Pub Date : 2024-04-22DOI: 10.1186/s40164-024-00510-w
Huageng Huang, Wei Zhang, Xinyi Deng, He Huang, Zhao Wang, Huangming Hong, Tongyu Lin
Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of hematological malignancies with poor survival, while treatment options for relapsed or refractory (R/R) disease remain quite limited, with a median progression-free survival of only 3–4 months. Notably, the emergence of innovative therapeutic agents and regimens holds promise for durable responses and improved survival for patients with R/R PTCL. We summarize recent advances in the treatment of R/R PTCL from the 2023 ASH Annual Meeting, highlighting novel agents targeting EZH1/2, JAK1, PI3K, KIR3DL2, CD38/CD3xCD28, or CDK9, as well as therapeutic regimens in combination with stem cell transplantation, immunomodulators, epigenetic modifying agents, or CD30/CD16A bispecific antibodies.
外周 T 细胞淋巴瘤（PTCL）是一种异质性血液恶性肿瘤，生存率很低，而复发或难治性（R/R）疾病的治疗方案仍然非常有限，中位无进展生存期仅为 3-4 个月。值得注意的是，创新治疗药物和方案的出现为复发性或难治性 PTCL 患者带来了持久应答和改善生存的希望。我们总结了2023年ASH年会上治疗R/R PTCL的最新进展，重点介绍了靶向EZH1/2、JAK1、PI3K、KIR3DL2、CD38/CD3xCD28或CDK9的新型药物，以及与干细胞移植、免疫调节剂、表观遗传修饰药物或CD30/CD16A双特异性抗体相结合的治疗方案。
{"title":"Novel agents and regimens in relapsed or refractory peripheral T-cell lymphoma: latest updates from 2023 ASH annual meeting","authors":"Huageng Huang, Wei Zhang, Xinyi Deng, He Huang, Zhao Wang, Huangming Hong, Tongyu Lin","doi":"10.1186/s40164-024-00510-w","DOIUrl":"https://doi.org/10.1186/s40164-024-00510-w","url":null,"abstract":"Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of hematological malignancies with poor survival, while treatment options for relapsed or refractory (R/R) disease remain quite limited, with a median progression-free survival of only 3–4 months. Notably, the emergence of innovative therapeutic agents and regimens holds promise for durable responses and improved survival for patients with R/R PTCL. We summarize recent advances in the treatment of R/R PTCL from the 2023 ASH Annual Meeting, highlighting novel agents targeting EZH1/2, JAK1, PI3K, KIR3DL2, CD38/CD3xCD28, or CDK9, as well as therapeutic regimens in combination with stem cell transplantation, immunomodulators, epigenetic modifying agents, or CD30/CD16A bispecific antibodies.","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"7 1","pages":""},"PeriodicalIF":10.9,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140636415","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}
Chimeric antigen receptors (CAR) are engineered fusion proteins that target T-cells to specific surface antigens of tumor cells to generate effective anti-tumor responses. CAR T-cell therapy is playing an increasingly important role in the treatment of relapsed/refractory B-cell malignancies (R/R BCM). Attempting to make CAR T-cells safer and more effective in treating R/R BCM, various novel engineered CAR T-cell agents are currently in the research and development or clinical trial stages. We have summarized here the latest reports on the novel CAR T-cell therapies for R/R BCM presented at the 2023 ASH Annual Meeting as well as the latest updates in related clinical trials.
