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

Publication date: 1 June 2018
Source:Cell Stem Cell, Volume 22, Issue 6
Author(s): Michael Y. Choi, George F. Widhopf, Emanuela M. Ghia, Reilly L. Kidwell, Md Kamrul Hasan, Jian Yu, Laura Z. Rassenti, Liguang Chen, Yun Chen, Emily Pittman, Minya Pu, Karen Messer, Charles E. Prussak, Januario E. Castro, Catriona Jamieson, Thomas J. Kipps
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.

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Teaser

Choi et al. find that cirmtuzumab, a humanized mAb specific for the cancer stem cell antigen ROR1, was well tolerated and stable in clinical testing in patients with relapsed chronic lymphocytic leukemia. Treatment inhibited activation of Rho-GTPase and HS1 in vivo and reversed the stemness gene expression signatures in leukemia cells.


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