University of Helsinki

THURSDAY, Dec. 12, 2024 -- Initiation of an automated insulin delivery (AID) system improves glycemic control in children and adolescents with type 1 diabetes (T1D), according to a study published in the January issue of Diabetes, Obesity and Metabolism . Maaria Kiilavuori, M.D., from the University of Helsinki, and colleagues investigated the influence of an AID system on glycemic control in children and adolescents with T1D who do not reach optimal glycemic control with traditional treatment options (hemoglobin A1C >53 mmol/mol/7.0 percent). The analysis included 79 patients (aged 7 to 16 years) with T1D. The researchers found that after the initiation of an AID system, glycemic control improved and the effect persisted throughout the study period. Between zero and three months, time in tight range and time in range increased (mean, 11.7 and 18.1 percent, respectively). During the same follow-up period, hemoglobin A1c and mean sensor glucose values decreased significantly. These effects were sustained at 12 and 24 months. "Glycemic control in patients not reaching treatment goals improved significantly after the initiation of the AID system, and the favorable effect lasted throughout the follow-up," the authors write. "AID treatment could be an option for also those pediatric patients with T1D who do not have good skills in diabetes management." Several authors disclosed ties to the pharmaceutical and medical device industries. Abstract/Full Text Whatever your topic of interest, subscribe to our newsletters to get the best of Drugs.com in your inbox.

*仅供医学专业人士阅读参考前两天奇点糕才提到，对免疫治疗维持“绝对防御”的卵巢癌，可以通过分泌白介素-4（IL-4）调控巨噬细胞，构建免疫抑制性微环境，如果要给这种行为定性一下，大概可以算是卵巢癌对免疫治疗不敏感的“内因”。既然有内因，相对就一定会有不利于抗肿瘤免疫应答的“外因”，内外交困也是现阶段免疫治疗的日常了。但如果背刺免疫治疗的是化疗，又该如何应对呢？近日，芬兰赫尔辛基大学团队在Cancer Cell期刊发表的最新研究成果显示，在占卵巢癌70-80%的高级别浆液性卵巢癌中，当前临床采用的标准化疗方案，会导致由巨噬细胞驱动的CD8+T细胞耗竭和排斥，能一定程度上解释免疫治疗对卵巢癌的效果不佳。研究者们发现，导致CD8+T细胞耗竭的巨噬细胞，是名为“Myelonets”的免疫抑制性髓系细胞网络的一部分，这些髓系细胞不仅会相互串联，还会通过NECTIN2-TIGIT信号轴调控CD8+T细胞转入耗竭状态，而这也就是治疗干预来增敏卵巢癌免疫治疗的切入点。一图总结论文核心内容卵巢癌算是对含铂化疗比较敏感的实体瘤了，不然临床上也不会有铂敏感/铂耐药卵巢癌之分，但化疗终究会有失效的时候，特别是对于不存在BRCA1/2等同源重组修复缺陷（HRD）突变，不适合在化疗后接受PARP抑制剂维持治疗的患者，化疗耐药来得相当之快。按说在这种场景里，免疫治疗往往能站出来，但临床研究的结果大多不尽如人意。赫尔辛基大学研究团队认为，此前学界对化疗影响卵巢癌免疫微环境的了解还是太少[2]，相当于两眼一抹黑就用药了。因此本次研究一上来，研究者们就对来自75例高级别浆液性卵巢癌患者的117例样本“火力全开”，进行基因组学、空间组学分析和单细胞测序，重点分析一线化疗（新辅助性质）前后发生的各种改变。多组学数据首先显示，化疗确实会使卵巢癌免疫微环境发生显著改变，最明显的特征就是CD8+T细胞浸润显著增多，同时B细胞、调节性T细胞和髓系细胞浸润也上升，但结合空间组学数据来看，这种改变并不是均一的，因为肿瘤不同部位原本就存在各种癌细胞、间质细胞（如成纤维细胞）和免疫细胞的各自抱团，正式名叫“重复出现的细胞邻域”（RCNs），其中免疫细胞抱团的RCNs内，主要细胞类别就是包括巨噬细胞在内的各种髓系细胞。肿瘤不同部位存在成分区别显著的“重复出现的细胞邻域”而化疗不仅会导致各个RCNs的细胞构成发生显著改变，还会影响它们与其它细胞的相互作用，例如CD8+T细胞就从此前主要接触癌细胞，变成了主要接触M2型巨噬细胞和CD4+T细胞，且这种改变与患者“无铂间期”（PFI）较短、即对化疗应答较差有关。研究者们又借助空间组学数据证实，不同于化疗前主要集中在“T细胞枢纽”（T cell Hub）内，化疗后浸润显著增多的CD8+T细胞，会广泛分布在髓系、间质细胞乃至癌细胞为主的RCNs内，且呈现明显的耗竭表型（表达关键标志物TIM-3）和激活状态下降（表达pSTAT1），免疫浸润增加反而不利于抗肿瘤免疫，确实是不太常见的现象。而进入到不同RCNs的CD8+T细胞，在TIM-3等标志物表达方面也有明显不同，改变可以说是“空间限制性”的。