嵌合抗原受体（CAR）是一种经过设计的融合蛋白，能将 T 细胞靶向肿瘤细胞的特异性表面抗原，从而产生有效的抗肿瘤反应。CAR T细胞疗法在治疗复发/难治性B细胞恶性肿瘤（R/R BCM）中发挥着越来越重要的作用。为了使 CAR T 细胞在治疗复发性/难治性 B 细胞恶性肿瘤（R/R BCM）时更安全、更有效，各种新型工程 CAR T 细胞制剂目前正处于研发或临床试验阶段。我们在此总结了2023年ASH年会上关于治疗R/R BCM的新型CAR T细胞疗法的最新报告以及相关临床试验的最新进展。
{"title":"Novel CAR T-cell therapies for relapsed/refractory B-cell malignancies: latest updates from 2023 ASH annual meeting","authors":"Wenjie Zhang, Sumei Li, Jinlan Long, Shufeng Xie, Minghui Wang, Han Liu, Zhenshu Xu","doi":"10.1186/s40164-024-00508-4","DOIUrl":"https://doi.org/10.1186/s40164-024-00508-4","url":null,"abstract":"Chimeric antigen receptors (CAR) are engineered fusion proteins that target T-cells to specific surface antigens of tumor cells to generate effective anti-tumor responses. CAR T-cell therapy is playing an increasingly important role in the treatment of relapsed/refractory B-cell malignancies (R/R BCM). Attempting to make CAR T-cells safer and more effective in treating R/R BCM, various novel engineered CAR T-cell agents are currently in the research and development or clinical trial stages. We have summarized here the latest reports on the novel CAR T-cell therapies for R/R BCM presented at the 2023 ASH Annual Meeting as well as the latest updates in related clinical trials.","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"225 1","pages":""},"PeriodicalIF":10.9,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140630342","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}
Chemotherapy is a commonly effective treatment for most types of cancer. However, many patients experience a relapse due to minimal residual disease (MRD) after chemotherapy. Previous studies have analyzed the changes induced by chemotherapy for specific types of cancer, but our study is the first to comprehensively analyze MRD across various types of cancer. We included both bulk and single-cell RNA sequencing datasets. We compared the expression of the entire genome and calculated scores for canonical pathway signatures and immune infiltrates before and after chemotherapy across different types of cancer. Our findings revealed that DUSP1 was the most significantly and widely enriched gene in pan-cancer MRD. DUSP1 was found to be essential for MRD formation and played a role in T cell-fibroblast communications and the cytotoxic function of CD4 + T cells. Overall, our analysis provides a comprehensive understanding of the changes caused by chemotherapy and identifies potential targets for preventing and eliminating MRD, which could lead to long-term survival benefits for patients.
{"title":"Pan-cancer transcriptional atlas of minimal residual disease links DUSP1 to chemotherapy persistence","authors":"Yuanhui Liu, Bi Peng, Ziqi Chen, Yimin Shen, Jingmin Zhang, Xianglin Yuan","doi":"10.1186/s40164-024-00509-3","DOIUrl":"https://doi.org/10.1186/s40164-024-00509-3","url":null,"abstract":"Chemotherapy is a commonly effective treatment for most types of cancer. However, many patients experience a relapse due to minimal residual disease (MRD) after chemotherapy. Previous studies have analyzed the changes induced by chemotherapy for specific types of cancer, but our study is the first to comprehensively analyze MRD across various types of cancer. We included both bulk and single-cell RNA sequencing datasets. We compared the expression of the entire genome and calculated scores for canonical pathway signatures and immune infiltrates before and after chemotherapy across different types of cancer. Our findings revealed that DUSP1 was the most significantly and widely enriched gene in pan-cancer MRD. DUSP1 was found to be essential for MRD formation and played a role in T cell-fibroblast communications and the cytotoxic function of CD4 + T cells. Overall, our analysis provides a comprehensive understanding of the changes caused by chemotherapy and identifies potential targets for preventing and eliminating MRD, which could lead to long-term survival benefits for patients.","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"46 1","pages":""},"PeriodicalIF":10.9,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140561488","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}
Despite major therapeutic advances for two decades, including the most recently approved anti-HER2 drugs, brain metastatic localizations remain the major cause of death for women with metastatic HER2 breast cancer. The main reason is the limited drug passage of the blood-brain barrier after intravenous injection and the significant efflux of drugs, including monoclocal antibodies, after administration into the cerebrospinal fluid. We hypothesized that this efflux was linked to the presence of a FcRn receptor in the blood-brain barrier. To overcome this efflux, we engineered two Fab fragments of trastuzumab, an anti-HER2 monoclonal antibody, and did a thorough preclinical development for therapeutic translational purpose. We demonstrated the safety and equal efficacy of the Fabs with trastuzumab in vitro, and in vivo using a patient-derived xenograft model of HER2 overexpressing breast cancer. For the pharmacokinetic studies of intra-cerebrospinal fluid administration, we implemented original rat models with catheter implanted into the cisterna magna. After intraventricular administration in rats, we demonstrated that the brain-to-blood efflux of Fab was up to 10 times lower than for trastuzumab, associated with a two-fold higher brain penetration compared to trastuzumab. This Fab, capable of significantly reducing brain-to-blood efflux and enhancing brain penetration after intra-cerebrospinal fluid injection, could thus be a new and original effective drug in the treatment of HER2 breast cancer brain metastases, which will be demonstrated by a phase I clinical trial dedicated to women in resort situations.
