完全缓解率达100%的CAR-T疗法；延长胰腺癌患者生存期的组合疗法…… | 一周盘点

2024-06-23

细胞疗法临床结果免疫疗法临床2期

▎药明康德内容团队编辑本期看点 1. CD19靶向候选CAR-T细胞疗法GLPG5101在1项早期临床试验中治疗5例套细胞淋巴瘤（MCL）患者，客观缓解率（ORR）和完全缓解率（CRR）均为100%。 2. 靶向信号调节蛋白（SIRP）的抗体疗法ELA026治疗初治恶性肿瘤相关噬血细胞性淋巴组织细胞增多症（mHLH）的总缓解率达100%，并提高了此类患者的两个月生存率。 3. 抗体疗法Natrunix联用化疗治疗晚期胰腺癌，在早期临床试验中延长了患者的生存期并改善了化疗的耐受性。药明康德内容团队整理 GLPG5101：公布1/2期临床试验数据 Galapagos公司公布了其CD19靶向候选CAR-T细胞疗法GLPG5101治疗复发/难治性非霍奇金淋巴瘤（NHL）的1/2期临床试验ATALANTA-1的新数据。该细胞疗法从制备到回输到患者体内的中位时间仅需7天。截至2023年12月20日的数据，在研究的第一部分，中位随访时间为13.1个月，接受GLPG5101治疗的16例可评估患者的ORR为87.5%（14/16），CRR为75%（12/16）。71%的患者在数据截止时保持缓解。在研究的第二部分，中位随访时间为4.2个月，15例可评估患者的ORR和CRR均为93.3%（14/15）。100%的患者在数据截止时保持持续缓解。合并两部分的研究结果后根据肿瘤类型进行划分，弥漫性大B细胞淋巴瘤（DLBCL）患者的ORR为78%（7/9），CRR为56%（5/9）；滤泡性淋巴瘤（FL）或边缘区淋巴瘤（MZL）患者的ORR和CRR均为94%（16/17）；套细胞淋巴瘤患者的ORR和CRR均为100%（5/5）。安全性方面，大多数治疗伴发不良事件为1/2级，在研究的第一部分观察到2例3级细胞因子释放综合征（CRS），在研究的第二部分观察到1例3级免疫效应细胞相关神经毒性综合征（ICANS）。 ELA026：公布1b期临床试验的新数据 Electra Therapeutics公司公布了其靶向信号调节蛋白（SIRP）的单克隆抗体ELA026治疗继发性噬血细胞性淋巴组织细胞增生症（sHLH）的1b期研究的最新临床数据。ELA026靶向细胞表面的SIRP，能够靶向清除血液循环中驱动炎症的髓系细胞和T细胞，并且不破坏SIRPα/CD47免疫检查点功能。该疗法旨在治疗伴有异常髓系和T细胞活性的重度炎性疾病。此次公布的结果显示，ELA026在sHLH患者中具有良好的安全性，不良事件可控。在已完成入组的队列1和2中（n=12），ELA026在第4周时的总缓解率为75%，在8例未接受过治疗的mHLH（sHLH的一种亚型）患者中，总缓解率为100%，两个月时的生存率为88%。此类患者在自然史研究中的两个月时的死亡率约为50%。 Natrunix：公布1/2期临床试验数据 XBiotech公司公布了其靶向白细胞介素-1α（IL-1α）的抗体疗法Natrunix联用化疗治疗晚期胰腺癌的1/2期多中心研究的数据。除了能够作为一种抗癌疗法，该公司认为Natrunix还有望改善化疗的耐受性。该研究中采用的化疗方案为ONIVYDE（ON）+5-氟尿嘧啶（5FU）+亚叶酸（LV）。此次公布的结果显示，与安慰剂+化疗组相比，Natrunix+化疗组在24周的治疗周期内发生任何类型的不良事件的数量（297例对比336例）、发生重大不良事件的患者比例（9/33对比12/32）和住院天数（80天对比120天）均明显减少。此外，接受Natrunix+化疗组患者的生存期得到了延长，接受治疗第330天时有8例患者存活，而安慰剂+化疗组没有患者存活超过330天。 ▲患者的生存曲线（图片来源：参考资料[9]） Petrelintide：公布1b期临床试验数据 Zealand Pharma公司公布了其在研长效、潜在“best-in-class”减重疗法petrelintide的1b期试验第二部分的顶线结果。Petrelintide（ZP8396）是一种适合每周一次皮下注射的长效胰淀素类似物，具有中性pH下的化学和物理稳定性。胰淀素在胰腺β细胞中产生，并与胰岛素一起分泌以响应摄入的营养物质。目前的临床或临床前数据表明，petrelintide有潜力实现与GLP-1受体激动剂相当的体重减轻，但具有更好的耐受性，为患者提供更好的用药体验和体重减轻，同时保留患者的肌肉质量。此次公布的结果显示，患者在接受16周高剂量petrelintide治疗后，体重较基线平均减少了8.6%，而安慰剂组仅为1.7%。安全性方面，petrelintide显示良好的耐受性，没有出现严重的不良事件。所有胃肠道（GI）不良事件均为轻度，除了一名受试者在第三次治疗后因中度恶心和呕吐而停止治疗。值得注意的是，没有其他受试者因不良事件停止治疗或报告呕吐，只有两例轻度腹泻报告。恶心在活性组中报告比例为16.7-33.3%，在安慰剂组为16.7%。