LAT2

撰文 | 郑诗蔚    责编 | 周叶斌 T 细胞谱系急性淋巴细胞白血病（T-lineage ALL）来源于 T 细胞前体的克隆性扩增，如今尽管化疗方案的进步提高了儿童患者的生存率，但复发或耐药病例的预后仍不理想。根据免疫表型，T细胞谱系 ALL可以被细分为处在不同分化阶段的亚型，依次从最具干细胞特性到最具 T 细胞谱系特征，分为谱系不明确的急性白血病（T/My-MPAL）、早期 T 细胞前体 ALL（ETP-ALL）和 T 细胞 ALL。然而，ALL的分子亚型往往能够跨越免疫表型定义的边界，而且ALL细胞的分化状态与治疗反应密切相关。这说明我们需要更精准的策略来表征 T 系 ALL 的分化状态，从而识别针对个体患者最有效的治疗靶点。 近日，由多伦多大学 Soheil Jahangiri 和 Anastasia N. Tikhonova 带领的课题组在 Science Translational Medicine 发表题为 An inflammatory state defines a high-­ risk T-­ lineage acute lymphoblastic leukemia subgroup 的文章，运用多组学全面解析 T 系 ALL 的发育状态及肿瘤异质性的研究成果。 作者使用 CITE-seq、TCR-seq 和单细胞转录组分析对儿童和成人患者的骨髓及血液样本进行研究，并与健康供体进行比较，以探讨 T 系 ALL 的异质性。SCENIC 分析鉴定了异常的转录因子活性，而整合的 scRNA-seq 数据集和 Symphony 映射显示，T 系ALL 的转录特征与造血和胸腺前体细胞相似。CITE-seq 分析进一步根据谱系标志物区分了白血病细胞和非白血病细胞。最终，结合多细胞组学分析和流式细胞术，研究确定了 8 个白血病细胞簇和 5 个非白血病细胞簇，其中健康供体样本富集于非白血病细胞簇。 尽管其免疫表型或基因特征相似，T 系ALL表现出的显著分子异质性，能大幅度影响治疗反应。作者随后对上述白血病细胞进行无偏聚类分析，揭示了 T-ALL 与 ETP-ALL/T/My-MPAL 之间存在不同的基因表达模式，包括转录因子活性和细胞周期调控的差异。基因共表达模块分析鉴定了 22 个功能模块，其中 T-ALL 富集了与 TCR 信号传导和细胞增殖相关的“常规”模块，而 ETP-ALL/T/My-MPAL 则表现出与免疫应答和早期分化停滞相关的“炎症”模块。层次聚类进一步将 T 细胞谱系 ALL 按照转录相似性而非免疫表型分为常规和炎症两个亚型。 22个基因表达模块在各样本中的表达，及常规和炎症性亚型的划分 作者还发现，炎症性 T系ALL 在转录上类似于停滞在早期 T 细胞发育阶段的细胞，主要映射到造血干/祖细胞（HSPC）、早期胸腺祖细胞（ETP）和浆细胞样树突细胞（pDC），而常规 T-ALL 显示出更异质的分化状态。此外，炎症性基因模块的激活与未成熟的分化状态相关，并且 HSPC、ETP 和 pDC 映射的白血病细胞表现出干扰素活性模块的富集以及 IRF5 活性的升高，表明IRF5与炎症状态之间存在关联。用IRF5的六个规管子IRF5，MEF2C，LAT2，MCTP2，PRSS57和ARRB1对T细胞谱系ALL细胞进行打分，不仅能区分炎症性和常规性白血病样本，还与炎症基因模块活性及 HSPC 映射频率呈正相关，说明使用IRF5活性可被用作炎症性 T 系ALL的潜在标志。 划分为常规和炎症性亚型的白血病细胞以及其IRF5的活性状态 IRF5活性与各个基因表达模块的关联 作者接下来重点分析了AALL0434 儿童 T-ALL 数据集，先用 k-means 聚类分析，根据 IRF5 规管子活动将患者分类为炎症状态（IRF5HIGH）和常规状态（IRF5LOW），并确定 38.7% 的患者属于炎症状态，其中包括大多数 ETP-ALL 病例。炎症状态（IRF5HIGH）样本表现出强烈的 IRF5 规管子活性、炎症基因表达的富集、IL-1 信号通路的激活以及 ETP 样分子亚型，而常规状态（IRF5LOW）样本则显示与后期 T 细胞发育和细胞周期通路相关基因的上调。此外，炎症样本与 WT1 和 EZH2 突变相关，这些突变在前人研究中已被发现与炎症过程有关，而常规样本则富含 CDKN2A 突变，突显出由 IRF5 规管子活性驱动的不同分子特征。炎症状态（IRF5HIGH）患者的无事件生存期（EFS）显著较差，但整体生存期（OS）无明显差异，即使在排除 ETP-ALL 病例后，该趋势仍然显著。此外，较高的 IRF5 评分与较差的治疗反应相关，包括第 29 天的微小残留病（MRD）水平升高以及诱导失败率增加，表明炎症与治疗耐受性之间存在关联。在两个独立队列的验证结果证实，高 IRF5 规管子评分与高 MRD 和较差预后相关，进一步加强了炎症性 T 系ALL与不良预后的关联性。 处于炎症状态与常规状态患者的生存期对比 对患者来源的异种移植（PDX）样本进行的体外药物敏感性测试表明，炎症性和常规 T 系ALL对 l-天冬酰胺酶、长春新碱和阿霉素的反应无显著差异，但炎症性样本对地塞米松持续表现出耐药性。炎症性 T 系ALL对地塞米松更强的耐药性，可能是导致这些患者较高的微小残留病（MRD）的原因。作者还发现炎症性 T 系ALL样本中 BCL-2 表达水平升高，并进一步证实这类ALL对 BCL-2 抑制剂 venetoclax 高度敏感。炎症性 T-ALL 样本及 IRF5 高表达的细胞系在体外实验中对 venetoclax 反应良好，且临床前 PDX 模型显示 venetoclax 治疗可减少外周血、骨髓和脾脏中的白血病细胞负荷。这些研究结果表明，炎症性 T 系白血病对地塞米松不敏感，但对 venetoclax 具有高度敏感性，BCL-2 抑制可能成为一种潜在的治疗策略。 炎症性T- ALL对Venetoclax反应良好 综上，本研究确定了一种炎症状态作为高风险 T 系白血病（T-ALL）亚群的标志性特征。通过利用多组学技术和基于 IRF5 的基因特征，研究人员深入揭示了 T 系ALL的生物学特性，并鉴定出一个具有独特治疗脆弱性的临床相关亚群。这些发现对精准医学和针对这种侵袭性白血病的靶向治疗开发具有重要意义。研究最终得出结论：炎症状态并不体现在免疫表型上。这些发现强调了 IRF5 规管子评分作为 T 系白血病患者风险分层和治疗决策重要工具的潜在价值。 撰文 责编 制作 排版 | Sheila   校对 | uu 延伸阅读 儿童T细胞急性淋巴细胞白血病的多组学分析 史上最大队列！儿童急性淋巴细胞白血病全基因组及基因表达图谱发表 *本文由深圳市拾玉儿童公益基金会“儿童肿瘤前沿”团队编译或约稿，文中图表均源引自文献原文。本文著作权归文章作者所有，欢迎个人转发分享，未经允许禁止转载，作者拥有所有法定权利，违者必究。如需转载，请留言或联系shiyu@curekids.cn。本文旨在分享儿童肿瘤科研前沿成果，不是治疗方案推荐。如需获得疾病治疗方案指导，请前往正规医院就诊。 ▼滑动查看更多▼ 原文摘要（Abstract） T-lineage acute lymphoblastic leukemia (ALL) is an aggressive cancer comprising diverse subtypes that are challenging to stratify using conventional immunophenotyping. To gain insights into subset-specific therapeutic vulnerabilities, we performed an integrative multiomics analysis of bone marrow samples from newly diagnosed T cell ALL, early T cell precursor ALL, and T/myeloid mixed phenotype acute leukemia. Leveraging cellular indexing of transcriptomes and epitopes in conjunction with T cell receptor sequencing, we identified a subset of patient samples characterized by activation of inflammatory and stem gene programs. These inflammatory T-lineage samples exhibited distinct biological features compared with other T-lineage ALL samples, including the production of proinflammatory cytokines, prevalence of mutations affecting cytokine signaling and chromatin remodeling, an altered immune microenvironment, and poor treatment responses. Moreover, we found that, although inflammatory T-lineage ALL samples were less sensitive to dexamethasone, they exhibited unique sensitivity to a BCL-2 inhibitor, venetoclax. To facilitate classification of patients with T-lineage ALL, we developed a computational inflammatory gene signature scoring system, which stratified patients and was associated with disease prognosis in three additional patient cohorts. By identifying a high-risk T-lineage ALL subtype on the basis of an inflammatory score, our study provides a framework for targeted therapeutic approaches for these challenging-to-treat cancers. DOI: 110.1126/scitranslmed.adr2012 👇点击此处，直达原文