{"title":"A Fab of trastuzumab to treat HER2 overexpressing breast cancer brain metastases","authors":"Eurydice Angeli, Justine Paris, Olivier Le Tilly, Céline Desvignes, Guillaume Gapihan, Didier Boquet, Frédéric Pamoukdjian, Diaddin Hamdan, Marthe Rigal, Florence Poirier, Didier Lutomski, Feriel Azibani, Alexandre Mebazaa, Amaury Herbet, Aloïse Mabondzo, Géraldine Falgarone, Anne Janin, Gilles Paintaud, Guilhem Bousquet","doi":"10.1186/s40164-024-00513-7","DOIUrl":"https://doi.org/10.1186/s40164-024-00513-7","url":null,"abstract":"Despite major therapeutic advances for two decades, including the most recently approved anti-HER2 drugs, brain metastatic localizations remain the major cause of death for women with metastatic HER2 breast cancer. The main reason is the limited drug passage of the blood-brain barrier after intravenous injection and the significant efflux of drugs, including monoclocal antibodies, after administration into the cerebrospinal fluid. We hypothesized that this efflux was linked to the presence of a FcRn receptor in the blood-brain barrier. To overcome this efflux, we engineered two Fab fragments of trastuzumab, an anti-HER2 monoclonal antibody, and did a thorough preclinical development for therapeutic translational purpose. We demonstrated the safety and equal efficacy of the Fabs with trastuzumab in vitro, and in vivo using a patient-derived xenograft model of HER2 overexpressing breast cancer. For the pharmacokinetic studies of intra-cerebrospinal fluid administration, we implemented original rat models with catheter implanted into the cisterna magna. After intraventricular administration in rats, we demonstrated that the brain-to-blood efflux of Fab was up to 10 times lower than for trastuzumab, associated with a two-fold higher brain penetration compared to trastuzumab. This Fab, capable of significantly reducing brain-to-blood efflux and enhancing brain penetration after intra-cerebrospinal fluid injection, could thus be a new and original effective drug in the treatment of HER2 breast cancer brain metastases, which will be demonstrated by a phase I clinical trial dedicated to women in resort situations. ","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"80 1","pages":""},"PeriodicalIF":10.9,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140561477","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 : 2024-04-13DOI: 10.1186/s40164-024-00512-8
Yating Shen, Dexter Kai Hao Thng, Andrea Li Ann Wong, Tan Boon Toh
Glioblastoma (GBM) is a fatal brain tumour that is traditionally diagnosed based on histological features. Recent molecular profiling studies have reshaped the World Health Organization approach in the classification of central nervous system tumours to include more pathogenetic hallmarks. These studies have revealed that multiple oncogenic pathways are dysregulated, which contributes to the aggressiveness and resistance of GBM. Such findings have shed light on the molecular vulnerability of GBM and have shifted the disease management paradigm from chemotherapy to targeted therapies. Targeted drugs have been developed to inhibit oncogenic targets in GBM, including receptors involved in the angiogenic axis, the signal transducer and activator of transcription 3 (STAT3), the PI3K/AKT/mTOR signalling pathway, the ubiquitination-proteasome pathway, as well as IDH1/2 pathway. While certain targeted drugs showed promising results in vivo, the translatability of such preclinical achievements in GBM remains a barrier. We also discuss the recent developments and clinical assessments of targeted drugs, as well as the prospects of cell-based therapies and combinatorial therapy as novel ways to target GBM. Targeted treatments have demonstrated preclinical efficacy over chemotherapy as an alternative or adjuvant to the current standard of care for GBM, but their clinical efficacy remains hindered by challenges such as blood-brain barrier penetrance of the drugs. The development of combinatorial targeted therapies is expected to improve therapeutic efficacy and overcome drug resistance.