少数参与者报告了注射部位反应，均为轻度。未观察到患者产生抗药抗体。新闻稿指出，该积极结果支持petrelintide作为GLP-1受体激动剂类药物之外，在体重管理上的另一选择。 Amezalpat（TPST-1120）：公布1b/2期临床试验的新数据 Tempest Therapeutics公司公布了其在研口服、选择性小分子PPAR⍺拮抗剂amezalpat（TPST-1120）在一项全球随机的1b/2期临床试验中获得的积极结果。临床前数据显示，amezalpat可直接杀死肿瘤细胞，并靶向肿瘤微环境中的抑制性免疫通路。这两种类型中的靶向细胞皆依赖脂肪酸代谢，该代谢过程由PPARα转录因子调节。在一项针对接受过多次治疗的晚期实体瘤患者的1期临床试验中，amezalpat单药治疗和与PD-1抑制剂nivolumab联合应用均导致肿瘤缩小及生物标志物的变化。此次公布的结果显示，与标准治疗方案相比，amezalpat与标准治疗方案（抗PD-L1抗体atezolizumab和抗VEGF抗体bevacizumab）联用，在无法切除或转移性肝细胞癌（HCC）患者的一线治疗中，显著提高患者的中位总生存期（OS）达6个月（21个月对比15个月）。此外，按照RECIST v1.1标准评估，amezalpat组的确认客观缓解率（cORR）为30%，对照组为13.3%。安全性方面，amezalpat的耐受性良好，两组之间的安全数据相当。 ▲Amezalpat试验的OS结果（图片来源：参考资料[29]） MB-106：公布1/2期临床试验数据 Mustang Bio公司公布了其在研、可通过门诊给药、靶向CD20的自体CAR-T细胞疗法MB-106治疗华氏巨球蛋白血症（WM）的1/2期临床试验最新数据。该试验中的所有十例患者均曾接受过布鲁顿酪氨酸激酶抑制剂（BTKi）的治疗，并且在接受BTKi治疗期间病情持续恶化。患者之前接受过中位9线疗法，只有一例患者在接受MB-106治疗后开始接受额外的抗WM治疗。总体而言，接受MB-106治疗的患者中有90%（9/10）对治疗产生应答，包括3名患者达完全缓解（CR）、2名达非常好的部分缓解和4名部分缓解。此外，1例患者的病情稳定。其中一名获得CR的患者已持续缓解31个月，该患者的免疫球蛋白M（IgM）水平在接受MB-106治疗后迅速降至正常范围，此后一直保持正常。安全性方面，9例患者发生了CRS（5例患者为1级，4例患者为2级），一例患者经历了1级ICANS。尽管剂量增加，但并未观察到3级或4级CRS或2、3或4级ICANS。 NX-594：公布1a/b期临床试验数据 Nurix Therapeutics公司公布了其在研口服BTK降解剂NX-5948治疗复发难治性慢性淋巴细胞白血病（CLL）的1a/b期临床试验的积极数据。NX-5948是一种生物利用度高、可穿越血脑屏障的口服BTK小分子降解剂。 ▲NX-5948的疗效结果（图片来源：参考资料[5]）此次公布的结果显示，NX-594在复发难治性CLL患者身上引起了快速、深度的缓解，ORR达69.2%，这些患者之前曾接受大量治疗并带有BTK抑制剂耐药突变。最早在第一次肿瘤扫描（8周）时就观察到患者出现缓解，许多患者在治疗时间延长后缓解加深。截至4月17日数据截止，所有缓解仍在持续。 ▲一例患者接受NX-5948治疗24周内，脑脊液中的恶性肿瘤细胞消除（图片来源：参考资料[5]） ▲一例曾接受过11线疗法的患者在接受NX-5948治疗后肿瘤持久消退（图片来源：参考资料[2]）此外，一例在进入研究时伴有中枢神经系统受累的CLL患者在接受NX-5948治疗的24周内消除了脑脊液（CSF）中的恶性肿瘤细胞，并在36周时达到接近CR的标准。还有一例曾接受过11线疗法的患者在接受NX-5948治疗后肿瘤持久消退已超过6个月。安全性方面，NX-5948在所有评估剂量下均耐受性良好，最常见的治疗不良事件为紫癜/挫伤、血小板减少和中性粒细胞减少。Nurix预计在2025年启动NX-5948的关键临床试验。 SL-172154：公布1b期临床试验数据 Shattuck Labs公布了其在研疗法SL-172154在1b期剂量扩展临床试验的最新中期数据。SL-172154（SIRPα-Fc-CD40L）是一款在研重定向检查点激动剂（ARC）融合蛋白，旨在同时抑制CD47/SIRPα检查点的相互作用并激活CD40共刺激受体，以增强晚期癌症患者的抗肿瘤免疫反应。此次公布的结果显示，SL-172154与阿扎胞苷（AZA）联用作为高风险骨髓增生异常综合征（HR-MDS）和TP53突变（TP53m）急性髓性白血病（AML）患者的一线疗法时，患者的ORR分别达67%与43%，CRR分别为42%与29%。截至2024年4月23日，SL-172154表现出可控的安全性。输液相关反应（IRRs）是SL-172154治疗过程中最常见的不良事件。 KT-333：公布1期临床试验的新数据 Kymera Therapeutics公布了其在研药物KT-333的1期临床试验的更新数据。