化疗后卵巢癌的CD8+T细胞浸润虽显著增多，但整体状态却不利于抗肿瘤免疫鉴于化疗后巨噬细胞与CD8+T细胞的相互作用更密切，而癌细胞与CD8+T细胞发生相互作用的绝对频率不变（相对下降），研究者们推测导致CD8+T细胞耗竭的元凶就是巨噬细胞，并通过细胞直接接触分析（Delaunay clustering），找出了髓系细胞们相互串联构成的Myelonets网络，它们小到由十几个细胞构成，大到参与的细胞成千上万。而与Myelonets中髓系细胞发生相互作用的CD8+T细胞，普遍都进入了耗竭状态（TIM-3表达显著较高），可以说Myelonets就是一张抑制CD8+T细胞免疫应答的大网。而且相当反常规的一点是，在Myelonets中导致CD8+T细胞耗竭的巨噬细胞，竟然表型主要是M1型，和以往M1型巨噬细胞抑癌、M2型巨噬细胞促癌的常态是反过来的。最后，通过进一步分析转录组学数据，研究者们证实化疗会使M1型巨噬细胞激活并表达NECTIN2，与表达NECTIN2相应配体TIGIT的CD8+T细胞在肿瘤外周间质发生相互作用，最终使CD8+T细胞进入耗竭状态，那结论也就不言自明了：用TIGIT抑制剂阻断NECTIN2-TIGIT信号轴，就有望逆转CD8+T细胞在化疗后的耗竭状态，为PD-1/L1抑制剂的使用奠定基础，不知道未来能不能看到这样的临床研究启动呢？化疗导致CD8+T细胞耗竭的动态改变过程和TIGIT抑制剂的干预窗口参考文献：[1]Launonen I-M, Niemiec I, Hincapié-Otero M, et al. Chemotherapy induces myeloid-driven spatially confined T cell exhaustion in ovarian cancer[J]. Cancer Cell, 2024, 42(12): 2045-2063.e10.[2]Färkkilä A, Gulhan D C, Casado J, et al. Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer[J]. Nature Communications, 2020, 11: 1459.本文作者丨谭硕

Poster highlights TURKU, Finland I December 10, 2024 I Faron Pharmaceuticals Ltd. (AIM: FARN, First North: FARON), a clinical-stage biopharmaceutical company focused on tackling cancers via novel immunotherapies, today announced full analysis of the positive Phase 2 interim readout presented at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition. “The BEXMAB results continue to improve over time showing a remarkable 80% ORR in r/r MDS patients,” said Dr. Juho Jalkanen, Chief Executive Officer of Faron . “The combination is well-tolerated and generates strong and durable cancer blast reduction and hematological improvements. This solidifies bexmarilimab’s unique and leading mechanism of action for the treatment of MDS and in the field of myeloid cell re-programming. With this compelling evidence, we are well positioned to advance to the full Phase 2 efficacy readout and actively pursue further regulatory interactions to navigate and refine the pivotal pathway for BLA filing.” Dr. Mika Kontro, MD, PhD, Associate Professor at the Helsinki University Hospital Comprehensive Cancer Center and Principal Investigator of the BEXMAB trial, said : “Addressing MDS remains a considerable therapeutic challenge due to the limited efficacy of the current standard of care, particularly in TP53 mutated and HMA-failed MDS patient populations. The data presented at ASH are highly promising, showing notable improvements in overall response rate and overall survival. These findings highlight the meaningful strides Faron is making in improving treatment outcomes for r/r MDS.” The BEXMAB study is a multicenter study, taking place in Finland, UK and the U.S., evaluating the safety and efficacy of bexmarilimab , a novel anti-Clever-1 humanized antibody, with standard of care in patients with aggressive myeloid leukemias. Faron will host a virtual webinar to discuss the full analysis of data today, 10 December 2024 at 16.00 EET/9am ET/6am PT. To register for the event visit: BEXMAB Study Update The ASH Annual Meeting takes place from 7-10 December 2024, in