{"title":"Mechanistic insights and the clinical prospects of targeted therapies for glioblastoma: a comprehensive review","authors":"Yating Shen, Dexter Kai Hao Thng, Andrea Li Ann Wong, Tan Boon Toh","doi":"10.1186/s40164-024-00512-8","DOIUrl":"https://doi.org/10.1186/s40164-024-00512-8","url":null,"abstract":"Glioblastoma (GBM) is a fatal brain tumour that is traditionally diagnosed based on histological features. Recent molecular profiling studies have reshaped the World Health Organization approach in the classification of central nervous system tumours to include more pathogenetic hallmarks. These studies have revealed that multiple oncogenic pathways are dysregulated, which contributes to the aggressiveness and resistance of GBM. Such findings have shed light on the molecular vulnerability of GBM and have shifted the disease management paradigm from chemotherapy to targeted therapies. Targeted drugs have been developed to inhibit oncogenic targets in GBM, including receptors involved in the angiogenic axis, the signal transducer and activator of transcription 3 (STAT3), the PI3K/AKT/mTOR signalling pathway, the ubiquitination-proteasome pathway, as well as IDH1/2 pathway. While certain targeted drugs showed promising results in vivo, the translatability of such preclinical achievements in GBM remains a barrier. We also discuss the recent developments and clinical assessments of targeted drugs, as well as the prospects of cell-based therapies and combinatorial therapy as novel ways to target GBM. Targeted treatments have demonstrated preclinical efficacy over chemotherapy as an alternative or adjuvant to the current standard of care for GBM, but their clinical efficacy remains hindered by challenges such as blood-brain barrier penetrance of the drugs. The development of combinatorial targeted therapies is expected to improve therapeutic efficacy and overcome drug resistance.","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"73 1","pages":""},"PeriodicalIF":10.9,"publicationDate":"2024-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140561652","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}
Paradoxically, tumor development and progression can be inhibited and promoted by the immune system. After three stages of immune editing, namely, elimination, homeostasis and escape, tumor cells are no longer restricted by immune surveillance and thus develop into clinical tumors. The mechanisms of immune escape include abnormalities in antitumor-associated immune cells, selection for immune resistance to tumor cells, impaired transport of T cells, and the formation of an immunosuppressive tumor microenvironment. A population of distinct immature myeloid cells, myeloid-derived suppressor cells (MDSCs), mediate immune escape primarily by exerting immunosuppressive effects and participating in the constitution of an immunosuppressive microtumor environment. Clinical trials have found that the levels of MDSCs in the peripheral blood of cancer patients are strongly correlated with tumor stage, metastasis and prognosis. Moreover, animal experiments have confirmed that elimination of MDSCs inhibits tumor growth and metastasis to some extent. Therefore, MDSCs may become the target of immunotherapy for many cancers, and eliminating MDSCs can help improve the response rate to cancer treatment and patient survival. However, a clear definition of MDSCs and the specific mechanism involved in immune escape are lacking. In this paper, we review the role of the MDSCs population in tumor development and the mechanisms involved in immune escape in different tumor contexts. In addition, we discuss the use of these cells as targets for tumor immunotherapy. This review not only contributes to a systematic and comprehensive understanding of the essential role of MDSCs in immune system reactions against tumors but also provides information to guide the development of cancer therapies targeting MDSCs.
{"title":"Myeloid-derived suppressor cells in cancer: therapeutic targets to overcome tumor immune evasion","authors":"Junli Lu, Yiming Luo, Dean Rao, Tiantian Wang, Zhen Lei, Xiaoping Chen, Bixiang Zhang, Yiwei Li, Bifeng Liu, Limin Xia, Wenjie Huang","doi":"10.1186/s40164-024-00505-7","DOIUrl":"https://doi.org/10.1186/s40164-024-00505-7","url":null,"abstract":"Paradoxically, tumor development and progression can be inhibited and promoted by the immune system. After three stages of immune editing, namely, elimination, homeostasis and escape, tumor cells are no longer restricted by immune surveillance and thus develop into clinical tumors. The mechanisms of immune escape include abnormalities in antitumor-associated immune cells, selection for immune resistance to tumor cells, impaired transport of T cells, and the formation of an immunosuppressive tumor microenvironment. A population of distinct immature myeloid cells, myeloid-derived suppressor cells (MDSCs), mediate immune escape primarily by exerting immunosuppressive effects and participating in the constitution of an immunosuppressive microtumor environment. Clinical trials have found that the levels of MDSCs in the peripheral blood of cancer patients are strongly correlated with tumor stage, metastasis and prognosis. Moreover, animal experiments have confirmed that elimination of MDSCs inhibits tumor growth and metastasis to some extent. Therefore, MDSCs may become the target of immunotherapy for many cancers, and eliminating MDSCs can help improve the response rate to cancer treatment and patient survival. However, a clear definition of MDSCs and the specific mechanism involved in immune escape are lacking. In this paper, we review the role of the MDSCs population in tumor development and the mechanisms involved in immune escape in different tumor contexts. In addition, we discuss the use of these cells as targets for tumor immunotherapy. This review not only contributes to a systematic and comprehensive understanding of the essential role of MDSCs in immune system reactions against tumors but also provides information to guide the development of cancer therapies targeting MDSCs.","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"23 1","pages":""},"PeriodicalIF":10.9,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140561493","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 : 2024-04-05DOI: 10.1186/s40164-024-00503-9
