ROR1 CAR-T (Oncternal Therapeutics)

ROR1 CAR-T细胞疗法LYL797，在报告了临床死亡事件后，研发公司Lyell Immunopharma努力挣扎了4个月后，最终还是宣布停止对其的开发。 又一领先的ROR1 CAR-T管线停止，预示着ROR1靶点的不详。 患者死亡事件 2024年6月，Lyell报告了LYL797在三阴乳腺癌（TNBC）的I期临床中发生了一例死亡事件。 延伸阅读：实体瘤CAR-T患者死亡，股价跌去36% LYL797是一款基于Lyell公司专有的Gen-R技术平台开发的ROR1靶向CAR-T细胞，经过体外重编程使T细胞过表达蛋白质c-JUN，从而实现延缓衰竭并保持抗肿瘤功能。 在一项针对三阴乳腺癌的I期临床中，一名患者在第41天出现5级呼吸衰竭后死亡。此外，22%的患者中出现肺炎相关的剂量限制毒性，最常见的严重程度为3级或更高。 出现死亡事件的可能原因是ROR1靶点。 虽然ROR1在正常的肺部细胞中几乎不表达，但是在一些肺癌中呈现出异常高表达，而考虑到乳腺癌的特殊位置，一些患者实际上已经出现了乳腺癌的肺转移情况，这也使得一些患者出现肺部受累的情况。 LYL797挣扎无效 实际上，LYL797的这例死亡事件并没有引起美国FDA的警惕，临床并未暂停。Lyell公司仅是对临床进行了调整。 Lyell公司在2024年8月发布的第二季度财报中，还报告了LYL797的临床开发计划，包括针对三阴性乳腺癌（TNBC）或非小细胞肺癌（NSCLC）的临床继续进行，扩大标签至卵巢癌和子宫内膜癌，以及下半年提交针对多发性骨髓瘤和慢性淋巴细胞白血病的第二个IND。 很明显，死亡事件一开始并未打击到Lyell公司对于LYL797的信心。同时，该公司以TNBC研究的最高剂量队列中，40%的客观缓解率和60%的临床获益率，作为宣传的主要数据。 然后，期间不知道发生了什么，在距第二季度财报发布2个月多后，Lyell公司突然宣布要停止对LYL797的开发工作。 Lyell公司的首席执行官Lynn Seely在电话会议上，表明LYL797遇到了安全问题，并且没有“足够广泛的治疗窗口”。 另外，同时被放弃的还包括LYL845在内的TIL项目，停止LYL845的原因很明确，因为临床数据不符合持续开发的预期标准，导致其他TIL项目也一同被放弃了。 仍然死磕ROR1 小编猜测，LYL797的安全问题主要还是归因于，ROR1靶点比较难把控。 无独有偶，另一家ROR1开发公司Oncternal也报告了ROR1 CAR-T（ONCT-808）临床发生了死亡案例，同时预期ONCT-808治疗会发生不良事件。ONCT-808的临床已经停止，同时该公司现在正在考虑战略代替方案....... 延伸阅读： 2个核心管线同时暴雷，首席医疗官出走 ROR1 CAR-T：临床数据出炉 但是，ROR1开发难度高也不好使。在LYL797失败后，Lyell公司仍然在死磕ROR1 CAR-T。 因为Lyell公司在管线重组以后，新的核心管线赫然是以LYL797为基础开发的下一代的ROR1 CAR-T疗法LYL119。Lyell公司表示，LYL119能够在更低剂量下产生更好的疗效，并具有更广泛的治疗窗口。 ROR1 CAR-T的下一代产品LYL119在c-JUN过表达的基础上还增添了多项技术，例如敲除NR4A3基因进一步减少T细胞凋亡和衰竭，采用Stim-R™技术来强化信号转导，采用该公司的Epi-R™技术生产具有持久干细胞特性的T细胞。 最后在本身的技术之外，还结合了来自哈佛大学Wyss研究所的T细胞增强支架技术来强化临床获益，这种技术提供了一种能够模拟人体淋巴系统的支架材料，这种支架材料可以携带激活CAR-T需要的IL-2以及CAR-T上的CD3受体和CD28受体。 目前，该公司已经完成了LYL119的IND提交，预计将于今年或明年初启动针对铂类耐药卵巢癌或复发/难治性子宫内膜癌的1期临床。 CD19/CD20 CAR-T也挺香 另一个好消息是，Lyell公司也没有头铁到眼里只有ROR1。 在自身管线或是因为安全性、或是因为疗效被放弃，只剩下一根独苗LYL119后，Lyell公司将目光放到了外部，瞄准了一家小型CAR-T研发公司ImmPACT Bio，并以3000万美元现金和3750万股Lyell普通股对ImmPACT Bio进行收购。 被Lyell公司看中的是ImmPACT管线内一款CD19/CD20 CAR-T细胞候选产品IMPT-314。ImmPACT的其他管线（包括Claudin 18.2 CAR-T）优先级并不高。 IMPT-314是一款自体的、CD19/CD20双特异性CAR-T细胞，被开发用于治疗B细胞淋巴瘤和自身免疫性疾病。Lyell公司将优先开发IMPT-314的B细胞淋巴瘤适应症。 IMPT-314目前正在进行临床研究，预计将于今年晚些时候发布IMPT-314针对大B细胞淋巴瘤的临床数据。IMPT-314的关键试验预计将于2025年启动。 根据Lyell公司第二季度财报，截止2024年6月30日，拥有现金、现金等价物和有价证券4.911亿美元。 尽管收购ImmPACT需要花费一定现金，但是Lyell公司删减了管线的开发工作，仅剩2条临床管线，这使得Lyell公司的现金流支持公司运营至2027年。 小结 虽然但是，Lyell公司一口气停了好几个内部管线的开发，包括LYL797和全部的TIL项目，还是令人对其的研发实力产生质疑。 这一点也反应到了股市上，Lyell公司的股票持续下跌，截止本文发布前，已经跌至1美元以下，报9.27美分/股。 参考资料： 1.https://ir.lyell.com/news-releases/news-release-details/lyell-immunopharma-acquire-immpact-bio-and-prioritizes-its 2.https://ir.lyell.com/news-releases/news-release-details/lyell-immunopharma-reports-business-highlights-and-financial-5 本周好文推荐 如需转载请联系佰傲谷并在醒目位置注明出处 · · · · · · · ·