KT-333是一种潜在“first-in-class”、强效、高选择性的STAT3靶向小分子降解剂。根据新闻稿，KT-333是靶向未成药转录因子的首个进入临床阶段的降解剂。 ▲KT-333试验临床结果摘要（图片来源：参考资料[3]）此次公布的结果显示，KT-333完成初步临床概念验证，在多种血液恶性肿瘤中展示了抗肿瘤活性。其中，两名经典霍奇金淋巴瘤患者达到CR，1名STAT3突变的NK细胞淋巴瘤 STAT3突变的NK细胞淋巴瘤患者达到CR。安全性方面，KT-333耐受性良好，主要不良事件为1级和2级，包括口腔炎和疲劳。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料（可上下滑动查看） [1] Shattuck Labs Announces Updated Positive Interim Data from the Phase 1B Dose Expansion Clinical Trial of SL-172154 in Combination with Azacitidine (AZA) in Frontline Higher-Risk Myelodysplastic Syndromes (HR-MDS) and TP53 mutant (TP53m) Acute Myeloid Leukemia (AML) Patients. 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Retrieved June 21, 2024, from https://ir.tempesttx.com/news-releases/news-release-details/tempest-unveils-new-survival-data-amezalpat-tpst-1120-randomized [27] Escend Announces Poster Presentation at the Annual Meeting of the European Hematology Association (EHS) from an Investigator-Initiated Phase I/II study evaluating ES-3000 in Myelodysplastic Syndrome (MDS). Retrieved June 21, 2024, from https://www.prnewswire.com/news-releases/escend-announces-poster-presentation-at-the-annual-meeting-of-the-european-hematology-association-ehs-from-an-investigator-initiated-phase-iii-study-evaluating-es-3000-in-myelodysplastic-syndrome-mds-302177666.html [28] Tubulis Doses First Patient in Phase I/IIa Trial Investigating ADC Candidate TUB-040 in Ovarian Cancer and Lung Adenocarcinoma. Retrieved June 21, 2024, from https://www.businesswire.com/news/home/20240620456143/en/ [29] Amezalpat (TPST-1120) Randomized 1L HCC Data Updat. Retrieved June 20, 2024 https://ir.tempesttx.com/static-files/8ba2d665-884e-47f7-89c2-adbba73378b2 [30] Mustang Bio Announces Favorable Efficacy and Safety Data from Complete Waldenstrom Macroglobulinemia Cohort of Phase 1/2 Clinical Trial of MB-106, CD20-Targeted Autologous CAR-T Therapy. Retrieved June 18, 2024 from https://ir.mustangbio.com/news-events/press-releases/detail/180/mustang-bio-announces-favorable-efficacy-and-safety-data 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新