Gabriel Gallo-Oller, Guillem Pons, Júlia Sansa-Girona, Natalia Navarro, Patricia Zarzosa, Lia García-Gilabert, Paula Cabré-Fernandez, Gabriela Guillén Burrieza, Lorena Valero-Arrese, Miguel F. Segura, José M. Lizcano, José Sánchez de Toledo, Lucas Moreno, Soledad Gallego, Josep Roma
Rhabdomyosarcoma (RMS), such as other childhood tumors, has witnessed treatment advancements in recent years. However, high-risk patients continue to face poor survival rates, often attributed to the presence of the PAX3/7-FOXO1 fusion proteins, which has been associated with metastasis and treatment resistance. Despite efforts to directly target these chimeric proteins, clinical success remains elusive. In this study, the main aim was to address this challenge by investigating regulators of FOXO1. Specifically, we focused on TRIB3, a potential regulator of the fusion protein in RMS. Our findings revealed a prominent TRIB3 expression in RMS tumors, highlighting its correlation with the presence of fusion protein. By conducting TRIB3 genetic inhibition experiments, we observed an impairment on cell proliferation. Notably, the knockdown of TRIB3 led to a decrease in PAX3-FOXO1 and its target genes at protein level, accompanied by a reduction in the activity of the Akt signaling pathway. Additionally, inducible silencing of TRIB3 significantly delayed tumor growth and improved overall survival in vivo. Based on our analysis, we propose that TRIB3 holds therapeutic potential for treating the most aggressive subtype of RMS. The findings herein reported contribute to our understanding of the underlying molecular mechanisms driving RMS progression and provide novel insights into the potential use of TRIB3 as a therapeutic intervention for high-risk RMS patients.
{"title":"TRIB3 silencing promotes the downregulation of Akt pathway and PAX3-FOXO1 in high-risk rhabdomyosarcoma","authors":"Gabriel Gallo-Oller, Guillem Pons, Júlia Sansa-Girona, Natalia Navarro, Patricia Zarzosa, Lia García-Gilabert, Paula Cabré-Fernandez, Gabriela Guillén Burrieza, Lorena Valero-Arrese, Miguel F. Segura, José M. Lizcano, José Sánchez de Toledo, Lucas Moreno, Soledad Gallego, Josep Roma","doi":"10.1186/s40164-024-00503-9","DOIUrl":"https://doi.org/10.1186/s40164-024-00503-9","url":null,"abstract":"Rhabdomyosarcoma (RMS), such as other childhood tumors, has witnessed treatment advancements in recent years. However, high-risk patients continue to face poor survival rates, often attributed to the presence of the PAX3/7-FOXO1 fusion proteins, which has been associated with metastasis and treatment resistance. Despite efforts to directly target these chimeric proteins, clinical success remains elusive. In this study, the main aim was to address this challenge by investigating regulators of FOXO1. Specifically, we focused on TRIB3, a potential regulator of the fusion protein in RMS. Our findings revealed a prominent TRIB3 expression in RMS tumors, highlighting its correlation with the presence of fusion protein. By conducting TRIB3 genetic inhibition experiments, we observed an impairment on cell proliferation. Notably, the knockdown of TRIB3 led to a decrease in PAX3-FOXO1 and its target genes at protein level, accompanied by a reduction in the activity of the Akt signaling pathway. Additionally, inducible silencing of TRIB3 significantly delayed tumor growth and improved overall survival in vivo. Based on our analysis, we propose that TRIB3 holds therapeutic potential for treating the most aggressive subtype of RMS. The findings herein reported contribute to our understanding of the underlying molecular mechanisms driving RMS progression and provide novel insights into the potential use of TRIB3 as a therapeutic intervention for high-risk RMS patients.","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"58 1","pages":""},"PeriodicalIF":10.9,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140561369","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}
Adoptive immunotherapy in the T cell landscape exhibits efficacy in cancer treatment. Over the past few decades, genetically modified T cells, particularly chimeric antigen receptor T cells, have enabled remarkable strides in the treatment of hematological malignancies. Besides, extensive exploration of multiple antigens for the treatment of solid tumors has led to clinical interest in the potential of T cells expressing the engineered T cell receptor (TCR). TCR-T cells possess the capacity to recognize intracellular antigen families and maintain the intrinsic properties of TCRs in terms of affinity to target epitopes and signal transduction. Recent research has provided critical insight into their capability and therapeutic targets for multiple refractory solid tumors, but also exposes some challenges for durable efficacy. In this review, we describe the screening and identification of available tumor antigens, and the acquisition and optimization of TCRs for TCR-T cell therapy. Furthermore, we summarize the complete flow from laboratory to clinical applications of TCR-T cells. Last, we emerge future prospects for improving therapeutic efficacy in cancer world with combination therapies or TCR-T derived products. In conclusion, this review depicts our current understanding of TCR-T cell therapy in solid neoplasms, and provides new perspectives for expanding its clinical applications and improving therapeutic efficacy.