MELBOURNE, Australia, Aug. 28, 2024 /PRNewswire/ -- Telix Pharmaceuticals Limited (ASX: TLX, Telix, the Company) today announces it has submitted a New Drug Application (NDA) to the United States (U.S.) Food and Drug Administration (FDA) for TLX101-CDx, (Pixclara®[1], 18F-floretyrosine or 18F-FET), an investigational PET[2] agent for the characterisation of progressive or recurrent glioma (brain cancer) from treatment related changes in both adult and pediatric patients. Given the potential to address significant unmet medical need, Pixclara®1 has been granted Orphan Drug[3] and Fast Track[4] designation by the FDA, which facilitates expedited review and closer consultation with the agency during the review process. FET PET (Pixclara®1) is already included in international clinical practice guidelines for the imaging of gliomas[5], however there is currently no FDA-approved targeted amino acid PET agent for adult and pediatric brain cancer imaging commercially available in the U.S. There is a critical unmet need to improve the diagnosis and management of glioma, particularly in the post-treatment setting. With low survival rates and the need to make rapid decisions, precision imaging is paramount. Subject to regulatory approval, Pixclara®1 has the potential to address this need, enabling patients to receive greater clarity in their diagnosis and treatment decision making. Pixclara®1 is also being developed as the "companion" theranostic imaging agent for TLX101, Telix's investigational neuro-oncology drug candidate, which targets the same amino acid transporter mechanism with therapeutic targeted radiation. Kevin Richardson, Chief Executive Officer, Telix Precision Medicine, stated, "Gliomas are the most common primary brain tumours of the central nervous system. Conventional imaging with MRI[6] often yields inconclusive results in characterising recurrent disease and therefore delays time-sensitive decision making4. Limitations of conventional imaging techniques include the lack of biological specificity, dependency on blood-brain barrier disruption, and an inherent inability to differentiate between tumour progression or treatment-related causes[7]. Telix's filing of this NDA for Pixclara®1 is an important milestone, reflecting our commitment to improved and accessible neuro-oncology imaging in the U.S., and taking us one step closer to commercial availability in 2025, subject to FDA approval." About TLX101-CDx TLX101-CDx (Pixclara®1) is a PET imaging agent, which has been granted fast track and orphan drug designations by the FDA as an imaging agent for the characterisation of glioma. TLX101-CDx targets membrane transport proteins known as LAT1 and LAT2[8]. This enables TLX101-CDx to be potentially utilised as a companion diagnostic agent to TLX101 (4-L-[131I] iodo-phenylalanine, or 131I-IPA), Telix's LAT1-targeting investigational glioblastoma (GBM) therapy, currently under investigation in the IPAX-2[9] and IPAX-Linz[10] studies. About gliomas in the U.S. Gliomas are very diffusely infiltrative tumours that affect the surrounding brain tissue. They are the most common form of central nervous system (CNS) neoplasm that originates from glial cells, accounting for approximately 30% of all brain and CNS tumours and 80% of all malignant brain tumours[11]. In the U.S., there are six cases of gliomas diagnosed per 100,000 people every year. GBM is a high-grade glioma and the most common and aggressive form of primary brain cancer, with approximately 22,000 new cases diagnosed annually in the U.S.