Avelumab

引言：近年来，免疫疗法在乳腺癌（BC）治疗中显示出鼓舞人心的成果。程序性死亡配体1（PD-L1）是一种跨膜蛋白，被认为在免疫反应中发挥共抑制因子的作用，通过与程序性死亡蛋白1（PD-1）协同作用，诱导凋亡、抑制PD-1阳性细胞的细胞因子释放并限制其增殖。此外，PD-L1在多种恶性肿瘤中削弱免疫系统对肿瘤细胞的反应。这些观察表明，PD-1/PD-L1轴在癌症治疗和免疫逃逸机制调控中至关重要。本文旨在综述PD-1和PD-L1在乳腺癌治疗中的功能。方法：本研究为文献综述，聚焦PD-1/PD-L1通路相关主题。通过三个在线数据库进行文献检索。结果：关键词检索共获得248篇研究，经筛选后纳入4篇文献进行综述。结论：PD-1/PD-L1组合对多种恶性肿瘤至关重要。现有证据表明，该通路既是癌症治疗的机遇也是挑战。由于许多实体瘤（尤其是乳腺癌）高表达PD-1/PD-L1，靶向治疗成为主要手段。1 引言 乳腺癌的治疗需根据个体情况定制方案。肿瘤学研究（基因组学、转录组学、代谢组学、蛋白质组学）、设备开发（诊断与治疗）及药物发现对乳腺癌治疗至关重要。手术仍是主要治疗手段，乳房切除术技术已历经多次革新。 传统癌症研究聚焦于癌细胞及其基因层面，但随着对癌症系统性特征的深入探索，研究者逐渐转向基于宿主免疫系统功能的整体视角。癌症的两大免疫相关特征为：慢性炎症促进肿瘤发展，以及癌细胞逃避免疫系统杀伤的能力。免疫系统可能无法抑制癌细胞增殖，甚至促进其进展，这一现象称为“免疫编辑假说”。逃避免疫攻击是Hanahan和Weinberg提出的癌细胞十大特征之一（图1）。 近年来，免疫疗法在乳腺癌治疗中展现出潜力。PD-1通过阻止调节性T细胞凋亡、诱导抗原特异性T细胞凋亡及调控T细胞活性，促进自身耐受并抑制免疫反应。PD-L1与PD-1协同作用，抑制T细胞功能，削弱抗肿瘤免疫。本文旨在概述PD-1/PD-L1在乳腺癌中的功能，以优化治疗策略。2 方法 本研究为传统文献综述，检索PubMed、Crossref和Google Scholar数据库，关键词包括“程序性死亡受体1”、“程序性死亡配体1”、“乳腺癌”及“免疫系统”，筛选全文可获取且以英文发表的研究。3 结果 关键词检索获得248篇文献，经标题、摘要筛选及纳入排除标准后，最终纳入4篇研究（图2）。 4 讨论4.1 癌症免疫系统 有效清除癌细胞需依赖“癌症免疫循环”（图3）。癌细胞释放的新抗原被抗原呈递细胞（APC）捕获并呈递给T细胞。效应T细胞识别肿瘤抗原后，其与调节性T细胞（Treg）的比例决定免疫反应类型。激活的效应T细胞迁移至肿瘤部位并杀伤癌细胞。然而，肿瘤微环境可能抑制效应细胞功能，导致免疫逃逸。 免疫检查点蛋白（如PD-L1）通过抑制T细胞功能调节免疫反应。例如，PD-1与肿瘤细胞表面的PD-L1结合可抑制T细胞活性。PD-L1过表达与多种癌症预后不良相关。4.2 免疫编辑 免疫编辑过程分为清除、平衡和逃逸三阶段（图4）。清除阶段中，免疫系统识别并消灭癌细胞；平衡阶段中，残留癌细胞通过免疫抑制机制存活；逃逸阶段中，癌细胞通过基因变异和免疫抑制微环境实现转移。 4.3 免疫反应对肿瘤发展的影响 循环肿瘤细胞（CTC）的转移依赖于免疫逃逸。原发肿瘤释放的CTC在血液中可能被免疫细胞攻击，但部分细胞通过抑制NK细胞和T细胞活性存活（图5）。肿瘤微环境中，M2型巨噬细胞和Treg细胞通过分泌IL-10等因子抑制免疫反应，而M1型巨噬细胞和细胞毒性T细胞则发挥抗肿瘤作用。 5 PD-L15.1 PD-L1结构 PD-1由PDCD1基因编码，包含IgV结构域、跨膜区和细胞内区。PD-L1（CD274基因编码）含290个氨基酸，分子量40 kDa（图6）。其启动子区含IFN-γ响应元件，受炎症信号调控。PD-L1蛋白含两个胞外结构域（IgV和IgC）及一个短胞内结构域（图7）。 5.2 PD-L1的调控 PD-L1表达受多种信号通路、转录因子和表观遗传机制调控（图8）。促炎因子（如IFN-γ、TNF-α）上调PD-L1，而TGF-β、PTEN和p53抑制其表达。 5.2.1 信号通路 MAPK通路：EGFR激活MAPK可上调PD-L1，化疗药物（如顺铂）通过MAPK增强PD-L1表达。 PI3K/Akt通路：PI3K抑制剂可降低PD-L1表达，Akt通过激活NF-κB促进转录。 JAK-STAT通路：IFN-γ激活JAK/STAT3通路，上调PD-L1。FGFR2信号通过该通路促进PD-L1表达。 WNT通路：WNT信号异常导致PD-L1降解减少，GSK3β抑制剂可增强抗肿瘤免疫。 NF-κB通路：TLR或IFN-γ激活NF-κB促进PD-L1表达，抑制NF-κB可增强免疫疗法效果。 Hedgehog通路：Hh信号通过调控PD-L1表达促进免疫抑制，靶向Hh通路可增强T细胞活性。6 PD-1/PD-L1在癌症中的功能6.1 乳腺癌 PD-L1在乳腺癌干细胞（BCSC）中高表达，与上皮-间质转化（EMT）相关。ERα阴性乳腺癌中PD-L1表达显著高于ERα阳性亚型。沉默PD-L1可增强化疗药物（如多柔比星）的促凋亡作用。7 PD-1/PD-L1抑制剂7.1 派姆单抗（Pembrolizumab） 对肺转移患者疗效显著（62%），肝转移患者生存率较低（53%）。在头颈鳞癌中，派姆单抗单药治疗的中位生存期为6-8个月。7.2 纳武单抗（Nivolumab） 完全人源化单抗，用于晚期尿路上皮癌和NSCLC，3年生存率优于化疗（17% vs. 8%）。7.3 JQ1 抑制PD-L1转录，降低多种癌细胞中PD-L1表达，增强抗肿瘤免疫。7.4 西米普利单抗（Cemiplimab） FDA批准用于晚期皮肤鳞状细胞癌，阻断PD-1与PD-L1/PD-L2结合。7.5 阿替利珠单抗（Atezolizumab） 靶向PD-L1，联合抗VEGF药物在肾细胞癌中显示优越无进展生存期。7.6 阿维鲁单抗（Avelumab） 联合阿昔替尼治疗晚期肾癌，58%患者达到客观缓解。8 结论 PD-1/PD-L1通路是癌症治疗的重要靶点。乳腺癌等高表达患者可从免疫治疗中获益，但剂量、疗效及安全性仍需进一步研究。 识别微信二维码，添加抗体圈小编，符合条件者即可加入抗体圈微信群！ 请注明：姓名+研究方向！ 本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

