2024-04-17DOI: 10.1158/2326-6066.cir-23-0757
David König, Michael Sandholzer, Sarp Uzun, Andreas Zingg, Reto Ritschard, Helen Thut, Katharina Glatz, Elisabeth A. Kappos, Dirk J. Schaefer, Christoph Kettelhack, Jakob R. Passweg, Andreas Holbro, Katharina Baur, Michael Medinger, Andreas Buser, Didier Lardinois, Lukas T. Jeker, Nina Khanna, Frank Stenner, Benjamin Kasenda, Krisztian Homicsko, Matthias Matter, Natalia Rodrigues Mantuano, Alfred Zippelius, Heinz Läubli
Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) is effective in melanoma patients, although long-term responses seem restricted to patients who have complete remissions. Many patients develop secondary resistance to TIL-ACT but the involved mechanisms are unclear. Here, we describe a case of secondary resistance to TIL-ACT likely due to intratumoral heterogeneity and selection of a resistant tumor cell clone by the transferred T cells. To our knowledge, this is the first case of clonal selection of a pre-existing non-dominant tumor cell clone and it demonstrates a mechanism involved in secondary resistance to TIL-ACT that could potentially change current clinical practice, because it advocates for T-cell collection from multiple tumor sites and analysis of tumor heterogeneity before the treatment with TIL-ACT.
使用肿瘤浸润淋巴细胞（TIL）的适应性细胞疗法（ACT）对黑色素瘤患者有效，但长期反应似乎仅限于完全缓解的患者。许多患者会对TIL-ACT产生继发性耐药性，但其中的机制尚不清楚。在这里，我们描述了一例对 TIL-ACT 产生继发性耐药的病例，其原因可能是瘤内异质性和转移的 T 细胞选择了耐药的肿瘤细胞克隆。据我们所知，这是第一例对已存在的非优势肿瘤细胞克隆进行克隆选择的病例，它展示了TIL-ACT继发性耐药的机制，有可能改变目前的临床实践，因为它提倡在使用TIL-ACT治疗前从多个肿瘤部位收集T细胞并分析肿瘤的异质性。
{"title":"Melanoma clonal heterogeneity leads to secondary resistance after adoptive cell therapy with tumor-infiltrating lymphocytes","authors":"David König, Michael Sandholzer, Sarp Uzun, Andreas Zingg, Reto Ritschard, Helen Thut, Katharina Glatz, Elisabeth A. Kappos, Dirk J. Schaefer, Christoph Kettelhack, Jakob R. Passweg, Andreas Holbro, Katharina Baur, Michael Medinger, Andreas Buser, Didier Lardinois, Lukas T. Jeker, Nina Khanna, Frank Stenner, Benjamin Kasenda, Krisztian Homicsko, Matthias Matter, Natalia Rodrigues Mantuano, Alfred Zippelius, Heinz Läubli","doi":"10.1158/2326-6066.cir-23-0757","DOIUrl":"https://doi.org/10.1158/2326-6066.cir-23-0757","url":null,"abstract":"Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) is effective in melanoma patients, although long-term responses seem restricted to patients who have complete remissions. Many patients develop secondary resistance to TIL-ACT but the involved mechanisms are unclear. Here, we describe a case of secondary resistance to TIL-ACT likely due to intratumoral heterogeneity and selection of a resistant tumor cell clone by the transferred T cells. To our knowledge, this is the first case of clonal selection of a pre-existing non-dominant tumor cell clone and it demonstrates a mechanism involved in secondary resistance to TIL-ACT that could potentially change current clinical practice, because it advocates for T-cell collection from multiple tumor sites and analysis of tumor heterogeneity before the treatment with TIL-ACT.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":10.1,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140611082","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}
Pub Date : 2024-04-09DOI: 10.1158/2326-6066.cir-23-0706