T 细胞的适应性免疫疗法在癌症治疗中显示出疗效。过去几十年来，转基因 T 细胞，特别是嵌合抗原受体 T 细胞在治疗血液恶性肿瘤方面取得了显著进展。此外，对治疗实体瘤的多种抗原的广泛探索，也使临床对表达工程化 T 细胞受体（TCR）的 T 细胞的潜力产生了兴趣。TCR-T 细胞具有识别细胞内抗原家族的能力，并在与目标表位的亲和力和信号转导方面保持 TCR 的固有特性。最近的研究对TCR-T细胞的能力和多种难治性实体瘤的治疗靶点提出了重要的见解，但也暴露出了持久疗效方面的一些挑战。在这篇综述中，我们介绍了现有肿瘤抗原的筛选和鉴定，以及用于 TCR-T 细胞疗法的 TCR 的获取和优化。此外，我们还总结了 TCR-T 细胞从实验室到临床应用的完整流程。最后，我们展望了利用联合疗法或 TCR-T 衍生产品提高癌症疗效的未来前景。总之，这篇综述描述了我们目前对实体瘤 TCR-T 细胞疗法的理解，并为扩大其临床应用和提高疗效提供了新的视角。
{"title":"Novel insights into TCR-T cell therapy in solid neoplasms: optimizing adoptive immunotherapy","authors":"Weihuan Shao, Yiran Yao, Ludi Yang, Xiaoran Li, Tongxin Ge, Yue Zheng, Qiuyi Zhu, Shengfang Ge, Xiang Gu, Renbing Jia, Xin Song, Ai Zhuang","doi":"10.1186/s40164-024-00504-8","DOIUrl":"https://doi.org/10.1186/s40164-024-00504-8","url":null,"abstract":"Adoptive immunotherapy in the T cell landscape exhibits efficacy in cancer treatment. Over the past few decades, genetically modified T cells, particularly chimeric antigen receptor T cells, have enabled remarkable strides in the treatment of hematological malignancies. Besides, extensive exploration of multiple antigens for the treatment of solid tumors has led to clinical interest in the potential of T cells expressing the engineered T cell receptor (TCR). TCR-T cells possess the capacity to recognize intracellular antigen families and maintain the intrinsic properties of TCRs in terms of affinity to target epitopes and signal transduction. Recent research has provided critical insight into their capability and therapeutic targets for multiple refractory solid tumors, but also exposes some challenges for durable efficacy. In this review, we describe the screening and identification of available tumor antigens, and the acquisition and optimization of TCRs for TCR-T cell therapy. Furthermore, we summarize the complete flow from laboratory to clinical applications of TCR-T cells. Last, we emerge future prospects for improving therapeutic efficacy in cancer world with combination therapies or TCR-T derived products. In conclusion, this review depicts our current understanding of TCR-T cell therapy in solid neoplasms, and provides new perspectives for expanding its clinical applications and improving therapeutic efficacy.","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"46 1","pages":""},"PeriodicalIF":10.9,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140561474","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 : 2024-03-29DOI: 10.1186/s40164-024-00501-x
Yusheng Lin, Ghizlane Choukrani, Lena Dubbel, Lena Rockstein, Jimena Alvarez Freile, Yuzhu Qi, Valerie Wiersma, Hao Zhang, Karl-Wilhelm Koch, Emanuele Ammatuna, Jan Jacob Schuringa, Tom van Meerten, Gerwin Huls, Edwin Bremer