Oct. 22, 2024 -- Oncternal Therapeutics, Inc. (Nasdaq: ONCT) (the “Company”) today announced updated data from its Phase 1/2 Study of ONCT-534 for the treatment of patients with relapsed or refractory metastatic Castration-Resistant Prostate Cancer (mCRPC). Based on initial pharmacokinetic results, two additional dosing cohorts with twice daily (BID) oral dosing of ONCT-534 had been incorporated in the Phase 1/2 study ONCT-534-101 (NCT05917470). Overall, fifteen patients received ONCT-534 once daily (QD) in six dosing cohorts and six patients received ONCT-534 BID in two dosing cohorts. Based on a data cut off of September 30, 2024, the BID dosing schedule was well tolerated, with no related Grade 3 or higher toxicities. One patient, who experienced a rising PSA on ONCT-534 at 160 mg BID, had a subsequent 50% reduction in PSA after four weeks of ONCT-534 at 300 mg BID, and at the same time the CAT Scan showed a 16% reduction in target lesions compared to baseline. Enumeration and biomarker analysis of circulating tumor cells (CTCs) showed promising effects on expression of androgen receptor (AR)-regulated genes, and AR nuclear translocation in six additional patients. CTC analysis also showed that some patients who did not respond to ONCT-534 had prostate cancer that had developed neuroendocrine features, which are associated with AR independent disease. “While we still believe the decision to discontinue the ONCT-534-101 clinical trial remains the correct one in the current biotechnology environment, the updated clinical results highlight the potential of ONCT-534 in prostate cancer. We believe there is value in exploring BID dosing further, as well as studying ONCT-534 in earlier lines of therapy for advanced prostate cancer,” said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO. “We continue to explore strategic alternatives for our product candidates, including ONCT-534, ONCT-808, zilovertamab and ONCT-216 in an ongoing effort to maximize value to our shareholders.” Oncternal Therapeutics is a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies for the treatment of patients with cancers that have critical unmet medical need. Oncternal pursues drug development targeting promising, yet untapped biological pathways implicated in cancer generation or progression, focusing on hematological malignancies and prostate cancer. More information on our company and programs is available at https://oncternal.com/. ONCT-534 is an investigational dual-action androgen receptor inhibitor (DAARI) with demonstrated preclinical activity in prostate cancer models against both unmutated androgen receptor (AR), and against multiple forms of AR mutation and aberration. It is a potential treatment for patients with mCRPC with unmet medical need because of resistance to androgen receptor pathway inhibitors, including those with AR amplification, mutations in the AR ligand binding domain (LBD), or splice variants with loss of the AR LBD. It was investigated in Study ONCT-534-101 (NCT05917470) for the treatment of patients with mCRPC who are resistant to current AR pathway inhibitors. ONCT-808 is an investigational autologous chimeric antigen receptor T (CAR T) cell therapy that targets Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1) using the binding domain from zilovertamab. ONCT-808 has demonstrated activity in