[12]. The mainstay of treatment for GBM comprises surgical resection, followed by combined radiotherapy and chemotherapy. Despite such treatment, recurrence occurs in almost all patients[13], with an expected survival duration of 12-15 months from diagnosis[14]. About Telix Pharmaceuticals Limited Telix is a biopharmaceutical company focused on the development and commercialisation of diagnostic and therapeutic radiopharmaceuticals and associated medical devices. Telix is headquartered in Melbourne, Australia, with international operations in the United States, Europe (Belgium and Switzerland), and Japan. Telix is developing a portfolio of clinical and commercial stage products that aims to address significant unmet medical needs in oncology and rare diseases. Telix is listed on the Australian Securities Exchange (ASX: TLX). Telix's lead imaging product, gallium-68 (68Ga) gozetotide injection (also known as 68Ga PSMA-11 and marketed under the brand name Illuccix®), has been approved by the U.S. Food and Drug Administration (FDA)[15], by the Australian Therapeutic Goods Administration (TGA) [16], and by Health Canada[17]. No other Telix product has received a marketing authorisation in any jurisdiction. Visit for further information about Telix, including details of the latest share price, announcements made to the ASX, investor and analyst presentations, news releases, event details and other publications that may be of interest. You can also follow Telix on X and LinkedIn. Telix Investor Relations Ms. Kyahn Williamson Telix Pharmaceuticals Limited SVP Investor Relations and Corporate Communications Email: [email protected] This announcement has been authorised for release by the Telix Pharmaceuticals Limited Disclosure Committee on behalf of the Board. Legal Notices You should read this announcement together with our risk factors, as disclosed in our most recently filed reports with the Australian Securities Exchange (ASX) or on our website. The information contained in this announcement is not intended to be an offer for subscription, invitation or recommendation with respect to securities of Telix Pharmaceuticals Limited (Telix) in any jurisdiction, including the United States. The information and opinions contained in this announcement are subject to change without notification. To the maximum extent permitted by law, Telix disclaims any obligation or undertaking to update or revise any information or opinions contained in this announcement, including any forward-looking statements (as referred to below), whether as a result of new information, future developments, a change in expectations or assumptions, or otherwise. 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Forward-looking statements are based on Telix's good-faith assumptions as to the financial, market, regulatory and other risks and considerations that exist and affect Telix's business and operations in the future and there can be no assurance that any of the assumptions will prove to be correct. In the context of Telix's business, forward-looking statements may include, but are not limited to, statements about: the initiation, timing, progress and results of Telix's preclinical and clinical trials, and Telix's research and development programs; Telix's ability to advance product candidates into, enrol and successfully complete, clinical studies, including multi-national clinical trials; the timing or likelihood of regulatory filings and approvals for Telix's product candidates, manufacturing activities and product marketing activities; Telix's sales, marketing and distribution and manufacturing capabilities and strategies; the commercialisation of Telix's product candidates, if or when they have been approved; Telix's ability to obtain an adequate supply of raw materials at reasonable costs for its products and product candidates; estimates of Telix's expenses, future revenues and capital requirements; Telix's financial performance; developments relating to Telix's competitors and industry; and the pricing and reimbursement of Telix's product candidates, if and after they have been approved. Telix's actual results, performance or achievements may be materially different from those which may be expressed or implied by such statements, and the differences may be adverse. Accordingly, you should not place undue reliance on these forward-looking statements. ©2024 Telix Pharmaceuticals Limited. The Telix Pharmaceuticals®, Illuccix® and Pixclara® names and logos are trademarks of Telix Pharmaceuticals Limited and its affiliates – all rights reserved. Pixclara trade name is subject to final regulatory approval. Logo -