Assaf Menachem, Zoya Alteber, Gady Cojocaru, Tal Fridman Kfir, Dan Blat, Olga Leiderman, Moran Galperin, Lital Sever, Nadav Cohen, Keren Cohen, Roy Z. Granit, Sandra Vols, Masha Frenkel, Liron Soffer, Karin Meyer, Keren Menachem, Hadas Galon Tilleman, Dina Morein, Itamar Borukhov, Amir Toporik, Michal Perpinial Shahor, Evgeny Tatirovsky, Aviram Mizrachi, Adva Levy-Barda, Eran Sadot, Yulia Strenov, Ram Eitan, Ariella Jakobson-Setton, Natalia Yanichkin, Pierre Ferre, Eran Ophir
Recombinant cytokines have limited anticancer efficacy mostly due to a narrow therapeutic window and systemic adverse effects. IL18 is an inflammasome-induced proinflammatory cytokine, which enhances T- and NK-cell activity and stimulates IFNγ production. The activity of IL18 is naturally blocked by a high-affinity endogenous binding protein (IL18BP). IL18BP is induced in the tumor microenvironment (TME) in response to IFNγ upregulation in a negative feedback mechanism. In this study, we found that IL18 is upregulated in the TME compared with the periphery across multiple human tumors and most of it is bound to IL18BP. Bound IL18 levels were largely above the amount required for T-cell activation in vitro, implying that releasing IL18 in the TME could lead to potent T-cell activation. To restore the activity of endogenous IL18, we generated COM503, a high-affinity anti-IL18BP that blocks the IL18BP:IL18 interaction and displaces precomplexed IL18, thereby enhancing T- and NK-cell activation. In vivo, administration of a surrogate anti-IL18BP, either alone or in combination with anti-PD-L1, resulted in significant tumor growth inhibition and increased survival across multiple mouse tumor models. Moreover, the anti-IL18BP induced pronounced TME-localized immune modulation including an increase in polyfunctional nonexhausted T- and NK-cell numbers and activation. In contrast, no increase in inflammatory cytokines and lymphocyte numbers or activation state was observed in serum and spleen. Taken together, blocking IL18BP using an Ab is a promising approach to harness cytokine biology for the treatment of cancer.
重组细胞因子的抗癌疗效有限，主要原因是治疗窗口狭窄和全身不良反应。IL18 是一种炎性体诱导的促炎细胞因子，可增强 T 细胞和 NK 细胞的活性，刺激 IFNγ 的产生。IL18 的活性被一种高亲和力内源性结合蛋白（IL18BP）天然阻断。在负反馈机制中，IL18BP 在肿瘤微环境（TME）中被诱导，以响应 IFNγ 的上调。在这项研究中，我们发现在多种人类肿瘤中，IL18 在肿瘤微环境中比在外周上调，而且大部分都与 IL18BP 结合。结合的IL18水平大大高于体外激活T细胞所需的量，这意味着在TME中释放IL18可导致强效的T细胞激活。为了恢复内源性IL18的活性，我们制备了一种高亲和力抗IL18BP的药物COM503，它能阻断IL18BP与IL18的相互作用并置换预复合的IL18，从而增强T细胞和NK细胞的活化。在体内，单独或与抗-PD-L1联合使用代用抗IL18BP可显著抑制肿瘤生长，提高多种小鼠肿瘤模型的存活率。此外，抗IL18BP还能诱导明显的TME定位免疫调节，包括增加多功能非耗竭T细胞和NK细胞的数量和活化。相比之下，在血清和脾脏中没有观察到炎性细胞因子和淋巴细胞数量或活化状态的增加。综上所述，使用抗体阻断 IL18BP 是利用细胞因子生物学治疗癌症的一种很有前景的方法。
{"title":"Unleashing Natural IL18 Activity Using an Anti-IL18BP Blocker Induces Potent Immune Stimulation and Antitumor Effects","authors":"Assaf Menachem, Zoya Alteber, Gady Cojocaru, Tal Fridman Kfir, Dan Blat, Olga Leiderman, Moran Galperin, Lital Sever, Nadav Cohen, Keren Cohen, Roy Z. Granit, Sandra Vols, Masha Frenkel, Liron Soffer, Karin Meyer, Keren Menachem, Hadas Galon Tilleman, Dina Morein, Itamar Borukhov, Amir Toporik, Michal Perpinial Shahor, Evgeny Tatirovsky, Aviram Mizrachi, Adva Levy-Barda, Eran Sadot, Yulia Strenov, Ram Eitan, Ariella Jakobson-Setton, Natalia Yanichkin, Pierre Ferre, Eran Ophir","doi":"10.1158/2326-6066.cir-23-0706","DOIUrl":"https://doi.org/10.1158/2326-6066.cir-23-0706","url":null,"abstract":"Recombinant cytokines have limited anticancer efficacy