preclinical models against multiple hematological malignancies and solid tumors and has been shown to be specific for cancer cells expressing ROR1. Oncternal has developed a robust and reproducible manufacturing process that has the potential to reduce the time patients must wait for their individual CAR T therapy to be produced compared with currently approved CAR T products. It was investigated in Study ONCT-808-101 (NCT05588440) with relapsed or refractory aggressive B-cell lymphoma, including patients who have failed previous CD19 CAR T treatment. Zilovertamab (previously called cirmtuzumab and UC-961) is an investigational monoclonal antibody designed to inhibit the function of Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1). Zilovertamab has been evaluated in Phase 1/2 Study CIRM-0001 (NCT03088878) in combination with ibrutinib for the treatment of patients with mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and marginal zone lymphoma (MZL), which resulted in 100% progression free survival (PFS) at 48 months in CLL patients whose tumors harbored del(17p)/p53 mutation, a population underserved by current treatment options. The U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to zilovertamab for the treatment of CLL and MCL. The results of an investigator-sponsored, Phase 1b clinical trial of zilovertamab in combination with paclitaxel for the treatment of women with HER2-negative metastatic or locally advanced, unresectable breast cancer were recently published (Shatsky 2023). Zilovertamab was evaluated in an investigator-initiated Phase 1b study of zilovertamab in combination with docetaxel in patients with metastatic castration-resistant prostate cancer (NCT05156905), and an investigator-initiated Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, in patients with relapsed/refractory (R/R) CLL (NCT04501939). ONCT-216 (previously called TK216) is an investigational targeted small-molecule inhibitor of the E26 transformation-specific (ETS) family of oncoproteins including fusion proteins. Tumorigenic fusion proteins involving the EWS protein and an ETS protein can be found in most cases of Ewing sarcoma. ETS-related translocations or overexpression are also found in many other tumors such as acute myeloid leukemia (AML), diffuse large B cell lymphoma (DLBCL), and prostate cancer. In preclinical models, ONCT-216 was observed to bind to EWS-FLI1, blocking the interaction between this fusion protein and other transcriptome proteins such as RNA helicase A, leading to tumor cell apoptosis and inhibiting tumor growth in animal models. The U.S. Food and Drug Administration (FDA) has granted Rare Pediatric Disease Designation, Orphan Drug Designation and Fast Track Status to ONCT-216 for the treatment of Ewing sarcoma. The results of a Phase 1/ 2 clinical trial of ONCT-216 in patients with Ewing sarcoma (NCT02657005) were recently published (Myers 2024). The content above comes from the network. if any infringement, please contact us to modify.