VISTA is a well-known immune checkpoint in T cell biology, but its role in innate immunity is less established. Here, we investigated the role of VISTA on anticancer macrophage immunity, with a focus on phagocytosis, macrophage polarization and concomitant T cell activation. Macrophages, differentiated from VISTA overexpressed THP-1 cells and cord blood CD34+ cell-derived monocytes, were used in phagocytosis assay using B lymphoma target cells opsonized with Rituximab. PBMC-derived macrophages were used to assess the correlation between phagocytosis and VISTA expression. qRT-PCR, flow cytometry, and enzyme-linked immunosorbent assay were performed to analyze the impact of VISTA on other checkpoints and M1/M2-like macrophage biology. Additionally, flow cytometry was used to assess the frequency of CD14+ monocytes expressing VISTA in PBMCs from 65 lymphoma patients and 37 healthy donors. Ectopic expression of VISTA in the monocytic model cell line THP-1 or in primary monocytes triggered differentiation towards the macrophage lineage, with a marked increase in M2-like macrophage-related gene expression and decrease in M1-like macrophage-related gene expression. VISTA expression in THP-1 and monocyte-derived macrophages strongly downregulated expression of SIRPα, a prominent ‘don’t eat me’ signal, and augmented phagocytic activity of macrophages against cancer cells. Intriguingly, expression of VISTA’s extracellular domain alone sufficed to trigger phagocytosis in ∼ 50% of cell lines, with those cell lines also directly binding to recombinant human VISTA, indicating ligand-dependent and -independent mechanisms. Endogenous VISTA expression was predominantly higher in M2-like macrophages compared to M0- or M1-like macrophages, with a positive correlation observed between VISTA expression in M2c macrophages and their phagocytic activity. VISTA-expressing macrophages demonstrated a unique cytokine profile, characterized by reduced IL-1β and elevated IL-10 secretion. Furthermore, VISTA interacted with MHC-I and downregulated its surface expression, leading to diminished T cell activation. Notably, VISTA surface expression was identified in monocytes from all lymphoma patients but was less prevalent in healthy donors. Collectively, VISTA expression associates with and drives M2-like activation of macrophages with a high phagocytic capacity yet a decrease in antigen presentation capability to T cells. Therefore, VISTA is a negative immune checkpoint regulator in macrophage-mediated immune suppression.
VISTA 是 T 细胞生物学中一个众所周知的免疫检查点，但它在先天免疫中的作用却鲜为人知。在这里，我们研究了 VISTA 对抗癌巨噬细胞免疫的作用，重点是吞噬、巨噬细胞极化和伴随的 T 细胞活化。由 VISTA 过表达的 THP-1 细胞和脐带血 CD34+ 细胞衍生的单核细胞分化出的巨噬细胞被用于利妥昔单抗鸦片化的 B 淋巴瘤靶细胞的吞噬试验。采用 qRT-PCR、流式细胞术和酶联免疫吸附试验分析 VISTA 对其他检查点和 M1/M2 样巨噬细胞生物学的影响。此外，还使用流式细胞术评估了 65 名淋巴瘤患者和 37 名健康供体的 PBMC 中表达 VISTA 的 CD14+ 单核细胞的频率。在单核细胞模型细胞系 THP-1 或原代单核细胞中异位表达 VISTA 会引发向巨噬细胞系的分化，M2 样巨噬细胞相关基因表达明显增加，M1 样巨噬细胞相关基因表达减少。VISTA 在 THP-1 和单核细胞衍生巨噬细胞中的表达强烈下调了 SIRPα 的表达，这是一个显著的 "别吃我 "信号，并增强了巨噬细胞对癌细胞的吞噬活性。耐人寻味的是，仅表达VISTA的胞外结构域就足以触发50%细胞系的吞噬作用，这些细胞系还能直接与重组人VISTA结合，这表明了配体依赖性和非依赖性机制。与 M0 或 M1 样巨噬细胞相比，M2 样巨噬细胞中内源性 VISTA 的表达主要较高，在 M2c 巨噬细胞中观察到 VISTA 的表达与其吞噬活性呈正相关。表达 VISTA 的巨噬细胞表现出独特的细胞因子谱，其特点是 IL-1β 分泌减少，IL-10 分泌增加。此外，VISTA 与 MHC-I 相互作用并下调其表面表达，从而导致 T 细胞活化减弱。值得注意的是，在所有淋巴瘤患者的单核细胞中都发现了 VISTA 的表面表达，但在健康供体中却不常见。总之，VISTA 的表达与巨噬细胞的 M2 类活化有关，并驱动巨噬细胞的 M2 类活化，巨噬细胞的吞噬能力很强，但向 T 细胞呈递抗原的能力却下降了。因此，在巨噬细胞介导的免疫抑制中，VISTA 是一种负性免疫检查点调节因子。