mostly due to a narrow therapeutic window and systemic adverse effects. IL18 is an inflammasome-induced proinflammatory cytokine, which enhances T- and NK-cell activity and stimulates IFNγ production. The activity of IL18 is naturally blocked by a high-affinity endogenous binding protein (IL18BP). IL18BP is induced in the tumor microenvironment (TME) in response to IFNγ upregulation in a negative feedback mechanism. In this study, we found that IL18 is upregulated in the TME compared with the periphery across multiple human tumors and most of it is bound to IL18BP. Bound IL18 levels were largely above the amount required for T-cell activation in vitro, implying that releasing IL18 in the TME could lead to potent T-cell activation. To restore the activity of endogenous IL18, we generated COM503, a high-affinity anti-IL18BP that blocks the IL18BP:IL18 interaction and displaces precomplexed IL18, thereby enhancing T- and NK-cell activation. In vivo, administration of a surrogate anti-IL18BP, either alone or in combination with anti-PD-L1, resulted in significant tumor growth inhibition and increased survival across multiple mouse tumor models. Moreover, the anti-IL18BP induced pronounced TME-localized immune modulation including an increase in polyfunctional nonexhausted T- and NK-cell numbers and activation. In contrast, no increase in inflammatory cytokines and lymphocyte numbers or activation state was observed in serum and spleen. Taken together, blocking IL18BP using an Ab is a promising approach to harness cytokine biology for the treatment of cancer.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":10.1,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140573462","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}
Pub Date : 2024-04-08DOI: 10.1158/2326-6066.cir-23-0722
Jiuling Yang, Li Wang, James R. Byrnes, Lisa L. Kirkemo, Hannah Driks, Cassandra D. Belair, Oscar A. Aguilar, Lewis L. Lanier, James A. Wells, Lawrence Fong, Robert Blelloch
Poliovirus receptor-related 2 (PVRL2, also known as nectin-2 or CD112) is believed to act as an immune checkpoint protein in cancer; however, most insight into its role is inferred from studies on its known receptor, poliovirus receptor (PVR)-related immunoglobulin domain protein (PVRIG, also known as CD112R). Here, we study PVRL2 itself. PVRL2 levels were found to be high in tumor cells and tumor-derived exosomes. Deletion of PVRL2 in multiple syngeneic mouse models of cancer showed a dramatic reduction in tumor growth that was immune dependent. This effect was even greater than that seen with deletion of PD-L1. PVRL2 was shown to function by suppressing CD8+ T and natural killer cells in the tumor microenvironment. The loss of PVRL2 suppressed tumor growth even in the absence of PVRIG. In contrast, PVRIG loss showed no additive effect in the absence of PVRL2. T-cell immunoreceptor with Ig and ITIM domains (TIGIT) blockade combined with PVRL2 deletion resulted in a near complete block in tumor growth. This effect was not recapitulated by the combined deletion of PVRL2 with its paralog, PVR, which is the ligand for TIGIT. These data uncover PVRL2 as a distinct inhibitor of the antitumor immune response with functions beyond that of its known receptor PVRIG. Moreover, the data provide a strong rationale for combinatorial targeting of PVRL2 and TIGIT for cancer immunotherapy.
