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The antibody drug conjugate VLS-101 targeting ROR1 is effective in CAR T-resistant mantle cell lymphoma
Journal of Hematology & Oncology ( IF 28.5 ) Pub Date : 2021-08-28 , DOI: 10.1186/s13045-021-01143-w
Vivian Changying Jiang 1 , Yang Liu 1 , Alexa Jordan 1 , Joseph McIntosh 1 , Yijing Li 1 , Yuxuan Che 1 , Katti A Jessen 2 , Brian J Lannutti 2 , Michael Wang 1, 3
Affiliation  

Mantle cell lymphoma (MCL) is a rare, aggressive and incurable subtype of non-Hodgkin’s B-cell lymphoma. The principal barrier is frequent clinical relapse to multiple lines of therapies, including new FDA-approved biologics and cell therapy. Brexucabtagene autoleucel, the first and only FDA approved chimeric antigen receptor (CAR) T product in MCL, demonstrated unprecedented efficacy in overcoming resistance to Bruton’s tyrosine kinase inhibitors. However, relapses have inevitably occurred and once relapsed these patients display a very poor clinical outcome. Currently, there is no optional therapy specifically designed for these patients. The development of tailored and more efficacious therapies is therefore critical and represents a new medical need. We found that while the receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed across most of the MCL cells, it is significantly elevated in CAR T-relapsed MCL tumors. To see whether this aberrant ROR1 expression contributed to CAR T resistance, we targeted ROR1 using VLS-101, a monomethyl auristatin E conjugated anti-ROR1 antibody. VLS-101 showed potent anti-MCL activity in vitro in ROR1-expressing MCL cell lines and ex vivo in primary patient samples. Importantly, VLS-101 safely induced tumor regression in PDX models resistant to CAR T-cell therapy, ibrutinib and/or venetoclax. These data advocate for targeting ROR1 as a viable approach in the treatment of ROR1-positive MCL tumors, especially those with failure to prior therapies. These data also provide strong evidence for future enrollment of post-CD19 CAR T-cell relapsed MCL patients in a first in-human phase 1b VLS-101 trial. The upcoming testing in a clinical setting will provide important insights on this new therapeutic development aiming to overcome the CAR T resistance via targeting ROR1, which is a rising unmet clinical need in MCL.

中文翻译:

靶向 ROR1 的抗体药物偶联物 VLS-101 对 CAR T 耐药的套细胞淋巴瘤有效

套细胞淋巴瘤 (MCL) 是非霍奇金 B 细胞淋巴瘤的一种罕见、侵袭性和无法治愈的亚型。主要障碍是对多种疗法的频繁临床复发,包括 FDA 批准的新生物制剂和细胞疗法。Brexucabtagene autoleucel 是第一个也是唯一一个 FDA 批准的 MCL 嵌合抗原受体 (CAR) T 产品,在克服对布鲁顿酪氨酸激酶抑制剂的耐药性方面表现出前所未有的功效。然而,复发不可避免地发生,一旦复发,这些患者的临床结果非常差。目前,没有专门为这些患者设计的可选疗法。因此,开发量身定制的更有效的疗法至关重要,并代表了一种新的医疗需求。我们发现,虽然受体酪氨酸激酶样孤儿受体 1 (ROR1) 在大多数 MCL 细胞中表达,但它在 CAR T 复发的 MCL 肿瘤中显着升高。为了了解这种异常的 ROR1 表达是否导致 CAR T 抗性,我们使用 VLS-101(一种单甲基 auristatin E 偶联的抗 ROR1 抗体)靶向 ROR1。VLS-101 在体外在表达 ROR1 的 MCL 细胞系中和在原发患者样本中体外显示出有效的抗 MCL 活性。重要的是,VLS-101 在对 CAR T 细胞疗法、依鲁替尼和/或 venetoclax 耐药的 PDX 模型中安全地诱导肿瘤消退。这些数据主张将 ROR1 作为治疗 ROR1 阳性 MCL 肿瘤的可行方法,尤其是那些先前治疗失败的肿瘤。这些数据还为未来在第一个人体 1b 期 VLS-101 试验中招募 CD19 CAR T 细胞后复发的 MCL 患者提供了强有力的证据。即将在临床环境中进行的测试将为这一旨在通过靶向 ROR1 克服 CAR T 耐药性的新疗法开发提供重要见解,这是 MCL 中不断增长的未满足临床需求。
更新日期:2021-08-29
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