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Pub Date : 2024-03-29DOI: 10.1186/s40164-024-00502-w
Alaa M. Khalifa, Takashi Nakamura, Yusuke Sato, Hideyoshi Harashima
Natural killer (NK) cells are effective in attacking tumor cells that escape T cell attack. Memory NK cells are believed to function as potent effector cells in cancer immunotherapy. However, knowledge of their induction, identification, and potential in vivo is limited. Herein, we report on the induction and identification of memory-like NK cells via the action of a combination of a stimulator of interferon genes (STING) agonist loaded into lipid nanoparticles (STING-LNPs) and cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG-ODNs), and the potential of the inducted memory-like NK cells to prevent melanoma lung metastasis. The antitumor effects of either the STING-LNPs, CpG-ODNs, or the combination therapy were evaluated using a B16-F10 lung metastasis model. The effect of the combined treatment was evaluated by measuring cytokine production. The induction of memory-like NK cells was demonstrated via flow cytometry and confirmed through their preventative effect. The combination of STING-LNPs and CpG-ODNs tended to enhance the production of interleukin 12 (IL-12) and IL-18, and exerted a therapeutic effect against B16-F10 lung metastasis. The combination therapy increased the population of CD11bhighCD27low NK cells. Although monotherapies failed to show preventative effects, the combination therapy induced a surprisingly strong preventative effect, which indicates that CD11bhighCD27low cells could be a phenotype of memory-like NK cells. As far as could be ascertained, this is the first report of the in vivo induction, identification, and confirmation of a phenotype of the memory-like NK cells through a prophylactic effect via the use of an immunotherapeutic drug. Our findings provide novel insights into the in vivo induction of CD11bhighCD27low memory-like NK cells thus paving the way for the development of efficient immunotherapies.
自然杀伤（NK）细胞能有效攻击躲过 T 细胞攻击的肿瘤细胞。记忆 NK 细胞被认为是癌症免疫疗法中有效的效应细胞。然而，人们对记忆 NK 细胞的诱导、鉴定和体内潜能了解有限。在此，我们报告了通过将干扰素基因刺激剂（STING）激动剂装入脂质纳米颗粒（STING-LNPs）和胞嘧啶-硫代磷酸鸟嘌呤寡脱氧核苷酸（CpG-ODNs）的组合作用诱导和识别记忆样NK细胞的情况，以及诱导的记忆样NK细胞预防黑色素瘤肺转移的潜力。利用 B16-F10 肺转移模型评估了 STING-LNPs、CpG-ODNs 或联合疗法的抗肿瘤效果。联合疗法的效果通过测量细胞因子的产生来评估。通过流式细胞术证明了记忆样 NK 细胞的诱导作用，并通过其预防效果予以证实。STING-LNPs 和 CpG-ODNs 的联合治疗往往能提高白细胞介素 12（IL-12）和 IL-18 的产生，并对 B16-F10 肺转移产生治疗效果。联合疗法增加了 CD11bhighCD27low NK 细胞的数量。虽然单一疗法未能显示出预防效果，但联合疗法却产生了令人惊讶的强大预防效果，这表明 CD11bhighCD27low 细胞可能是记忆类 NK 细胞的一种表型。据目前所知，这是首次报道通过使用免疫治疗药物的预防作用，在体内诱导、鉴定和确认记忆样 NK 细胞的表型。我们的发现为体内诱导 CD11bhighCD27low 记忆样 NK 细胞提供了新的见解，从而为开发高效的免疫疗法铺平了道路。
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