{"title":"PVRL2 Suppresses Antitumor Immunity through PVRIG- and TIGIT-independent Pathways","authors":"Jiuling Yang, Li Wang, James R. Byrnes, Lisa L. Kirkemo, Hannah Driks, Cassandra D. Belair, Oscar A. Aguilar, Lewis L. Lanier, James A. Wells, Lawrence Fong, Robert Blelloch","doi":"10.1158/2326-6066.cir-23-0722","DOIUrl":"https://doi.org/10.1158/2326-6066.cir-23-0722","url":null,"abstract":"Poliovirus receptor-related 2 (PVRL2, also known as nectin-2 or CD112) is believed to act as an immune checkpoint protein in cancer; however, most insight into its role is inferred from studies on its known receptor, poliovirus receptor (PVR)-related immunoglobulin domain protein (PVRIG, also known as CD112R). Here, we study PVRL2 itself. PVRL2 levels were found to be high in tumor cells and tumor-derived exosomes. Deletion of PVRL2 in multiple syngeneic mouse models of cancer showed a dramatic reduction in tumor growth that was immune dependent. This effect was even greater than that seen with deletion of PD-L1. PVRL2 was shown to function by suppressing CD8+ T and natural killer cells in the tumor microenvironment. The loss of PVRL2 suppressed tumor growth even in the absence of PVRIG. In contrast, PVRIG loss showed no additive effect in the absence of PVRL2. T-cell immunoreceptor with Ig and ITIM domains (TIGIT) blockade combined with PVRL2 deletion resulted in a near complete block in tumor growth. This effect was not recapitulated by the combined deletion of PVRL2 with its paralog, PVR, which is the ligand for TIGIT. These data uncover PVRL2 as a distinct inhibitor of the antitumor immune response with functions beyond that of its known receptor PVRIG. Moreover, the data provide a strong rationale for combinatorial targeting of PVRL2 and TIGIT for cancer immunotherapy.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":10.1,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140573629","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}
Pub Date : 2024-04-04DOI: 10.1158/2326-6066.cir-23-0158
Michael V. Martin, Salvador Aguilar-Rosas, Katka Franke, Mark Pieterse, Jamie van Langelaar, Renee RCE. Schreurs, Maarten F. Bijlsma, Marc G. Besselink, Jan Koster, Wim Timens, Mustafa Khasraw, David M. Ashley, Stephen T. Keir, Christian H. Ottensmeier, Emma V. King, Joanne Verheij, Cynthia Waasdorp, Peter J.M. Valk, Sem AG. Engels, Ellen Oostenbach, Jip T. van Dinter, Damon A. Hofman, Juk Yee Mok, Wim J.E. van Esch, Hanneke Wilmink, Kim Monkhorst, Henk M.W. Verheul, Dennis Poel, T Jeroen N. Hiltermann, Léon C. van Kempen, Harry JM. Groen, Joachim G.J.V. Aerts, Sebastiaan van Heesch, Bob Lowenberg, Ronald Plasterk, Wigard P. Kloosterman
Identification of immunogenic cancer neoantigens as targets for therapy is challenging. Here, we integrate cancer whole genome and long-read transcript sequencing to identify the collection of novel open reading frame peptides (NOPs) expressed in tumors, termed the framome. NOPs represent tumor-specific peptides that are different from wild-type proteins and may be strongly immunogenic. We describe an uncharacterized class of hidden NOPs, which derive from structural genomic variants involving an upstream protein coding gene driving expression and translation of non-coding regions of the genome downstream of a rearrangement breakpoint. NOPs represent a vast amount of possible neoantigens particularly in tumors with many (complex) structural genomic variants and a low number of missense mutations. We show that NOPs are immunogenic and epitopes derived from NOPs can bind to MHC class I molecules. Finally, we provide evidence for the presence of memory T-cells specific for hidden NOPs in lung cancer patient peripheral blood.