Preparations for pivotal-stage readiness of vididencel in AML on trackThe hard work of the Mendus team to advance the company’s lead product vididencel in acute myeloid leukemia (AML) continued to pay off during the fourth quarter of 2024. In December, we presented positive updated survival data of the ongoing ADVANCE II Phase 2 trial at ASH, demonstrating that the majority of patients treated remained alive at 41.8 months median follow-up. Also in Q4, we received positive EMA and FDA feedback endorsing our registration trial preparations. We successfully advanced our manufacturing alliance for the large-scale production of vididencel. The progress realized during the quarter keeps us on track to achieve pivotal-stage readiness of vididencel in AML as our lead program in the second half of 2025. Erik Manting, Ph.D.Chief Executive Officer Significant events of Q4 2024 Net sales for the period amounted to KSEK – (-) Result for the period amounted to KSEK -31,515 (-41,165) Earnings and diluted earnings per share totalled SEK -0.63 (-0.95*) Cash runway extended until beginning of 2026 versus earlier guidance until Q4 2025 Mendus presented preclinical data supporting the combination of its intratumoral primer ilixadencel with the immune checkpoint inhibitor avelumab at the 39th annual meeting of the Society for Immunotherapy of Cancer (SITC). Mendus announced that the members of the Nomination Committee for the 2025 Annual General Meeting were appointed. The Nomination Committee consists of Erik Esveld, appointed by Van Herk Investments B.V, Karl Elmqvist, appointed by Flerie Invest AB, and Mats Andersson, appointed by Holger Blomstrands Byggnads AB. Mendus presented positive survival data from the ongoing ADVANCE II Phase 2 trial at the ASH 2024 conference. The data showed that the majority of AML patients treated with vididencel remain alive and disease-free in long-term follow-up, with a median follow-up of 41.8 months. Mendus also presented two preclinical abstracts during the ASH 2024 conference. The first abstract demonstrated synergies between vididencel and the combination of venetoclax and azacitidine, two backbone drugs in the treatment of AML, with venetoclax having a direct