Phase I Trial: Cirmtuzumab Inhibits ROR1 Signaling and Stemness Signatures in Patients with Chronic Lymphocytic Leukemia

被引：155

作者：

Choi, Michael Y. ^{[1
,2
,3
,4
]}

Widhopf, George F., II ^{[1
,4
]}

Ghia, Emanuela M. ^{[1
]}

Kidwell, Reilly L. ^{[1
,2
,3
]}

Hasan, Md Kamrul ^{[1
]}

Yu, Jian ^{[1
]}

Rassenti, Laura Z. ^{[1
,4
]}

Chen, Liguang ^{[1
]}

Chen, Yun ^{[1
]}

Pittman, Emily ^{[1
,5
]}

Pu, Minya ^{[1
,5
]}

Messer, Karen ^{[1
,5
]}

Prussak, Charles E. ^{[1
]}

Castro, Januario E. ^{[1
,6
]}

Jamieson, Catriona ^{[1
,2
,3
,4
,7
]}

Kipps, Thomas J. ^{[1
,2
,3
,4
]}

机构：

[1] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA

[2] Univ Calif San Diego, CIRM Alpha Stem Cell Clin, La Jolla, CA 92037 USA

[3] Sanford Stem Cell Clin Ctr, La Jolla, CA 92037 USA

[4] Univ Calif San Diego, Div Hematol Oncol, Dept Med, La Jolla, CA 92093 USA

[5] Univ Calif San Diego, Dept Family Med & Publ Hlth, Div Biostat & Bioinformat, La Jolla, CA 92093 USA

[6] Univ Calif San Diego, Dept Med, Div Blood & Marrow Transplantat, La Jolla, CA 92093 USA

[7] Univ Calif San Diego, Dept Med, Div Regenerat Med, La Jolla, CA 92037 USA

来源：

CELL STEM CELL | 2018年 / 22卷 / 06期

关键词：

WNT5A INDUCES ROR1; SELF-RENEWAL; C-MYC; CELL; EXPRESSION; RITUXIMAB; CANCER; HS1; CHEMOTAXIS; RECEPTOR;

D O I：

10.1016/j.stem.2018.05.018

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Cirmtuzumab is a humanized monoclonal antibody (mAb) that targets ROR1, an oncoembryonic orphan receptor for Wnt5a found on cancer stem cells (CSCs). Aberrant expression of ROR1 is seen in many malignancies and has been linked to Rho-GTPase activation and cancer stem cell self-renewal. For patients with chronic lymphocytic leukemia (CLL), self-renewing, neoplastic B cells express ROR1 in 95% of cases. High-level leukemia cell expression of ROR1 is associated with an unfavorable prognosis. We conducted a phase 1 study involving 26 patients with progressive, relapsed, or refractory CLL. Patients received four biweekly infusions, with doses ranging from 0.015 to 20 mg/kg. Cirmtuzumab had a long plasma half-life and did not have dose-limiting toxicity. Inhibition of ROR1 signaling was observed, including decreased activation of RhoA and HS1. Transcriptome analyses showed that therapy inhibited CLL stemness gene expression signatures in vivo. Cirmtuzumab is safe and effective at inhibiting tumor cell ROR1 signaling in patients with CLL.

引用

页码：951 / +

页数：12

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