鉴定作为治疗靶点的免疫原性癌症新抗原具有挑战性。在这里，我们整合了癌症全基因组测序和长线程转录本测序，以鉴定肿瘤中表达的新型开放阅读框肽（NOPs）集合，称为 "framome"。NOPs 代表肿瘤特异性多肽，它们不同于野生型蛋白，可能具有很强的免疫原性。我们描述了一类尚未定性的隐性 NOPs，它们来自结构基因组变异，涉及上游蛋白编码基因驱动基因组重排断点下游非编码区的表达和翻译。NOPs 代表了大量可能的新抗原，尤其是在具有大量（复杂）结构基因组变异和少量错义突变的肿瘤中。我们的研究表明，NOPs 具有免疫原性，NOPs 衍生的表位可与 MHC I 类分子结合。最后，我们提供了肺癌患者外周血中存在特异于隐藏 NOPs 的记忆 T 细胞的证据。
{"title":"The neo-open reading frame peptides that comprise the tumor framome are a rich source of neoantigens for cancer immunotherapy","authors":"Michael V. Martin, Salvador Aguilar-Rosas, Katka Franke, Mark Pieterse, Jamie van Langelaar, Renee RCE. Schreurs, Maarten F. Bijlsma, Marc G. Besselink, Jan Koster, Wim Timens, Mustafa Khasraw, David M. Ashley, Stephen T. Keir, Christian H. Ottensmeier, Emma V. King, Joanne Verheij, Cynthia Waasdorp, Peter J.M. Valk, Sem AG. Engels, Ellen Oostenbach, Jip T. van Dinter, Damon A. Hofman, Juk Yee Mok, Wim J.E. van Esch, Hanneke Wilmink, Kim Monkhorst, Henk M.W. Verheul, Dennis Poel, T Jeroen N. Hiltermann, Léon C. van Kempen, Harry JM. Groen, Joachim G.J.V. Aerts, Sebastiaan van Heesch, Bob Lowenberg, Ronald Plasterk, Wigard P. Kloosterman","doi":"10.1158/2326-6066.cir-23-0158","DOIUrl":"https://doi.org/10.1158/2326-6066.cir-23-0158","url":null,"abstract":"Identification of immunogenic cancer neoantigens as targets for therapy is challenging. Here, we integrate cancer whole genome and long-read transcript sequencing to identify the collection of novel open reading frame peptides (NOPs) expressed in tumors, termed the framome. NOPs represent tumor-specific peptides that are different from wild-type proteins and may be strongly immunogenic. We describe an uncharacterized class of hidden NOPs, which derive from structural genomic variants involving an upstream protein coding gene driving expression and translation of non-coding regions of the genome downstream of a rearrangement breakpoint. NOPs represent a vast amount of possible neoantigens particularly in tumors with many (complex) structural genomic variants and a low number of missense mutations. We show that NOPs are immunogenic and epitopes derived from NOPs can bind to MHC class I molecules. Finally, we provide evidence for the presence of memory T-cells specific for hidden NOPs in lung cancer patient peripheral blood.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":10.1,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140573459","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}
Pub Date : 2024-04-04DOI: 10.1158/2326-6066.cir-23-0324
Ting Lu, Rui Ma, Anthony G. Mansour, Christian Bustillos, Zhiyao Li, Zhenlong Li, Shoubao Ma, Kun-Yu Teng, Hanyu Chen, Jianying Zhang, Miguel A. Villalona-Calero, Michael A. Caligiuri, Jianhua Yu
We described previously a human natural killer (NK) cell population that upregulates PD-L1 expression upon recognizing and reacting to tumor cells or exposure to a combination of IL12, IL18 and IL15. Here, to investigate the safety and efficacy of tumor-reactive and cytokine-activated (TRACK) NK cells, human NK cells from umbilical cord blood were expanded, transduced with a retroviral vector encoding soluble (s) IL15, and further cytokine activated to induce PD-L1 expression. Our results show cryopreserved and thawed sIL15_TRACK NK cells had significantly improved cytotoxicity against non-small cell lung cancer (NSCLC) in vitro when compared to non-transduced (NT) NK cells, PD-L1+ NK cells lacking sIL15 expression (NT_TRACK NK), or NK cells expressing sIL15 without further cytokine activation (sIL15 NK cells). Intravenous injection of sIL15_TRACK NK cells into immunodeficient mice with NSCLC significantly slowed tumor growth and improved survival when compared to NT NK and sIL15 NK cells. The addition of the anti–PD-L1 atezolizumab further improved control of NSCLC growth by sIL15_TRACK NK cells in vivo. Moreover, a dose-dependent efficacy was assessed for sIL15_TRACK NK cells without observed toxicity. These experiments indicate that the administration of frozen, off-the-shelf allogeneic sIL15_TRACK NK cells is safe in preclinical models of human NSCLC and has potent antitumor activity without and with the administration of atezolizumab. A Phase I clinical trial modeled after this preclinical study using sIL15_TRACK NK cells alone or with atezolizumab for relapsed or refractory NSCLC is currently underway (NCT05334329).