synergistic effect on vididencel’s mode of action. The second abstract supports the potential use of vididencel in the treatment of chronic myeloid leukemia (CML). Mendus reported positive topline data from the ALISON Phase 1 clinical trial with vididencel in ovarian cancer. The data confirmed that vididencel stimulates immune responses against ovarian cancer antigens, as a potential basis for an effective anti-tumor response, and the strong safety profile for vididencel. Mendus announced that Institut Bergonié was no longer in a position to study Mendus’ intratumoral immune primer ilixadencel in soft tissue sarcomas as part of the REGOMUNE trial, because third party funding for the trial had been terminated. Significant events after end of reporting period Mendus announced a summary of the feedback received from FDA and EMA in the fourth quarter of 2024. The feedback is supportive of the preparations for a registration trial with vididencel in AML. Financial summary * The comparative numbers recalculated taking into account the reverse split, 20:1 The full report is attached as PDF and is available on the company’s website: https://mendus.com/investors/financial-reports/ Webcast investor call, February 13, 08.30 CETThe company will host a live presentation and business update today at 08.30 CET. The presentation will be held in English and includes a Q&A session. If you wish to participate via webcast please use the link below.https://mendus.events.inderes.com/q4-report-2024/register If you wish to participate and ask questions via teleconference, please register on the link below. After registration you will be provided phone numbers and a conference ID to access the conference.https://conference.inderes.com/teleconference/?id=5004794 For more information, please contact:Erik MantingChief Executive OfficerE-mail: ir@mendus.com About Mendus AB (publ) Mendus is dedicated to changing the course of cancer treatment by addressing tumor recurrence and improving long-term survival for cancer patients, while preserving health and quality of life. We leverage our understanding of dendritic cell biology to develop an advanced clinical pipeline of immunotherapies which combine clinical efficacy with a benign safety profile. Based in Sweden and The Netherlands, Mendus is publicly traded on the Nasdaq Stockholm under the ticker IMMU.ST. https://www.mendus.com/ AttachmentsMendus Q4 2024 ENG 02 13 FinalMendus AB Year-end Report 2024