FDA Fast Track designation granted for TLX101-CDx for glioma (brain cancer) imaging Collaboration agreement announced for joint development and commercialisation with UCSF PharmaLogic announced as commercial manufacturing and pharmacy distribution partner April 16, 2024 (GLOBE NEWSWIRE) -- Telix Pharmaceuticals Limited (ASX: TLX, Telix, the Company) today announces that the United States (U.S.) Food and Drug Administration (FDA) has granted Fast Track designation1 for the Company’s investigational glioma imaging product, TLX101-CDx (Pixclara™2, 18F-floretyrosine or 18F-FET). The granted Fast Track designation is for the characterisation of progressive or recurrent glioma using positron emission tomography (PET). Concurrently, Telix is in the final stages of preparing its U.S. New Drug Application (NDA) for TLX101-CDx in this initial indication, in both adult and paediatric patients. This designation enables expedited review and closer consultation with the FDA during the review process. Amino acid PET is currently included in U.S. and European guidelines for the imaging of gliomas3, however there is no FDA-approved targeted PET agent for brain cancer imaging in the U.S. Telix’s goal is to make this product commercially available in the U.S., significantly increasing patient access to this important imaging agent. Telix has an exclusive research collaboration and data license agreement with the University of California, San Francisco (UCSF). UCSF is one of the leading academic centres conducting clinical research into the use of FET PET4 in a variety of neurological malignancies. This academic-industrial collaboration supporting joint development and commercialisation will enable Telix to offer TLX101-CDx access as a commercial product in the U.S., subject to regulatory approval. Thomas A. Hope, MD, Professor of Radiology at UCSF, said, “There is critical unmet need to improve the diagnosis and management of glioma, particularly in the post-treatment setting, and we are excited to leverage the clinical experience at UCSF to help make this investigational agent more widely available. 18F-FET has the potential to help determine if a glioma is truly progressing or undergoing a treatment-induced change, known as pseudo-progression, where MRI5 – the standard of care – can often be inconclusive.” David N. Cade, MD, Group Chief Medical Officer at Telix, stated, “This unique collaboration between Dr. Hope’s team at UCSF and Telix will enable us to utilise our collective clinical data and expertise to facilitate nationwide access to FET PET in the United States while fostering ongoing research and development with the objective of expanding the clinical utility of this advanced imaging agent for the benefit of patients.” Telix has selected PharmaLogic Holdings Corp (PharmaLogic) as its commercial manufacturing and pharmacy distribution partner, to supply finished unit doses of TLX101-CDx to the U.S. market. Steven Chilinski, President and CEO at Pharmalogic, added, “Telix has quickly grown into a global theranostics leader with an impressive product pipeline. Through this partnership, we’re delighted to bring this imaging agent to glioma patients in the U.S. upon regulatory approval.” Richard Valeix, Group Chief Commercial Officer at Telix, continued, “These milestones represent significant progress as we bring this investigational product closer to market in the U.S. and commercial launch. PharmaLogic has rapidly developed an excellent reputation for manufacturing radiopharmaceuticals to rigorous quality standards and will deliver a key component of Telix’s supply chain