我们以前曾描述过一种人类自然杀伤（NK）细胞群，它在识别肿瘤细胞并与之发生反应或暴露于 IL12、IL18 和 IL15 的联合作用时会上调 PD-L1 的表达。为了研究肿瘤反应和细胞因子激活（TRACK）NK细胞的安全性和有效性，我们扩增了来自脐带血的人类NK细胞，用编码可溶性（s）IL15的逆转录病毒载体进行转导，并进一步激活细胞因子以诱导PD-L1的表达。我们的研究结果表明，与未转导（NT）NK细胞、缺乏sIL15表达的PD-L1+ NK细胞（NT_TRACK NK）或表达sIL15但未进一步细胞因子活化的NK细胞（sIL15 NK细胞）相比，冷冻保存并解冻的sIL15_TRACK NK细胞在体外对非小细胞肺癌（NSCLC）的细胞毒性明显提高。与NT NK细胞和sIL15 NK细胞相比，向患有NSCLC的免疫缺陷小鼠静脉注射sIL15_TRACK NK细胞可显著减缓肿瘤生长并提高存活率。加入抗PD-L1的atezolizumab可进一步改善sIL15_TRACK NK细胞对体内NSCLC生长的控制。此外，还评估了 sIL15_TRACK NK 细胞的剂量依赖性疗效，且未观察到毒性。这些实验表明，在人类 NSCLC 临床前模型中使用冷冻的、现成的异体 sIL15_TRACK NK 细胞是安全的，而且在不使用或使用阿特珠单抗的情况下都具有很强的抗肿瘤活性。以这项临床前研究为蓝本，目前正在进行一项 I 期临床试验（NCT05334329），使用 sIL15_TRACK NK 细胞单独或联合阿特珠单抗治疗复发或难治性 NSCLC。
{"title":"Preclinical Evaluation of Off-The-Shelf PD-L1+ Human Natural Killer Cells Secreting IL15 to Treat Non-Small Cell Lung Cancer","authors":"Ting Lu, Rui Ma, Anthony G. Mansour, Christian Bustillos, Zhiyao Li, Zhenlong Li, Shoubao Ma, Kun-Yu Teng, Hanyu Chen, Jianying Zhang, Miguel A. Villalona-Calero, Michael A. Caligiuri, Jianhua Yu","doi":"10.1158/2326-6066.cir-23-0324","DOIUrl":"https://doi.org/10.1158/2326-6066.cir-23-0324","url":null,"abstract":"We described previously a human natural killer (NK) cell population that upregulates PD-L1 expression upon recognizing and reacting to tumor cells or exposure to a combination of IL12, IL18 and IL15. Here, to investigate the safety and efficacy of tumor-reactive and cytokine-activated (TRACK) NK cells, human NK cells from umbilical cord blood were expanded, transduced with a retroviral vector encoding soluble (s) IL15, and further cytokine activated to induce PD-L1 expression. Our results show cryopreserved and thawed sIL15_TRACK NK cells had significantly improved cytotoxicity against non-small cell lung cancer (NSCLC) in vitro when compared to non-transduced (NT) NK cells, PD-L1+ NK cells lacking sIL15 expression (NT_TRACK NK), or NK cells expressing sIL15 without further cytokine activation (sIL15 NK cells). Intravenous injection of sIL15_TRACK NK cells into immunodeficient mice with NSCLC significantly slowed tumor growth and improved survival when compared to NT NK and sIL15 NK cells. The addition of the anti–PD-L1 atezolizumab further improved control of NSCLC growth by sIL15_TRACK NK cells in vivo. Moreover, a dose-dependent efficacy was assessed for sIL15_TRACK NK cells without observed toxicity. These experiments indicate that the administration of frozen, off-the-shelf allogeneic sIL15_TRACK NK cells is safe in preclinical models of human NSCLC and has potent antitumor activity without and with the administration of atezolizumab. A Phase I clinical trial modeled after this preclinical study using sIL15_TRACK NK cells alone or with atezolizumab for relapsed or refractory NSCLC is currently underway (NCT05334329).","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":10.1,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140573627","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}
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