San Diego, California and virtually. ASH Poster presentation details: Title: Encouraging Efficacy of Bexmarilimab with Azacitidine in Relapsed or Refractory MDS in Bexmab Ph1/2 Study Session Time : Monday, 9 December 2024, 6:00 PM – 8:00 PM PT Session Title: Acute Myeloid Leukemias: Investigational Drug and Cellular Therapies: Poster III Location: San Diego Convention Center, Halls G-H Lead Authors: Dr. Mika Kontro, MD, PhD, Associate Professor at the University of Helsinki; Dr. Naval Daver, MD, Associate Professor of Leukemia at The University of Texas MD Anderson Cancer Center Abstract Number: 4265 The full Poster is available on the Company’s website at https://www.faron.com/investors and contains updated clinical data from the BEXMAB trial. About BEXMAB The BEXMAB study is an open-label Phase I/II clinical trial investigating bexmarilimab in combination with standard of care (SoC) in the aggressive hematological malignancies of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The primary objective is to determine the safety and tolerability of bexmarilimab in combination with SoC (azacitidine) treatment. Directly targeting Clever-1 could limit the replication capacity of cancer cells, increase antigen presentation, ignite an immune response, and allow current treatments to be more effective. Clever-1 is highly expressed in both AML and MDS and associated with therapy resistance, limited T cell activation and poor outcomes. About bexmarilimab Bexmarilimab is Faron’s wholly owned, investigational immunotherapy designed to overcome resistance to existing treatments and optimize clinical outcomes, by targeting myeloid cell function and igniting the immune system. Bexmarilimab binds to Clever-1, an immunosuppressive receptor found on macrophages leading to tumor growth and metastases (i.e. helps cancer evade the immune system). By targeting the Clever-1 receptor on macrophages, bexmarilimab alters the tumor microenvironment, reprogramming macrophages from an immunosuppressive (M2) state to an immunostimulatory (M1) one, upregulating interferon production and priming the immune system to attack tumors and sensitizing cancer cells to standard of care. About Faron Pharmaceuticals Ltd Faron (AIM: FARN, First North: FARON) is a global, clinical-stage biopharmaceutical company, focused on tackling cancers via novel immunotherapies. Its mission is to bring the promise of immunotherapy to a broader population by uncovering novel ways to control and harness the power of the immune system. The Company’s lead asset is bexmarilimab , a novel anti-Clever-1 humanized antibody, with the potential to remove immunosuppression of cancers through reprogramming myeloid cell function. Bexmarilimab is being investigated in Phase I/II clinical trials as a potential therapy for patients with hematological cancers in combination with other standard treatments. Further information is available at www.faron.com . SOURCE: Faron Pharmaceuticals