strategy for TLX101-CDx in the U.S., subject to regulatory approval.” TLX101-CDx (Pixclara™2) is a PET imaging agent, which has been previously granted orphan drug designation (ODD) in the U.S. as an imaging agent for the management of glioma6. TLX101-CDx targets membrane transport proteins known as LAT1 and LAT27. This enables TLX101-CDx to be potentially utilised as a companion diagnostic agent to TLX101 (4-L-[131I] iodo-phenylalanine, or 131I-IPA), Telix’s LAT1-targeting investigational glioblastoma (GBM) therapy, currently under investigation in the and IPAX-28 and IPAX-Linz9 studies. Gliomas are very diffusely infiltrative tumours that affect the surrounding brain tissue. They are the most common form of central nervous system (CNS) neoplasm that originates from glial cells, accounting for approximately 30% of all brain and CNS tumours and 80% of all malignant brain tumours10. In the U.S., there are six cases of gliomas diagnosed per 100,000 people every year. GBM is a high-grade glioma and the most common and aggressive form of primary brain cancer, with approximately 22,000 new cases diagnosed annually in the U.S.11. The mainstay of treatment for GBM comprises surgical resection, followed by combined radiotherapy and chemotherapy. Despite such treatment, recurrence occurs in almost all patients12, with an expected survival duration of 12-15 months from diagnosis13. PharmaLogic is a world-class contract development and manufacturing organisation specialising in novel diagnostic imaging and therapeutic radiopharmaceuticals for the treatment of cancers and other malignancies. In addition to an established and reliable network of radiopharmacies, PharmaLogic has decades of expertise in drug development from discovery, through manufacturing and commercialisation. The Company seeks to take the lead in the advancement of radiopharmaceutical technology for the benefit of patients worldwide. For more information, visit: www.radiopharmacy.com. Telix is a biopharmaceutical company focused on the development and commercialisation of diagnostic and therapeutic radiopharmaceuticals and associated medical devices. Telix is headquartered in Melbourne, Australia, with international operations in the United States, Europe (Belgium and Switzerland), and Japan. Telix is developing a portfolio of clinical and commercial stage products that aims to address significant unmet medical needs in oncology and rare diseases. Telix is listed on the Australian Securities Exchange (ASX: TLX). Telix’s lead imaging product, gallium-68 (68Ga) gozetotide injection (also known as 68Ga PSMA-11 and marketed under the brand name Illuccix®), has been approved by the FDA14, by the Australian Therapeutic Goods Administration (TGA)15, and by Health Canada16. No other Telix product has received a marketing authorisation in any jurisdiction. 1 Fast Track is a process designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need. The purpose is to get important new drugs to the patient earlier. More: https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/fast-track. 2 Brand name subject to final regulatory approval. 3 Joint European Association of Nuclear Medicine//European Association of Neurooncology/Response Assessment in Neurooncology practice guidelines/Society for Nuclear Medicine and Molecular Imaging procedure standards for the clinical use of PET imaging in gliomas. 4 Positron emission tomography with 18F-floretyrosine. 5 Magnetic resonance imaging. 6 Telix ASX disclosure 6 October 2020. 7 Large amino acid transporters 1 and 2. 8 Telix media release 8 August 2023. ClinicalTrials.gov ID: NCT05450744. 9 Telix media release 22 November 2022. 10 Goodenberger et al. Cancer Genet. 2012. 11 Ostrom 2022, CBTRUS (Central Brain Tumor Registry of the United States) Statistical Report. 12 Park et al. Journal of Clinical Oncology. 2010. 13 Ostrom et al. Neuro Oncol. 2018. 14 Telix ASX disclosure 20 December 2021. 15 Telix ASX disclosure 2 November 2021. 16 Telix ASX disclosure 14 October 2022. The content above comes from the network. if any infringement, please contact us to modify.